Scientists identify two classes of itch neuron by turning them off separately

For several years it’s been known that itch and pain signals from the skin are carried by different types of neuron to the spinal cord and brain. But there's more than one kind of itch. Scientists have now clearly identified at least two types of itch neuron—one that responds to histamine and a second type that responds to other itch-provoking molecules.

These results could lead to drugs that selectively shut down chronic itch in eczema patients but leave the rest of the sensory system intact.

Some itch is caused by histamine, which triggers an itch signal in certain neurons. But histamine is not the main source of itch for eczema patients. In eczema, most itch has its origins in allergy, when mast cells release “pruritogens” that bind to receptors on itch neurons.

For a long time it was an open question whether histamine and the other pruritogens were triggering itch signals in the same neurons, or different types that scientists could distinguish experimentally.

In late May, researchers led by Alexander Binshtok at the Hebrew University in Jerusalem and Clifford Woolf at Harvard Medical School reported results that clearly showed histamine and non-histamine itch signals are carried by different neurons. The research was published in the journal Nature Neuroscience.

The scientists used a novel two-stage experimental technique to shut the two neuron types down independently. Perhaps someday a similar technique might be embodied in an anti-itch therapy.

What they did was to exploit the fact that when neurons detect histamine and pruritogens, large-diameter channels open in the neurons to let in ions (charged particles) that initiate the electrochemical itch signal, which relies on sodium and potassium.

First, the scientists treated mice with either histamine or a non-histamine pruritogen. At the same time they injected the mice with QX-314, a molecule that blocks sodium ion channels (which are very small-diameter). The large-bore ion channels opened to let in sodium, potassium, and QX-314.

Thereafter, those neurons were unable to fire itch signals, because their sodium channels were blocked by QX-314. The scientists showed that when they dosed the mice with histamine and QX-314, one group of neurons didn’t work (and the mice didn't scratch). When they dosed the mice with other pruritogens and QX-314, the histamine itch neurons worked, but other subsets of neurons were shut off (and the mice didn't scratch).

The scientists’ technique is not directly translatable to therapy, because this study was conducted in mice and involved injection, which is not practical for daily use. But the molecular action they were studying takes place in the upper skin layers, and one could imagine that someday a cream or ointment might be developed that would include two components: one to open large-bore ion channels that detect pruritogens, and another to block the electrochemical signals in those neurons.

Hat tip to Ryan.

PS in a recent post I discussed the difference between TRPV1 ion channels, required for histamine itch, and TRPA1 channels, required for chronic itch. These are the "large-bore" channels mentioned above. Trivia: To trigger a histamine itch signal in a neuron, histamine must activate both TRPV1 and the H1 histamine receptor. To trigger a non-histamine itch signal in a neuron, a pruritogen must activate both TRPA1 and a special pruritogen receptor--"MrgprC11" in the case of dry skin.

Key to chronic eczema itch may lie in special ion channel

Recently scientists reported the discovery of an “itch molecule” (Nppb)  responsible for conveying the itch signal across the synapse from sensory neurons in the skin to neurons in the dorsal horn of the spinal cord.

The media made a great deal of this study, which laid out a substantial model for how we feel itch.

Something I hadn’t noticed, though, was that the Science study considered only a subset of neurons involved in sensing itch—those that are activated by histamine. These neurons, at the itch-sensing end, have a type of ion channel called “TRPV1” that detects histamine and other substances, or “pruritogens,” that induce itch.

An ion channel is a kind of gate that opens when a key--such as a histamine molecule--binds to it. The open gate lets in sodium or potassium ions. When this happens to ion channels in a neuron, the neuron sends an electrical pulse down its length, transmitting information, such as a sensation of itch.

But there are other triggers for itch besides histamine. “Histamine-independent” itch is particularly important in the chronic itch experienced by eczema patients. (And that's why antihistamines don't do us any good.)

Histamine-independent itch is transmitted by neurons that possess TRPA1 ion channels. A new study, published in the Journal of Neuroscience, shows that mice only feel chronic itch if they have neurons expressing TRPA1 channels. Strikingly, the scientists show that knocking out TRPV1 channels (the histamine-dependent kind) does not affect the ability of mice to feel chronic itch.

As a model of chronic itch, the researchers shaved the cheeks of lab mice and exposed the skin to drying chemicals over a period of a few days. The mice scratched their cheeks and developed classic signs of dry, itchy skin--unless their TRPA1 channels had either been genetically deleted or inhibited by a drug,in which cases they hardly scratched at all.

The researchers were also interested in whether the itch-scratch cycle affected the sensation of itch. If you don’t scratch an itch, does it get better or worse? The answer appears to be that if you (or, by proxy, a lab mouse) have an itch on your back that you can only scratch by rubbing it against the wall, it may torment you, but when measured by objective standards, skin that you don’t scratch ends up in better shape.

We can draw two practical conclusions from this work, which was led by Diana Bautista at UC Berkeley: that blocking TRPA1 channels with a drug in cream or ointment form could be a potential solution to the chronic itch of eczema; and that it really does appear that if you can break the itch-scratch cycle, your skin will be better off.

Now, we all know how difficult it is to stop scratching. It’s not as easy as saying that you’ll stop. But this type of research certainly highlights the positive feedback of habit-reversal, which uses psychiatric techniques to reduce habitual scratching. Scratch less…and you’ll feel less itchy.

I do have one question: does the molecule Nppb, reported in the Science paper two weeks ago, transmit chronic itch signals as well as histamine-induced itch? If so, it is still a valuable target for further research into eczema therapies.

"Itch molecule" discovery a big step forward

All over the media last week was the news that two scientists at the National Institutes of Health in Bethesda, MD had discovered “the molecule responsible for itch.”

This molecule, “Nppb,” relays signals from certain neurons that detect itch in the skin to other neurