Watch Out For Neuropathic Antibiotic Side Effects!

Today's post from collective-evolution.com (see link below) is another powerful argument against taking fluoroquinolone antibiotics (Cipro,Levaquin,Avalox etc), especially if you have or are prone to neuropathic problems. It's astonishing that many doctors are still unaware of the dangers and side effects of these drugs and prescribe them routinely without looking to see whether the patient is at risk. The best advice is to look at the pharmaceutical (not the brand name) name of any antibiotics you are given and check the side effects on the internet (Drugs.com has a reliable and trustworthy reputation in this regard). After that, if you are still worried, discuss it with your doctor with any evidence you might have gathered and ask for an alternative (there are plenty to choose from). Don't just stop taking them or ignore it - rely on your doctor making the right choice in the end.
 

Fluoroquinolone Antibiotics: Are You At Risk?
August 26, 2013 by Lisa Bloomquist. 

Fluoroquinolone antibiotics, Cipro, Levaquin, Avelox, etc. are broad-spectrum antibiotics used to treat a variety of infections, from urinary tract infections to anthrax and everything in between. The first quinolone created was Nalidixic Acid which was discovered by George Lesher in 1962. (Nalidixic Acid was added to the OEHHA prop 65 list of carcinogens in 1998.) Cipro (ciprofloxacin) is a second generation fluoroquinolone patented in 1983 by Bayer, Levaquin (levofloxacin) is a third generation fluroquinolone patented in 1987 by Ortho-McNeil-Janssen (a division of Johnson & Johnson), and Avelox (moxifloxacin) is a fourth generation fluoroquinolone patented in 1991 by Bayer.

Fluoroquinolone Antibiotics – Still on the Market

Of the 30 quinolones that have made it to market since the 1980s, all but 6 have either been removed from the US market or have severely restricted use.

The fluoroquinolone antibiotics that are still on the market are some of the most commonly prescribed antibiotics. Per the FDA, “Approximately 23.1 million unique patients received a dispensed prescription for an oral fluoroquinolone product from outpatient retail pharmacies during 2011,” and “Within the hospital setting, there were approximately 3.8 million unique patients billed for an injectable fluoroquinolone product during 2011.”

When used properly, such as in cases of life-threatening hospital acquired pneumonia, fluroquinolone antibiotics can save lives. 

Fluoroquinolone Antibiotic Side-Effects and Adverse Reactions

When used improperly, fluoroquinolone antibiotics can needlessly cause devastating side-effects. Devastating side-effects can also occur when fluoroquinolone antibiotics are used properly, but the devastation can be justified by weighing it against the alternative – death. In 2001, Dr. Jay S. Cohen published an article on the severe and often disabling reactions some people sustained as a result of taking a fluoroquinolone antibiotic. Dr. Cohen says,

It is difficult to describe the severity of these reactions. They are devastating. Many of the people in my study were healthy before their reactions. Some were high intensity athletes. Suddenly they were disabled, in terrible pain, unable to work, walk, or sleep

Dr. Cohen’s study of 45 subjects suffering from Fluoroquinolone Toxicity Syndrome, a name that I’m pushing for, (without an official name, it is difficult get the word out) showed that they had the following symptoms:

Peripheral Nervous System: Tingling, numbness, prickling, burning pain, pins/needles sensation, electrical or shooting pain, skin crawling, sensation, hyperesthesia, hypoesthesia, allodynia (sensitivity to touch) numbness, weakness, twitching, tremors, spasms.

Central Nervous System: Dizziness, malaise, weakness, impaired coordination, nightmares, insomnia, headaches, agitation, anxiety, panic attacks, disorientation, impaired concentration or memory, confusion, depersonalization, hallucinations, psychoses.

Musculoskeletal: Muscle pain, weakness, soreness, joint swelling, pain, tendon pain, ruptures.

Special Senses: Diminished or altered visual, olfactory, auditory functioning, tinnitus (ringing in the ears).

Cardiovascular: Tachycardia, shortness of breath, hypertension, palpitations, chest pain.

Skin: Rash, swelling, hair loss, sweating, intolerance to heat and\or cold.
Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain.

When a fluoroquinolone antibiotic triggers a toxic reaction in a person, multiple symptoms are often experienced.

Fluoroquinolone Antibiotic Damage – Technical Aspects

Fluoroquinolones are eukaryotic DNA gyrase and topoisomerase inhibitors very similar to many antineoplastic agents (source). What this means in plain English is that these drugs work the same way as chemotherapeutic drugs; they disrupt DNA and lead to destruction of cells. A recent (2013) study conducted by a team of scientists at the Wyss Institute for Biologically Inspired Engineering at Harvard University Studies showed that Ciprofloxacin, along with a couple of other non-fluoroquinolone antibiotics, causes oxidative stress and mitochondrial malfunction. A 2011 study published in the Journal of Young Pharmacists found that, “There is significant and gradual elevation of lipid peroxide levels in patients on ciprofloxacin and levofloxacin.” They also found that “There was substantial depletion in both SOD (superoxide dismutase, “a free radical scavenging enzyme”) and glutathione levels” and that “On the 5th day of treatment, plasma antioxidant status decreased by 77.6%, 50.5% (and) 7.56% for ciprofloxacin, levofloxacin and gatifloxacin respectively.” The study also notes that administration of fluoroquinolones leads to a marked increase in the formation of Reactive Oxygen Species (ROS) and that “reactive free radicals overwhelms the antioxidant defence, lipid peroxidation of the cell membrane occurs. This causes disturbances in cell integrity leading to cell damage/death.” 

How Many People are at Risk?

The exact rate of adverse reactions to fluoroquinolones is difficult to determine. Studies of adverse reactions to fluoroquinolones have noted that, “During clinical trials, the overall frequencies of adverse effects associated with (fluoroquinolones) to vary between 4.4 and 20%.” Just the fact that the spread is so large, a 15.6% spread in frequency of adverse reactions is a HUGE difference, it implies that the actual occurrence of adverse reactions is difficult to establish or unknown.

With the FDA figures above noting that 26.9 million unique patients were given fluoroquinolones in 2011, if you just take the conservative adverse reaction figure of 4.4%, you’ll get a horrifying number of people with adverse reactions in 2011 alone – 1,183,600 people. 20% of 26.9 million is 5,380,000 people adversely effected. That is scary. Those numbers are truly frightening given the severity of the adverse effects described above.
Fluoroquinolone Toxicity Syndrome

I see fluoroquinolone toxicity everywhere, and even I think that those numbers are high for severe, disabling reactions like mine where multiple symptoms develop simultaneously. Not everyone who has an adverse reaction to a fluoroquinolone has a reaction like mine, or even develops Fluoroquinolone Toxicity Syndrome. Many people have milder reactions. Milder symptoms include any one of the symptoms listed above as well as diarrhea, vomiting, mild tendinitis, decreased energy, painless muscle twitches, memory loss, urgency of urination, or any number of reactions that the body may have to a massive depletion of antioxidants and increases in lipid peroxide levels and reactive oxygen species production.

Even though severe adverse reactions to fluoroquinolones antibiotics can be painful and disabling for years, many (possibly most, but certainly not all) people recover from Fluoroquinolone Toxicity Syndrome with time. I anticipate that I will be fully recovered 2 years after my reaction started. Sadly, there are some people who don’t recover. They suffer from chronic pain, disability, impaired cognitive abilities, etc. permanently.

It is absurd, to say the least, that an acute problem, an infection, that can easily be taken care of with administration of an antibiotic that is not a fluoroquinolone, is converted into a chronic problem, a syndrome that can disable a person for years, by a prescription ANTIBIOTIC, used as prescribed. In my case, a urinary tract infection that could have likely been taken care of with macrobid or even cranberry juice and d-mannos, was treated with Cipro which left me unable to do many physical and mental tasks that I had previously been able to do with ease. It’s a crazy, absurd situation. It’s absurd and it’s wrong.

Some Antibiotics are More Dangerous than Others

The bottom line is that these popularly prescribed antibiotics are dangerous drugs that have caused thousands of people to suffer with a myriad of maladies. Undeniably, they have their place, in treating life-threatening infections. Unfortunately, they are not being reserved for use in life-threatening situations and people are being hurt after taking them for simple sinus, urinary tract, bronchial and prostate infections. A strict and rigorous protocol needs to be established to limit the damage that they cause; because it’s not right to maim and disable people to treat their sinus infections.

Sources are highlighted throughout the article.

http://www.collective-evolution.com/2013/08/26/fluoroquinolone-antibiotics-are-you-at-risk/

Using Gene Therapy To Relieve Neuropathic Pain

Today's post from newsmax.com (see link below) revisits a story reported earlier on this blog about the new non-viral gene-therapy called VM202, which can potentially reduce neuropathic pain in ways that standard medications currently can only dream of. To reiterate, the study showed that just two low doses of VM202 produced pain relief lasting for months, with the added bonus of no side effects. The article explains what VM202 is but doesn't tell us how widely it's used at the moment; whether it's still in the testing stages, or whether it's available to the main population of neuropathy patients. Maybe your area, or country is carrying out trials as you read this and maybe you can get onto those but until things are much clearer, the best you can do is discuss it with your doctor or neurologist and ensure that they are aware of both the option and the potential of this treatment.

New Gene Therapy Eases Diabetes-Related Pain
Thursday, 05 Mar 2015 By Nick Tate

Northwestern University geneticists have developed a promising new gene therapy technique that helps those who suffered from painful diabetic neuropathy (PDN).

The study, published in the journal Annals of Clinical and Translation Neurology, found that two low dose rounds of a non-viral gene therapy called VM202 greatly eased the pain in people with PDN and the relief lasted for months.

"Those who received the therapy reported more than a 50 percent reduction in their symptoms and virtually no side effects," said lead researcher Jack Kessler, a professor in the department of pharmacology at Northwestern University Feinberg School of Medicine and a physician at Northwestern Memorial Hospital. "Not only did it improve their pain, it also improved their ability to perceive a very, very light touch."

VM202 contains human hepatocyte growth factor (HGF) gene, a naturally occurring protein in the body that acts on nerve cells to keep them alive, healthy, and functioning.
 
Keith Wenckowski, one of the 84 participants in the study who suffers from PDN, said walking barefoot on sand "felt like walking on glass" because of the condition — forcing him to wear shoes, even to the beach.

But Wenckowski said the VM202 therapy significantly eased his pain.

"I can now go to a beach and walk on the sand without feeling like I am walking on glass," he said.

There is not existing treatment for PDN, which affects up to 25 percent of diabetics. Patients with the condition have abnormally high levels of glucose in their blood that can be toxic to vital organs, tissues, and nerve cells.

Painkillers and other medications can alleviate symptoms, but carry undesirable side effects.

"We are hoping that the treatment will increase the local production of hepatocyte growth factor to help regenerate nerves and grow new blood vessels and therefore reduce the pain," said Senda Ajroud-Driss, M.D., associate professor in neurology at Feinberg and an attending physician at Northwestern Memorial Hospital.

"We found that the patients who received the low dose had a better reduction in pain than the people who received the high dose or the placebo."

© 2015 NewsmaxHealth. All rights reserved.

http://www.newsmax.com/Health/Health-News/gene-therapy-diabetes-neuropathy/2015/03/05/id/628524/

Suicide And Chronic Neuropathic Pain

Today's post from psychologytoday.com (see link below) covers a very serious topic concerning people living with chronic pain (and that includes millions of neuropathy patients) and that is the risk that the stress becomes so great that the only option is suicide. People try to link suicides of this nature to the so-called 'opioid addiction crisis' but that is way too simplistic. Anyone living with non-stop, chronic, nerve pain will tell you that there are times when things seem so bleak that thoughts naturally go towards ending it all. Were it not for opioid (and many other) drug treatments, suicide statistics would be much much higher than they are. At the moment, there aren't any trustworthy statistics about exactly how many people commit suicide because of the pain they're in but it's likely that the problem is much greater than imagined and deserves some serious research and study. This article highlights the problem in an intelligent way.

A Nation in Pain: Chronic Pain and the Risk of Suicide
 Judy Foreman Posted Nov 24, 2015

Chronic pain significantly increases the danger.

This fall's grim report about rising suicide and overall death rates among white, middle-aged Americans contains a slim silver lining. Here it is:

The new analysis by two Princeton economists, Anne Case and Angus Deaton, suggests that chronic pain — and the opioids used to treat it — may be a key driver of the rising deaths. While the “noisy” opioid epidemic has garnered near-daily headlines across the country for several years now, the equally horrible but silent epidemic of chronic pain has not yet broken through into the nation’s consciousness. Maybe things are beginning to change.

Many people still don’t realize it, but 100 million American adults live with chronic pain, many of them with pain so bad it wrecks their work, their families, their mental health and their lives.

There are no hard data on how many people with chronic pain die by suicide every year. But there are inferences. The suicide rate among people with chronic pain is known to be roughly twice that for people without chronic pain.

Since there are 41,149 suicides every year in the U.S., according to the National Center for Health Statistics, it’s possible that many of these suicides are driven by pain. Not proven fact, but plausible hypothesis. This would suggest that perhaps as many 20,000 or more Americans a year with chronic pain kill themselves, which would be more than the government’s tally of 16,235 deaths from prescription opioids every year. According to a CDC spokeswoman:

In 2013, there were 8,257 deaths that involved heroin and 16,235 deaths that involved prescription opioids. These categories are not mutually exclusive: if a decedent had both a prescription opioid as well as heroin listed on their death certificate, their death is counted in both the heroin as well as the prescription opioid death categories.

The truth, of course, is devilishly difficult to figure out with any certainty. Many people in severe, chronic pain have, and should have, opioids available. But unless they leave a suicide note it’s virtually impossible to tell if they overdose on purpose or accidentally. That’s in stark contrast to a pain patient who ends his or her life using a gun. That’s clearly a suicide, with or without a note.

In the course of researching my 2014 book on chronic pain, I heard many grisly stories. One Salt Lake City truck driver I interviewed would be dead today if his wife hadn’t walked in on him with a gun in his mouth. He had been in severe headache pain and after many visits to the ER, was repeatedly dismissed as a drug seeker, even without a medical workup. (Eventually, he was diagnosed with two brain aneurysms, bulging weak spots in a blood vessel).

I also heard about a surgeon with shingles who could find no relief for his pain and took a scalpel to his back in an attempt to dig out the painful nerves; he wound up in his own ER — as a patient. I heard of another man with ophthalmic shingles who finally shot himself because of unrelieved pain. A Boston surgeon I met was on the verge of suicide due to unrelenting pain from a rare autoimmune disease.

The anecdotes go on and on. Unfortunately, from a statistical point of view, they are just anecdotes. And unlike opioid abuse deaths, the stories of these and other pain patients rarely make the headlines.

Nor do these cases routinely make it into the reports of medical examiners and coroners, according to Utah pain specialist Dr. Lynn Webster, writing in a recent issue of Pain Medicine News.

In this fall's Princeton study, the lead author, Anne Case, was particularly interested in the role poor health might play in suicide because, as she told The New York Times, she herself has suffered for 12 years from disabling and untreatable lower back pain. In her research, Case discovered that middle-aged people, unlike the young and unlike the elderly, were reporting more pain in recent years than in the past. One-third of people in this group had chronic joint pain in recent years and one in seven reported sciatica.

The dismal situation with chronic pain — and the potential link with suicide — is unlikely to improve until the federal government takes the pain epidemic seriously. While the government spends $2,562 on research for every person with HIV/AIDS, it spends only $4 for every person with pain.

Clearly, chronic pain needs more attention and more research dollars. After all, it is the main reason Americans go on disability.

And it appears to be driving growing numbers of Americans to kill themselves.

(Originally posted on WBUR’s CommonHealth)

https://www.psychologytoday.com/blog/nation-in-pain/201511/chronic-pain-and-the-risk-suicide

New Explanation For Diabetes Related Neuropathic Pain

Today's post from Sciencedaily.com (see link below) brings a dilemma with it. A study has shown that changes in 'dendritic spines' in the brain may play an important part in explaining neuropathic pain in diabetes-related cases! Yet nowhere does it say that this is exclusively a diabetes-related occurence. The article states that the reason why diabetes can cause neuropathy is still a mystery, so there is really no reason to assume that these changes in the nerve endings in the brain only occur in diabetes patients. We need the study to include HIV-related neuropathy and many other forms too, If the dendritic spines are not altered in other forms of neuropathy, then they have some important information but at the moment, to a layman like me, it's just not clear.
 Many people with HIV looking for information on neuropathy, may skip over articles about diabetic neuropathy because they think it doesn't apply. This is generally just not true. Most of the information about diabetic neuropathy applies to all neuropathies; it's just that diabetic neuropathy is by far the most common form amongst the general population. If you ask 99 out of a 100 diabetic neuropathy patients what their symptoms are, you'll find that they are exactly the same as your own. What the researchers mean to say is that they don't really understand the processes behind why neuropathy occurs in most of its forms and tying it to one disease depends on who their target readership is. If there are any experts out there who can explain (in relatively simple terms)  the real differences in disease-based neuropathies, please let us know - very many people are interested.

Unexpected Source for Diabetic Neuropathy Pain

ScienceDaily (May 15, 2012)

Normal dendritic spines — microscopic projections on the receiving branches of nerve cells — are shown at top compared to those of diabetic rat. At bottom, spines after receiving treatment. Yale study suggests that neuropathic pain associated with diabetes may be caused by reshaping of these spines in nerve cells, and might be treated by drugs. (Credit: Image courtesy of Yale University)

Nearly half of all diabetics suffer from neuropathic pain, an intractable, agonizing and still mysterious companion of the disease. Now Yale researchers have identified an unexpected source of the pain and a potential target to alleviate it.

A team of researchers from Yale and the West Haven Veterans Affairs Medical Center describes in the May 15 issue of the Journal of Neuroscience how changes in the structure of dendritic spines -- microscopic projections on the receiving branches of nerve cells -- are associated with pain in laboratory rats with diabetes.

"How diabetes leads to neuropathic pain is still a mystery," said Andrew Tan, an associate research scientist in neurology at the Yale School of Medicine and lead author of the study. "An interesting line of study is based on the idea that neuropathic pain is due to faulty 'rewiring' of pain circuitry."
With a growing number of diabetics, the condition represents a huge unmet medical need. Once neuropathic pain is established, it is a lifelong condition.

"Here we reveal that these dendritic spines, first studied in memory circuit processing, also contribute to the sensation of pain in diabetes," Tan said. A single neuron may contain hundreds to thousands of dendritic spines.

The Yale team led by Tan and senior author Dr. Stephen G. Waxman, the Bridget Marie Flaherty Professor of Neurology, professor of neurobiology and pharmacology,found abnormal dendritic spines were associated with the onset and maintenance of pain. They also found that a drug that interferes with formation of these spines reduced pain in lab animals, suggesting that targeting abnormal spines could be a therapeutic strategy.

Tan said that these dendritic spines in nerve cells seem to store memory of pain, just as they are crucial in memory and learning in the human brain.

"We have identified a single, key molecule that controls structural changes in these spines and hopefully we can develop therapeutic approaches that target that molecule and reduce diabetic pain," Waxman said.

Other authors on the paper are Omar A. Samad, Tanya Z. Fischer, Peng Zhao and Anna-Karin Persson,
The research was funded by the Department of Veterans Affairs.

http://www.sciencedaily.com/releases/2012/05/120515203056.htm

Gabapentin And Pregabalin Lyrica Really Are A Danger To Your Neuropathic Health!

Today's post from pulsetoday.co.uk (see link below) is an impassioned plea from a home doctor who is seeing the consequences of long-term gabapentin and pregabalin (Lyrica) use in his surgery. Finally, a doctor who stands up to the hype that the pharmaceutical companies use to promote their drugs! Many, many neuropathy patients across the world have been prescribed either gabapentin or pregabalin for their nerve pain and other symptoms. This blog has long warned of the dangers of Lyrica (pregabalin) and advised patient to have serious discussions with their doctors if they are being prescribed these drugs. This article explains why and in terms you can't ignore. These drugs aren't the first and they won't be the last to display dangerous side effects years after the profit on them has been made. As Dr Spence says: "If it quacks like a duck and looks like a duck, then it’s a ducking duck"!

Gabapentinoids - the new diazepam?
Posted by: Dr Des Spence 9 September 2016

The establishment ignores GPs. It prefers the advice and glamour of ‘expert’ or media doctors. But the deference shown to the ‘expert’ is creating overtreatment, medicalisation and iatrogenic harm.

GPs have to ignore this advice. We won’t prescribe statins to everyone because it is irrational and stupid. We don’t accept that ‘pain is what the patient says it is’, because common sense dictates that it isn’t.

And we have seen the damage when experts have free rein. Diazepam was peddled as a safe and effective treatment for anxiety by companies and experts alike. When I started work in the early 1990s the consequence of this advice was evident everywhere. Herds of middle-aged patients zonked out and dependent on benzodiazepines. And benzodiazepines were being widely abused by a younger generation. My surgeries were spent dealing with drug-seeking behaviours, lies, confrontation, rebound agitation, insomnia and withdrawal seizures. It took the establishment decades to realise the harms we caused. Even today, we are still dealing with it.

GPs are first to notice the danger posed by psychoactive drugs. In the past five years my sensor has been off the scale with the gabapentinoids (gabapentin and pregabalin). Patients are seeking them using the crude acting skills that I used to witness with benzodiazepines: anger, tears and threats; constant requests for dose increases; stories of lost scripts; and a tag-team approach with friends who ‘corroborate’ stories.

If you google ‘gabapentinoids’, it is clear they are being widely abused. Large quantities are taken as single doses. Users describe them as the ‘ideal psychotropic drug’ with effects of ‘great euphoria’, ‘disassociation’ and an ‘opiate buzz’ as they boost the effects of these drugs.[1,2]

I wrote an article in the BMJ in 2013[3] highlighting these concerns. Since then, prescriptions have nearly doubled in three years to 10 million scripts and more than £300m in costs.[4] Such rapid increases are the signature of inappropriate prescribing and iatrogenic harm. Many practices started prescribing gabapentinoids on the back of specialist endorsement, despite the existence of effective and less harmful alternatives.[5,6] But requests from pain clinics and psychiatry come thick and fast. We decline many, then weather the storm of protest.

Do we have a problem with gabapentinoid abuse? If it quacks like a duck and looks like a duck, then it’s a ducking duck. Pregabalin is already a controlled medication in the US and there is debate about controls in the UK. The research base for the benefits of gabapentinoids is of short duration and in a small, defined population where as few as one in 10 benefits.[7] We need to change our prescribing policy now and limit the use of gabapentinoids.[2]

We know the pattern: GPs will be blamed even if we just follow orders. I get tired that no one listens to generalists. This is déjà vu. Do we want another benzodiazepines disaster?

Dr Des Spence is a GP in Maryhill, Glasgow, and a tutor at the University of Glasgow

References Schifano F, D’Offizi S, et al. Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data. Psychother Psychosom 2011;80:118-22
Advice for prescribers on the risk of the misuse of pregabalin and gabapentin. Public Health England, 2014
Spence D. Bad medicine: gabapentin and pregabalin BMJ 2013; 347 08 November 2013
NHS Prescription Cost Analysis data. NHS Business Services Authority, 2016
Wiffen P, Derry S, et al. Antiepileptic drugs for neuropathic pain and fibromyalgia - an overview of Cochrane reviews Cochrane Database Syst Rev 11 November 2013; (11):CD010567
Moore R, Derry S, et al. Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012 Dec 12;12:CD008242
Advice on the anticonvulsant drugs pregabalin and gabapentin. Advisory Council on the Misuse of Drugs, 2106 

http://www.pulsetoday.co.uk/views/blogs/gabapentinoids-the-new-diazepam/20032721.blog

MDA7 To Inhibit Inflammation Causing Neuropathic Pain

When treatments only have letter and a number as a name, most people switch off before reading any further but today's post from consultqd.clevelandclinic.org (see link below) may be worth more attention from the casual reader. As a result of recent research into the sorts of inflammations that cause neuropathic pain, Cleveland Clinic investigators have synthesised a molecule that may inhibit the pathways that cause the inflammation. This molecule is called MDA7 and is a sort of synthetic cannabinoid. Dr. Naguib, who heads the team has high hopes for an eventual treatment based on this repression of microglial (15% of all nerve cells found in the brain) inflammation. At the moment, long-suffering rodents have been the recipients of this development but moves are underway for testing on humans. If you understand nothing else from this article, it's fascinating to learn that most of our neuropathic pain is caused by good old fashioned inflammation, which is a word most people will understand immediately. More hope for future generations.

Microglial Inflammation: A Promising Target in Neuropathic Pain Also Plays Role in Memory Deficiency
Pursuing a potentially treatable common pathway 
Feb. 2, 2015 
 
Promising research by Cleveland Clinic investigators demonstrates that microglial inflammation is a common pathway ‒ and a potentially treatable one ‒ for neuropathic pain and other treatment-resistant neuroinflammatory conditions, including Alzheimer disease (AD).

“Microglial inflammation is a mechanism of many CNS disorders ‒ neuropathic pain, AD, multiple sclerosis, parkinsonism, you name it,” says lead researcher Mohamed Naguib, MD, of Cleveland Clinic’s Anesthesiology Institute, which includes the Department of Pain Management.

His team has synthesized a molecule called MDA7, a cannabinoid type 2 (CB2) receptor-selective agonist, to inhibit microglial inflammation in hopes of effectively treating neuropathic pain and other conditions. “MDA7 prevents microglial activation and recruitment, which represent the elemental pathway of microglial inflammation,” explains Dr. Naguib. 

Efficacy in a Rodent Model of Chemo-Induced Neuropathic Pain

The researchers demonstrated as much in a 2012 paper in Anesthesia and Analgesia (2012;114[5]:1104-1120) reporting findings from a rodent model of paclitaxel-induced neuropathy, which is associated with activation of microglia followed by the activation and proliferation of astrocytes and the expression and release of pro-inflammatory cytokines. They found that MDA7 prevented paclitaxel-induced allodynia in rats and mice in a dose- and time-sensitive fashion without compromising paclitaxel’s anticancer effects. MDA7’s anti-allodynia effect was absent in CB2–/– mice and was countered by CB2 antagonists, which suggests it directly involves CB2 receptor activation.

Because all neuropathic pain shares the mechanism of microglial inflammation, Dr. Naguib expects the same effect in neuropathic pain types outside the chemotherapy setting. “We started with chemotherapy-induced neuropathy because it’s an area of unmet therapeutic need,” he says.

Similar Efficacy in CRPS

His team recently finished a study using a vascular occlusion model in the rat to replicate another form of chronic pain with a microglial inflammation mechanism, complex regional pain syndrome (CRPS). MDA7 was again highly effective, both at the molecular level and in terms of phenotypic response. They expect to submit the CRPS study for publication this year.

Promise for Alzheimer Disease

The wider biomedical community learned of the team’s work via an exciting study in February’s Nature Neuroscience (2014;17[2]:223-231) linking microglia-mediated inflammatory changes in a postsynaptic protein, neuroligin 1, to amyloid-associated memory deficiency in rodents.

Current models of AD hold that amyloid plaques accumulate in the brain, overwhelming the microglia that serve as the nervous system’s main form of active immune defense. When the microglia cannot clear out amyloid rapidly enough, they become inflamed, which leads to gene modifications in the brain.

“As our research into microglial inflammation advanced, it became clear how important this inflammation is to a variety of disease processes, which led down the Alzheimer path,” says Dr. Naguib.

His team’s Nature Neuroscience study showed that the microglial inflammation-induced gene changes in the brain include suppressed expression of the neuroligin 1 protein ‒ and that this suppression leads to hippocampal glutamatergic dysfunction and memory deficiency in rodents. The effects were ameliorated by inhibiting microglial activation. “These findings link neuroinflammation, synaptic efficacy and memory, thus providing insight into the pathogenesis of amyloid-associated diseases,” the researchers concluded.

Dr. Naguib notes that much research remains, but the findings suggest that MDA7 represents a promising new therapeutic approach to AD and other conditions involving microglia-mediated neuroinflammation, such as multiple sclerosis and Parkinson disease.

Next Steps

In the near term, the researchers are focused on gaining funding to move MDA7 into phase 1 human studies for chemotherapy-induced neuropathy, which they hope to begin by 2015. Studies of MDA7 in animal models of AD will take longer, due to the longitudinal nature of AD, but Dr. Naguib says the team is committed to pursuing that research as well.

Mohamed Naguib, MD is a professor of anesthesiology in the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University.

Consult QD—Neurosciences

The neurosciences field is changing rapidly, and so are all of our practices. Join clinicians and researchers from Cleveland Clinic’s Neurological Institute in this open forum for discussion of the latest advances in patient care, research, and technology — specifically for healthcare professionals.

http://consultqd.clevelandclinic.org/2015/02/microglial-inflammation-a-promising-target-in-neuropathic-pain-also-plays-role-in-memory-deficiency/

BL 7050 New Drug For Neuropathic Pain

Following on from yesterday's post, today's article from sciencedaily.com (see link below) goes into more detail about the potassium-based neuropathy drug (at the moment, charmingly named, BL-7050) developed in Israel. It is still in the trials and testing stage, so won't be appearing on your pharmacist's shelves for some time yet but it sounds promising. The reason for posting two similar stories after each other, is to give a little more weight to the subject. The more serious websites devote attention to new drugs, the more they are likely to be real prospects of progress.

A New Drug to Manage Resistant Chronic Pain

ScienceDaily (Apr. 30, 2012)

Neuropathic pain, caused by nerve or tissue damage, is the culprit behind many cases of chronic pain. It can be the result of an accident or caused by a variety of medical conditions and diseases such as tumors, lupus, and diabetes. Typically resistant to common types of pain management including ibuprofen and even morphine, neuropathic pain can lead to lifelong disability for many sufferers.

Now a drug developed by Tel Aviv University researchers, known as BL-7050, is offering new hope to patients with neuropathic pain. Developed by Prof. Bernard Attali and Dr. Asher Peretz of TAU's Department of Physiology and Pharmacology at the Sackler Faculty of Medicine, the medication inhibits the transmission of pain signals throughout the body. In both in-vitro and in-vivo experiments measuring electrical activity of neurons, the compound has been shown to prevent the hyper-excitability of neurons -- protecting not only against neuropathic pain, but epileptic seizures as well.

The medication has been licensed by Ramot, TAU's technology transfer company, for development and commercialization by BioLineRx, an Israeli biopharmaceutical development company.

Targeting potassium for pain control

According to Prof. Attali, the medication works by targeting a group of proteins which act as a channel for potassium. Potassium has a crucial role in the excitability of cells, specifically those in the nervous system and the heart. When potassium channels don't function properly, cells are prone to hyper-excitability, leading to neurological and cardiovascular disorders such as epilepsy and arrhythmias. These are also the channels that convey pain signals caused by nerve or tissue damage, known as neuropathic pain.

With few treatment options available for neuropathic pain, Prof. Attali set out to develop a medication that could bind to and stabilize the body's potassium channels, controlling their hyper-excitability and preventing the occurrence of pain by keeping the channels open for the outflow of potassium. This novel targeting approach has been recently reported in the journal PNAS.

Inducing calm in the neurons

Understanding the mechanism that controls these channels has been crucial to the development of the drug. By successfully controlling the excitability of the neurons, Prof. Attali believes that BL-7050 could bring relief to hundreds of millions of patients around the world who suffer from neuropathic pain. The medication will reach the first phase of clinical trials in the near future.

In pre-clinical trials, BL-7050 was tested in rats experiencing both epilepsy and neuropathic pain and was found to be efficient in protecting against both when taken as a pill. While on the medication, rats were no longer affected by stimuli that had previously caused pain. Measures in the electrical activities of neurons also revealed that the medication was able to induce "calm" in the neurons, inhibiting pain pathways.

The above story is reprinted from materials provided by American Friends of Tel Aviv University.
http://www.sciencedaily.com/releases/2012/04/120430124715.htm

Post Herpetic Neuralgia Related To Neuropathic Disorders

Today's short post from painhq.org (see link below) looks at postherpetic neuralgia which is a neurological extension of shingles. It's strange, almost everyone has heard of shingles and rightfully fears it for the pain it can bring but few associate it with neuropathy, yet in fact, it's one of the many forms of nerve damage that can fall under the general term of neuropathy. Shingles is a neuropathy caused by the reawakening of the varicella zoster virus, the same virus that causes chickenpox. In that respect it can be related to other forms of neuropathy brought about by viruses, such as HIV. This article sticks to the point and gives you a decent springboard for further research if you're suffering from either shingles or the misery of postherpetic neuralgia.
 

Postherpetic Neuralgia 
Info from Mayo Clinic and Wikipedia: Author unknown: 2014

What is Postherpetic Neuralgia? Postherpetic neuralgia is ​a complication of shingles. A case of shingles will typically only last a few weeks. If pain remains after the blisters and skin irritations subside, postherpetic neuralgia may be diagnosed. Early treatment of shingles can reduce the risk of developing postherpetic neuralgia.

Nerve fibres in the skin can be damaged during an outbreak of shingles, and the virus may remain resident in the nerve cell. When this happens, the nerves in the skin cannot communicate properly with the brain, resulting in postherpetic neuralgia.

What are the symptoms? Symptoms for postherpetic neuralgia present in the distribution of the nerve affected by the shingles. Individuals may experience a burning, sharp pain and a sensitivity to light touch (which may even include the touch of clothing against the skin). Less commonly, patients may experience a numb or itchy feeling in the affected areas, and in some cases, muscle weakness or paralysis.

Is there any treatment? Often a combination of different treatments are used to manage postherpetic neuralgia and any associated pain. Treatments include the use of topical medicines applied to the skin itself, such as lidocaine and capsaicin skin patches; as well as medicines taken by mouth such as anticonvulsants, antidepressants and opioid painkillers.

What treatment have you found most effective for Postherpetic Neuralgia?

Opioids (0)
Physical Therapy and Rehabilitation (0)
Gabapentin (1)
Pregabalin (1)
Topical Lidocaine (1)
Duloxetine (0)

What is the prognosis? Most individuals suffering from postherpetic neuralgia will experience a slow improvement of pain symptoms with treatment.

Related evidence 
Markley HG, Dunteman ED, Sweeney M. Real-World Experience with Once-Daily Gabapentin for the Treatment of Postherpetic Neuralgia (PHN). Clin J Pain. 2014 Jul 28. [Epub ahead of print]

Schlereth T, Heiland A, Breimhorst M, Féchir M, Kern U, Magerl W, Birklein F. Association between pain, central sensitization and anxiety in postherpetic neuralgia. Eur J Pain. 2014 Jul 28. doi: 10.1002/ejp.537. [Epub ahead of print]

References  
Mayo Clinic [Internet]. Postherpetic neuralgia [updated 2014; cited 2014 Aug 5]. Available from: http://www.mayoclinic.org/diseases-conditions/postherpetic-neuralgia/basics/definition/con-20023743

Wikipedia [Internet]. Postherpetic neuralgia [updated 2014 Aug 16; cited 2014 Aug 5]. Available from: http://en.wikipedia.org/wiki/Postherpetic_neuralgia
 
https://www.painhq.org/learning/knowledge-base/category/conditions/peripheral-neuropathic-pain/post-herpetic-neuralgia

Peptide Activates Receptor To Reduce Neuropathic Pain

Today's post from sciencedaily.com (see link below) looks at trials of ARA 290, which is a peptide. Peptides are naturally occurring biological molecules but that won't mean much to most people either. Put very simply, when neuropathic damage occurs, the nervous system's normal repair receptors are turned off. When ARA 290 is introduced, the repair receptor is reactivated, which in turn represses inflammation and restores the body's natural ability to repair damage. I know; it's incredibly difficult for the layman to understand but if you read the article, you should get the point. Basically, molecular science is being used to find a way for pain signals to be dampened and we should see that as good news. A feature of the last couple of years, is the emergence of news in the stem-cell and molecular science areas, that shows that neuropathic pain is being taken very seriously and there are serious efforts to find ways to tackle it. We don't have to understand exactly how it works but knowing that it shows progress towards a positive result for us all, is very reassuring. All we have to do now is wait and hope that they get to practical treatments as soon as possible.

Novel agent decreases neuropathic pain in patients with type 2 diabetes  Source: North Shore-Long Island Jewish (LIJ) Health System Date: December 15, 2014

Summary:

A promising profile of disease modification and pain reduction leads to proof-of-concept trials, scientists report. "The results from this study indicate a major breakthrough in the treatment of diabetes," said one expert.

Molecular Medicine, a peer-reviewed biomedical journal published by the Feinstein Institute Press, published the results of a new study reporting clinically significant pain reduction in type 2 diabetic patients. In an exploratory study conducted by Araim Pharmaceuticals, a biotech company developing novel treatments for chronic diseases, investigators also observed improvements in metabolic control in patients administered ARA 290. ARA 290 is a peptide engineered to activate the innate repair receptor, a receptor discovered by Araim scientists, which is only expressed following tissue damage or stress.

In the initial study, patients were administered ARA 290, a novel, first-in-class drug, daily for 28 days, with the purpose of evaluating its efficacy in treating neuropathic pain, a common condition among diabetics. When ARA 290 is administered, the repair receptor is activated and subsequently turns off inflammation and turns on the body's natural repair system. The short half-life of ARA 290, coupled with the restricted expression of the innate repair receptor, functions as a dual safety system to avoid potential side effects.

"The results from this study indicate a major breakthrough in the treatment of diabetes," said Kevin J. Tracey, MD, president of the Feinstein Institute for Medical Research and Editor of Molecular Medicine. "Over the years, Molecular Medicine has prided itself on publishing groundbreaking papers with implications on the broader medical community, and we're proud to have a potential disease-modifying solution to diabetes featured in the current issue."

The clinically significant results and excellent safety profile support Araim's development strategy of two future studies in 2015. First, metabolic improvement will be studied in type 2 diabetics with moderate kidney damage. Second, neuropathic pain reduction will be assessed in a multi-center proof of concept trial in type 1 diabetics. Both phase 2 clinical trials will be conducted in the United Kingdom, and patients will be dosed daily for six months to allow time for adequate tissue repair.

"We're excited to be on the cusp of the first diabetic disease modifier that demonstrates the potential to repair the complications of diabetes systemically," said Anthony Cerami, PhD, CEO of Araim Pharmaceuticals." Dr. Cerami developed the HbA1c diagnostic test, the current gold standard for diagnosing diabetes.

Story Source:

The above story is based on materials provided by North Shore-Long Island Jewish (LIJ) Health System. Note: Materials may be edited for content and length.

http://www.sciencedaily.com/releases/2014/12/141215101647.htm

The Single Gene That Could End Neuropathic Pain

Today's long but very readable post from wired.com (see link below) is a truly fascinating story of how people with rare conditions that lead to the inability to feel pain, may hold the genetic clue to creating a whole new set of pain relief drugs and genetic treatments that will end neuropathic pain for good. How good does that sound! That one single gene could provide the answer for millions suffering from chronic pain, is almost beyond belief and yet we're on the verge of being able to manipulate our genetic make-up in such a way that that single sodium channel could be successfully blocked. How long it will take depends on the willingness of pharmaceutical companies to enter and win the race to be the first to patent the treatments. Don't hold your breath but nevertheless. this sounds so hopeful!
 

End Pain Forever: How a Single Gene Could Become a Volume Knob for Human Suffering
by Erika Hayasaki | art by Sean Freeman 04.18.17

On a scale of 1 to 10, how would you rate your pain? Would you say it aches, or would you say it stabs? Does it burn, or does it pinch? How long would you say you’ve been hurting? And are you taking anything for it?

Steven Pete has no idea how you feel. Sitting in Cassava, a café in Longview, Washington, next to a bulletin board crammed with flyers and promises—your pain-free tomorrow starts today; remember: you’re not alone in your battle against peripheral neuropathy!—he tells me he cannot fathom aches or pinches or the searing scourge of peripheral neuropathy that keep millions of people awake at night or hooked on pills. He was born with a rare neurological condition called congenital insensitivity to pain, and for 36 years he has hovered at or near a 1 on the pain scale. He’s 5′ 8″, with glasses and thinning brown hair, and he has a road map of scars across his body, mostly hidden beneath a T-shirt bearing the partial crests of Batman, Green Lantern, Flash, and Superman. Because he never learned to avoid injury, which is the one thing pain is really good for, he gets injured a lot. When I ask how many bones he’s broken, he lets out a quick laugh. May 2017. Subscribe to WIRED.

“Oh gosh. I haven’t actually done the count yet,” he says. “But somewhere probably around 70 or 80.” With each fracture, he didn’t feel much of anything—or even notice his injury at all. Whether he saw a doctor depended on how bad the break appeared to be. “A toe or a finger, I’d just take care of that myself,” he says, wagging a slightly bent index finger. “Duct tape.”

What about something more serious? Pete pauses for a moment and recalls a white Washington day a few years ago. “We had thick snow, and we went inner-tubing down a hill. Well, I did a scorpion, where you take a running start and jump on the tube. You’re supposed to land on your stomach, but I hit it at the wrong angle. I face-planted on the hill, and my back legs just went straight up over my head.” Pete got up and returned to tubing, and for the next eight months he went on as usual, until he started noticing the movement in his left arm and shoulder felt off. His back felt funny too. He ended up getting an MRI. “The doctor looked at my MRI results, and he was like, ‘Have you been in a car accident? About six months ago? Were you skydiving?’ ”

“I haven’t done either,” Pete replied.

The doctor stared at his patient in disbelief. “You’ve got three fractured vertebrae.” Pete had broken his back.

Throughout his body today, Pete has a strange feeling: “a weird radiating sensation,” as he describes it, an overall discomfort but not quite pain as you and I know it. He and others born with his condition have been compared to superheroes—indomitable, unbreakable. In his basement, where the shelves are lined with videogames about biologically and technologically enhanced soldiers, there is even a framed sketch of a character in full body armor, with the words painless pete. But Pete knows better. “There’s no way I could live a normal life right now if I could actually feel pain,” he says. He would probably be constrained to a bed or wheelchair from all the damage his body has sustained.

His wife, Jessica, joins us at the café. She is petite and shy, with ice-blue eyes traced in black eyeliner. When I ask her what it’s like to live with a man who feels no pain, she sighs. “I worry about him all the time.” She worries about him working with his power tools in the basement. She worries about him cooking over a grill. She worries about bigger things too. “If he has a heart attack, he won’t be able to feel it,” she says. “He’ll rub his arm sometimes, and I freak out: ‘Are you OK?’ ” She looks over at Pete, who chuckles. “He thinks it’s funny,” she says. “I don’t think it’s funny.”

Pam Costa lives an hour and a half from Pete, outside Tacoma, Washington, and she occupies the other end of the pain scale. Costa is 51 and girlish, with shoulder-length auburn hair and a wide smile. At first glance, she has the rosy flush of someone who has spent time in the sun. But if you look closer at her cheeks, her feet, and her legs, they bear traces of a deeper shade of plum. Everywhere there is plum, there is pain. She was born with a rare neurological condition called erythromelalgia, otherwise known as man on fire syndrome, in which inflamed blood vessels throughout her body are constant sources of pain. Because the inflammation is exacerbated by physical contact, stress, and even the smallest elevation in surrounding temperature, Costa lives her life with great care. She wears loose-fitting clothes because fabric feels like a blowtorch against her skin. She sleeps with chilled pillows because the slightest heat makes her limbs feel like they are crackling. “Have you ever been out in the bitter, bitter cold, where your feet were ice?” she asks me. “Almost frostbite? Then you warm them up and it burns? That burning sensation: That is what it feels like all the time.”

Costa begins and ends every day with a 50-milligram dose of morphine, just as she has for the past 35 years. And there are other pills. “I pop a lot of these,” Costa, barefoot, tells me as she opens her medicine cabinet and twists open a jumbo bottle of Aleve. The directions say not to exceed three pills a day, and though it is early afternoon and this is her fourth such pill in the past five hours, she expects to take a couple more before the day’s over. She is an instructor of psychology at a local college and the mother of a teenage daughter, and she agonizes over her morphine dependency. “I have a drive to stop—to just not be dependent on opiates,” she says. But without her medication, her pain becomes unbearable.

A year ago she went to Las Vegas for a work conference, and the plane home got stuck on the tarmac with a mechanical issue. There was no air-conditioning, and the temperature started to rise. “An hour and a half in, people are taking off their clothes, fanning themselves,” she says. With the plane 20 feet from the gate and her skin throbbing, Costa persuaded a flight attendant to let her off. “I was so afraid I was going to pass out or throw up or get to where I was immobilized.” When the doors finally opened, she fled the plane, and she sat in the airport dousing herself with Smartwater.

Costa and Pete have never met. Their daily negotiations with the world could not be more different. Yet scientists have uncovered a genetic link that binds their mirror-image conditions together, and pharmaceutical researchers are now deep into clinical trials on a new type of drug that seeks to mimic Pete’s condition to treat Costa and others living with chronic pain. Such a drug would not merely dull inflammation the way ibuprofen does or alter our neurochemistry the way opioids do: It would block the transmission of pain signals from cell to cell without ruinous side effects on the brain or body.

The scale of the problem that this breakthrough could help solve is so vast that it’s difficult to take in. Pain has always been the price of being alive, but according to the National Institutes of Health, more than one in 10 American adults say that some part of their body hurts some or all of the time. That’s more than 25 million people. In study after study, more middle-aged Americans than ever before say they suffer from chronic pain. Because of that pain, more of them than ever before say they have trouble walking a quarter mile or climbing stairs. More say they have trouble spending time with friends. More say they can no longer work.

To get through the day, many of these people turn to pills, and nearly 2 million Americans say they’re addicted to painkillers. If the pills stop working, many people try something else—80 percent of heroin users previously abused prescriptions—or they simply up (and up, and up) their dosage. Opioid overdoses led to 33,000 deaths in 2015, an all-time high and four times as many as in 2000. They now kill as many Americans every year as car accidents or guns do, and the crisis, it seems, is only getting worse.

Pam Costa sleeps with chilled pillows because the slightest heat makes her limbs feel like they are crackling.Cait Oppermann


If you burn yourself on a stove, it hurts. More specifically, the nerve cells in your hand sense the heat and send pain signals to your spinal cord. The signal then travels up to the brain, which instructs you to howl with pain or issue the appropriate profanity. This is what’s known as acute pain. It can stab or pinch or shock, hurting like hell and telling us to stop doing what we are doing, take care of ourselves, get medicine, get help. The medical community knows how to treat most acute pain. Temporary prescriptions for opioids dull the sting from surgical incisions; anti-inflammatories can mask the discomfort of a sprain. Acute pain persists, but it also goes away. Acute pain is also easier to empathize with: Show someone an image of a pair of scissors cutting a hand, and the observer’s brain will react as much as if their own hand were being pinched.

Chronic pain, on the other hand, is a phantom: an enduring ache, a tenderness that does not turn off. It can be inflammatory (brought on by diseases like arthritis) or neuropathic (affecting the nerves, as in some cases of shingles, diabetes, or chemotherapy treatments). Some chronic pain never even traces back to a coherent cause, which makes it that much harder to understand. Give us broken bones, burn marks, blood—in the absence of proof (or personal experience), the hidden pain of others is easy to dismiss.

As a child, Costa would dawdle in the deep gutters lining the streets near her home, the cool, mucky water providing her momentary pain relief. In classrooms she would wrap her hands and feet around the poles of a desk, like a koala, to feel the coolness. And she’d sneak off to water fountains to wipe down her limbs with cold water.

Doctors didn’t know how to diagnose her. Some adults thought she had behavioral issues or depression. One physician said her symptoms were psychosomatic. The plum color was the only visible evidence that she might have any medical disorder at all. Then, in 1977, when Costa was 11, a letter arrived from the Mayo Clinic. A cousin had been referred to the medical center after complaining of constant pain, and the doctors there, intrigued by her mysterious condition, had begun interviewing members of Costa’s extended family. They discovered that many of them had the same symptoms (redness, irritation, swelling), and they found that 29 members of Costa’s family, spanning five generations, appeared to have man on fire syndrome. After corresponding with Costa’s parents and learning more about her symptoms, a Mayo researcher told them that their daughter had apparently inherited the same problem.

But a diagnosis didn’t mean that anyone understood why it happened or how it could be treated. The researchers created a family tree for the Costas, identifying every relative with erythromelalgia. For Costa, it was stunning to see the clean, clinical diagram of hereditary hurt. And though she realized there was a chance she wouldn’t pass on her condition to any children she might have, she wasn’t going to take the risk. “I had my tubes tied right after my 18th birthday,” she tells me, a hint of grief filling her voice. “Always, since I was a little girl, I wanted to be a mother more than anything in the world.” When dating, she’d tell her suitors that she couldn’t have biological children. “That was a deal breaker for many guys,” she says. Costa eventually did get married, and in 2000 she and her husband adopted a daughter.

For most of her life, the underlying cause of her condition remained a mystery, both to her and to the global scientific community. But that began to change in 2004 with a discovery in a Beijing lab. Scientists there had studied a family in which three generations had been afflicted with man on fire. They found that, of the 20,000-plus genes that make up the recently mapped human genome, mutations in a single gene, SCN9A, were somehow linked to erythromelalgia. It was the first evidence of a specific genetic cause of man on fire, and for people like Costa it was a sign of hope.

How Pain Works

From onset to agony. —­Gregory Barber



1 Detection

Acute pain begins with nociceptors—long neurons that originate in the spinal cord and end as thin fibers in the skin. Those fibers are tipped with receptors that respond to pain-inducing stimuli. When a stimulus is strong enough, these receptors generate an electrical current—the pain signal.

2 Transmission
The pain signal travels along the neurons through a series of channels that allow sodium ions back and forth across cell membranes. These channels, like Nav1.7, allow those charged particles across a membrane if the pain signal is strong enough. (If it isn’t, the person feels no pain.)

3 Perception

When a pain signal reaches the spinal cord, it continues up to the brain, where the somatosensory cortex is primarily responsible for translating information about the intensity of the pain signal. The brain’s motor cortex then generates the body’s response—a shout of surprise, a jerk of a hand.

4 Aftermath

After an injury, even an innocuous stimulus—like a warm bath or a pat on the back—can generate a pain signal at the site of the original injury.

When Stephen Waxman was a student at the Albert Einstein College of Medicine in the early 1970s, he became interested in pain—how people feel it, how the body transmits it, and how, as a future neurologist, he could learn to control it. Later in his career, after his father was in the final stages of agonizing diabetic neuropathy, he became obsessed with helping patients like his dad, who could find no relief from their pain. “We simply had to do better,” he says.

Today Waxman is the director of the Center for Neuroscience and Regeneration Research at the Yale University School of Medicine. He is 71, with oval-shaped glasses that rest on the ridge of his nose when he reads and eyebrows that arch toward each other like upward-facing arrows. He’s spent nearly half a century trying to chart the molecular and cellular pathways involving pain, and for much of this time Waxman was interested in the sodium channels found in the membranes of neurons—portals that allow charged particles to flow in and out of the nerve cells. In particular, he believed that one of those sodium channels, Nav1.7, played an especially powerful role in how we experience pain. In his theory, a stimulus triggers the Nav1.7 channel to open just long enough to allow the necessary amount of sodium ions to pass through, which then enables messages of stinging, soreness, or scalding to register in the brain. When the trigger subsides, Nav1.7 closes. In those with faulty Nav1.7 channels, sensations that typically wouldn’t register with the brain are instead translated into extreme pain.

That was his theory, anyway. As the Chinese researchers were finalizing their results, Waxman’s team was searching for human subjects with some form of inherited pain, so they could sequence their sodium-channel genes and test the Nav1.7 hypothesis. Among the genes they wanted to sequence was SCN9A, which encodes Nav1.7 and determines whether it works. When Waxman learned that the Chinese scientists had discovered a link between SCN9A and erythromelalgia, he thought, “My God, we’ve been scooped.” The Chinese scientists seemed to have solved a mystery he’d spent much of his career examining.

As Waxman dug deeper into the report, though, his mood lifted. The Beijing group had linked SCN9A mutations to man on fire, but they didn’t explain or uncover how they were linked. For Waxman and his team, there was still an opportunity to connect the biochemical dots between faulty SCN9A genes, dysfunctional Nav1.7 channels, and man on fire. To do that, they needed to show how cells with mutant Nav1.7 channels would react to pain. Thanks to the Beijing group, they knew just where to look: families with erythromelalgia.

This is how Waxman first encountered Pam Costa’s family. He reached out and began gathering DNA from 16 of her cousins, aunts, and uncles who suffer from erythromelalgia. He sequenced their genes and used them to create faulty Nav1.7 channels, which he added to cells; he then tracked how these channels responded to stimuli. The results not only demonstrated that SCN9A mutations made Nav1.7 channels more likely to open (meaning harmless stimuli often triggered feelings of pain) but also showed that when those channels opened, they did so for longer, amplifying the feeling of discomfort. It was the breakthrough Waxman had spent his life working toward: “We now had a fully convincing link from Nav1.7 to pain.” This meant that if his team could somehow regulate or even turn off the Nav1.7 channel, they could regulate or even turn off how we experience certain kinds of pain.


Steven Pete was born in 1981 in the 2,200-person town of Castle Rock, Washington, near Mount Saint Helens. At around 6 months old, when Pete started teething, he chewed off part of his tongue. As he got older he would bang his head against walls, not even stopping when it became swollen or indented. His parents made him wear a helmet, and they wrapped his arms and legs in long socks, securing them with duct tape, to prevent him from chewing away at his own limbs. His younger brother, Chris, had many of the same symptoms and all the same fearlessness. A day rarely passed when one of them didn’t bleed or bruise.

When his parents took Pete to a local pediatrician, they explained that they did not think he felt any pain. Maybe neither son did. The pediatrician hadn’t heard of a condition that prevented someone from experiencing pain, but after weeks of research, he found over 40 similar cases, including four siblings in Birmingham, England. The Pete boys were eventually diagnosed with congenital insensitivity to pain, and though the condition was likely passed down from one generation to another, there was no known cause, much less a cure.

Pete went on to live what appeared to be an ordinary life. In 2003, while working a security job at a mall, Pete met Jessica online. “We talked on the phone for hours,” Jessica remembers. Pete told her about his painlessness, and at the time she didn’t think much of it. “I guess I was like, ‘That’s pretty cool,’ ” she says now with a shrug. They married in 2005, and he started working at the Cowlitz Indian Tribe Health and Human Services Department. All that time, he was unaware that just a few hundred miles north, outside Vancouver, British Columbia, a small company was inching toward a breakthrough in understanding his condition.

For years that company, which is now called Xenon Pharmaceuticals, had been working to understand rare single-gene disorders such as familial exudative vitreoretinopathy (which causes vision loss) in order to create drugs that could be used to treat more common disorders with similar symptoms (like other conditions involving vision loss). In 2001 the company heard about a family in Newfoundland in which four members could not feel pain. One of the sons “actually stood on a nail and it had gone through his foot,” says Robin Sherrington, then senior director of biological sciences at Xenon. “He had no idea that it had happened until he got home and his parents saw it.” No gene had yet been linked with their condition, but given the familial links in the Newfoundland case, Xenon researchers suspected it was genetic. They started hunting for more subjects.

Following news reports and word of mouth, Xenon tracked down and studied 12 families from around the world with insensitivity to pain. (The Petes were not among them. Outside their immediate community, few people knew about the brothers’ condition.) For Sherrington, it was incredible that these individuals and their genomes existed. Evolution should have weeded out most of their ancestors. “Feeling pain is protective,” Sherrington says. “They would not have felt certain noxious stimuli. They should not have survived.” By studying those 12 families’ genomes throughout 2001 and 2002, Xenon found a common trait among those with insensitivity to pain: mutations in a single gene, SCN9A, and the non­functioning sodium channel it encodes, Nav1.7.

“This single channel, when it is nonfunctioning in a human being, renders them unable to understand or feel any form of pain,” Sherrington says, summarizing the team’s initial findings. And if Xenon could develop a new drug that could somehow mimic this condition—“to inhibit the Nav1.7 channel to partially replicate that absence of pain,” he explains—then it could relieve people’s pain without any of the side effects of opioids.

It is rare for biology to deliver such a seamless positive-negative effect within a single gene. In man on fire patients, one SCN9A mutation leads to a hyperactive Nav1.7 channel, which causes extreme discomfort. In those with insensitivity to pain, another SCN9A mutation leads to an inactive Nav1.7 channel, which results in total numbness. Given that the teams at Xenon and Yale were working on opposite coasts, and on conditions that fell on opposite sides of the pain spectrum, they only learned of each other’s discoveries through published reports and journal articles. (Sherrington first learned about Waxman’s study at Yale in 2004; Waxman only read about Sherrington’s work at Xenon after the company published its results in 2007.) Both teams arrived at the same clinical destination from a totally different direction, surprised as anyone that people like Pam Costa and Steven Pete had anything in common. “I was overwhelmed when we saw both sides of the genetic coin,” Waxman remembers. “SCN9A really is a master gene for pain.”


When Steven Pete was 6 months old, he chewed off part of his tongue. Today he has a road map of scars across his body.Cait Oppermann


Not long after their discovery, technicians at Xenon set to work putting Nav1.7 channels into tissue cultures, then testing each with a compound from their vast library of molecules. They were looking for a blocker that would shut off or at least turn down the faucet on Nav1.7 without affecting the body’s other eight sodium channels. If you block Nav1.4, for ­example, you might block muscle movement. Blocking Nav1.5 can inhibit the heart. Blocking Nav1.6 might impact the brain, causing double vision, confusion, balance problems, or even seizures. One by one, they experimented with thousands of combinations until they got a hit—a compound that plugs up Nav1.7 without major side effects. From that, researchers then created a drug called TV-45070 and conducted pilot tests on four erythromelalgia patients. In three of the four, “these individuals’ pain responses were markedly blunted, and in one case we couldn’t elicit pain at all,” says Simon Pimstone, president and CEO of Xenon. Now TV-45070 is being used in a phase 2 clinical trial on 330 patients who suffer from nerve pain.

As for Waxman, he and his researchers at Yale helped Pfizer test five erythromelalgia patients with another Nav1.7 blocker. Scientists triggered the subjects’ pain with heating blankets and asked them to rate their feelings before and after taking the drug. Last year Pfizer and Waxman’s team reported that three of the five patients described a decrease in pain with the blockers.

There are other, less conventional approaches under way too. At Amgen, a pharmaceutical company in Thousand Oaks, California, scientists test up to 10,000 molecules against Nav1.7 each week. In 2012 they discovered that the toxin of a Chilean tarantula can target Nav1.7 with minimal impact on other sodium channels. They’ve since engineered a synthetic version of the spider’s toxin that’s more potent than the original.

These findings, while significant, are still small steps forward. Over the next few years, with larger pools of patients suffering from arthritis, sciatica, shingles, and many other kinds of pain, researchers will continue to test the practical applications of these discoveries. “At least a half dozen companies are trying to develop sodium-channel blockers that preferentially or selectively block 1.7,” Waxman says. And while obstacles remain—ensuring that only the Nav1.7 channel is affected; creating compounds that will allow some pain to register without cutting it off altogether; surviving the rigors of FDA approval—he and many others see a way forward.

Whichever company gets a prescription drug to market first, no progress would have been made without people like Costa and Pete, both of whom have taken part in studies for years.

Costa still remembers the day in 2011 when she first visited Yale and met Waxman in person, after corresponding with him by email and phone for six years. She got a tour of the labs, meeting more than a dozen scientists from around the world who have been working to fix Nav1.7. While walking through the lab, Costa saw a row of computers. Waxman asked, “Do you want to see what happens with your sodium channels?” She did.

Waxman pulled up an image of a normal person’s sodium channel on the screen, the strings of amino acids that form it neatly folded. Then he pulled up another image: The protein here was a tangled clump, amino acids zigzagging almost off the screen. “This is you,” he said.

“I’ll never forget,” Costa says. Her entire life, she could only tell others how she felt—she could never show them. To see the medical proof of her pain for the first time, Costa says, “was the most validating experience in my entire life.”

At the end of my visit to her home, Costa rushes outside barefoot to catch me before I leave. As she stands on the grass in the 60-degree weather, her legs are already turning purplish with aggravation, and she pulls out a handwritten letter that she’s just found, from her cousin Helaine, who sent it in 1986. Helaine lived in Alabama and also had erythromelalgia. She was one of Costa’s favorite cousins. They looked alike. Helaine was divorced, living in a trailer. She never had access to the kind of medical treatment that Costa has received. When Costa and her cousin talked, it was often about their mutual state of hurt. In 2015, Helaine died. Costa doesn’t know how, exactly. She just knows her cousin never woke up.

Today when Costa resurrects memories of her own pain, they come with specific details and anecdotes—like that terrible day on the delayed plane, with the Smartwater bottles, or dunking her feet in gutter water as a child. Neurologists believe that, in the brain, pain is associated with memory-making processes, which explains the specificity of her stories. You don’t remember every time you’ve gone running, but you remember the day you slipped on ice and broke your knee. Pain also leaves an imprint on our cellular memory—the experiences our bodies hold on to and may pass on to our children and grand­children—which some scientists believe may one day help explain why chronic pain can persist even after an injury has healed. We live with the echo of pain inside us, constantly reminding us to watch our step, back away from the stove, slow down. Someone could get hurt.

For Pete, recalling details of his injuries does not come easily, and his memories of growing up with his younger brother, Chris, are often vague too. Pete wishes Chris could help refresh his memory. “I relied on my brother a lot for retelling my stories and holding on to my memories,” Pete says, breaking into tears. A lifetime of injuries caused so much damage to Chris’ body that a doctor told him he would likely end up in a wheelchair before he turned 30. Living the rest of his life incapacitated like that was too much for Chris to bear. Eight years ago, he hung himself in the barn on their parents’ property. He was only 26. “It felt like losing … my life,” Pete says.

He wipes his tears away and takes a deep breath. “I hope that one day parents will be able to make a choice for their children who don’t feel pain, to activate that sodium channel so that their children can live a normal life.” The work under way to target the Nav1.7 channel won’t help Pete or others with congenital insensitivity to pain—there’s no point blocking a portal that’s permanently closed. Instead, the condition remains the most frustrating of mysteries: one with a known cause but no cure, passed down from one generation to the next.

When his daughter was born in 2008, Pete asked the doctor in the delivery room, “Does she feel pain?”

“They pricked her,” his wife remembers. “And she cried.” It felt something like relief.

https://www.wired.com/2017/04/the-cure-for-pain/

What Do You Mean You Have Chronic Neuropathic Pain

Today's post from lifeinslowmotionblog.com (see link below) looks at a dilemma which faces us all when confronted by disbelieving or ignorant faces that don't have a clue what we're on about when we go on about neuropathic symptoms. It's human nature - people match what they hear our pain involves, with what they have experienced in their own lives. Only we know how different neuropathic pain is and how much it can influence our daily lives for the worse. The article talks about a 'communication dilemma' and indeed that's exactly what it is. Just explaining that 'chronic' pain is not a measure of how severe the pain is but a description of something that just never goes away, (chronic meaning, long-lasting) is difficult enough. This article attempts to put the problem into context and help us feel better about the situation when it comes to dealing with other people's opinions.

Explain Your Pain: The Communication Dilemma
Posted on July 30, 2015 by lifeinslowmotion

Hi Folks, I’m starting a new series called “Explain Your Pain” which will attempt to address the difficulty of explaining our chronic pain to our family, friends, and others who need to be in the know. In this first post “The Communication Dilemma” I lay out the problem, and in future posts I will give some thoughts on how to move productively move forward to explain our pain.

Something about chronic pain is mind-numbingly difficult to describe. Something about describing our chronic pain experience leaves us feeling ashamed, alone, and misunderstood. If you struggle to explain your chronic pain to family, friends, and loved ones, you are not alone.

We all have memories of those tongue-tied moments, those seconds that stretched into minutes, as we sifted through our brains to try and find the right words. The words never seem to come.

We all have those relationships that are just not the same, because we have never been able to find the right words to explain why we have suddenly become so unreliable, always cancelling plans.

We all have those tear-stained memories of feeling so misunderstood and so judged that we are unsure if we will ever talk to that one friend again.

We can all remember conversations that were intended to bring clarity and understanding but somehow ended up only adding to the overall confusion.

If you have chronic pain, you are familiar with this communication dilemma. You are familiar with the gap that exists between our intimate experience of chronic pain and how much our family and friends know about our daily experience. You are familiar with the gap, but so far have been unable to bridge it. So far, words have fallen short.

What about chronic pain is so impossible to describe and so difficult to comprehend? Why do conversations about chronic pain feel unnatural? Why is this communication dilemma a common and overarching theme in the lives of so many who struggle with chronic pain? Perhaps if we can begin to answer these questions, we can figure out how to move forward in this quest to explain, in this journey to be known.

Describing chronic pain is difficult because it requires that we put objective and concrete words to a subjective and abstract experience.

At first glance, chronic pain appears to be a tangible and physical experience, but this is not the full story. Our chronic pain is certainly physical, and it feels concrete to the one who experiences it, but in a somewhat paradoxical sense, it is also incredibly subjective and abstract.

Why? These paradoxical qualities exist simultaneously because of the discrepancy between what we experience and what the people around us see.

Chronic pain is tangible to the person who feels it, but abstract to the person who cannot see it. We are the only one who can feel our own pain, and depending on the type and severity of our pain, those on the outside are often unable to see any tangible evidence of what we are experiencing. Because no one can see our pain, the question of whether the pain is real or as bad as we say lingers between our relationships and underlies all of our conversations. And so people wonder, in silence or out loud, “If it cannot be seen, is it actually there?”

Our pain cannot be seen and it cannot be objectively measured beyond a wildly inaccurate 1-10 scale that means something different for each person who uses it. Because it is a subjective experience that cannot be objectively measured, the word of the chronic pain fighter must be taken as true despite no apparent evidence to confirm.

Because there is often no evidence of what we experience, our pain behaviors and responses to our pain are used to confirm our lack of sanity instead of the presence of our pain. Our grimaces, limps, and our groans, as well as our decisions to spend all day lying on the couch or cancelling work in response to something that is invisible are used to prove that we are exaggerating, crazy, or seeking attention, instead of serving as evidence for our pain.

Describing chronic pain is difficult because society has little understanding of the difference between acute and chronic instances of pain.

The terms “acute” and “chronic” as used to describe pain are not a part of our societal vocabulary. And because these important descriptive words have not become ingrained in our vocabulary, people tend to think that pain is simply pain.

When people believe that all pain is the same, this poses a huge problem, because most peoples’ experiences of pain are of the acute variety. When people hear the word “pain,” they then draw on their own experience of acute pain to understand our experience of chronic pain. They make the grave mistake of assuming that chronic pain and acute pain are more alike than they are unalike.

But all pain is not created equal. All pain is not the same. Chronic pain is vastly different than the more common experience of acute pain.

Chronic pain is a continuous and unrelenting experience, vastly different from acute experiences of pain. While acute pain has purpose, alerting us to bodily damage, chronic pain is often purposeless, our body’s pain system run amok. It is poorly understand that pain over time becomes magnified a hundred fold because of how it must be dealt with continuously and with no hope of a break. The hope that exists when pain is acute, that hope that the pain will one day go away gives strength to persist and keep going. However, this same type of hope for physical relief is not present when pain becomes chronic and may not ever go away.

Describing chronic pain is difficult because our pain is unpredictable and transforms over the course of an ever-changing story.

Our chronic pain is shifting and ever-changing. We feel one way on Monday and a different way on Tuesday. The intensity, quality, and presentation of our pain vary throughout the days, weeks, months, and changing seasons. New symptoms come and go. Old symptoms worsen and intensify. We have flares, relapses, setbacks, and periods of relative calm.

Because our pain is always changing, keeping people updated on our condition requires a continuous conversation. We cannot explain our pain one time and expect people to understand. With each new season, we have to supply updates and new information.

Our chronic pain is paradoxical and contradictory. It is a complex and multifaceted experience that is many times confusing even to those who experience it. If we don’t fully understand our own chronic pain, how can we explain it to others? We don’t know what triggers our pain or where that last flare came from. We don’t know how to explain why we felt good on Monday and bad on Tuesday, because we are unsure of the reasons ourselves. Oftentimes we are unsure if or how our various symptoms connect, and oftentimes we do not have a clear diagnosis. When we are dealing with conditions that we have a hard time explaining ourselves, we will struggle even more to convey what we do know to the people around us.

Describing chronic pain is difficult because long-term and unrelenting suffering makes people uncomfortable and sometimes people do not want to know.

Sometimes people do not want to understand our pain. Listening does not come naturally to people, and this is especially the case when the topic is one that makes people uncomfortable. Unrelenting suffering that may never go away makes people uncomfortable because they are unable to fix our problem or give us effective advice. Unrelenting suffering makes people uncomfortable because it inconveniences them and because when we suffer, oftentimes the corner edges of our suffering will affect them as well.

Sometimes describing our chronic pain is difficult because people do not want to listen long enough to fully understand. Sometimes people do not want to listen long enough to understand because our suffering makes people feel uncomfortable and they are unsure how to respond.

Describing chronic pain is difficult because we are too exhausted to keep explaining.

Because our pain is complex, confusing, and contradictory, it takes great energy to explain and keep people up to date. At times we feel able to explain our pain, but we choose not to because we want to save our precious energy for more important things. The physical effects of our chronic pain wear us down and exhaust us. We must carefully decide how we will use our small pool of energy, and sometimes explaining our pain doesn’t seem like a worthy enough endeavor.

For all of these reasons, we eventually reach a state in which we are no longer willing or able to attempt these difficult conversations. And over the years, we tend to move towards one of two tactics.

Instead of seeking to explain our pain, we start to complain about our pain.

We become so hardened and bitter towards those who never seem to want to understand that we move into angry and bitter complaining. Our attempts at productive conversations seem pointless, so instead we move towards ceaseless complaints of how horrible our pain is. Often this turns into a downward spiral as we push people further away, and confirm everyone’s beliefs that perhaps we really are crazy, exaggerating, and attention-seekers.

Instead of seeking to explain our pain, we burrow inward, shutting everyone out, living in silence.

Many of go into hiding. Explaining our pain has become such an exhausting and futile effort that we begin to live out our chronic pain in secret, hiding how much pain we are actually experiencing. Over and over again, we plaster a smile on our faces, pretending that everything is ok, when it is far from ok. We stop explaining because we are exhausted and need every drop of our strength to fight this pain that haunts us.

There is a third option. It is possible to move out of our silence without moving into unhelpful complaining. It is possible to successfully explain our pain. Most of our past conversations were unsuccessful because of the simple fact that we were not prepared, and I believe it is possible to prepared. Once we begin to understand the nature of our chronic pain ourselves, we will better know what topics are important to convey to other people. It is possible to speak the truth about our pain with confidence. It is possible to speak about our pain in a way that will enable others to truly understand.

Once we are prepared, explaining our pain will no longer be a hopeless endeavor.

Stay tuned!

http://www.lifeinslowmotionblog.com/explain-your-pain-the-communication-dilemma/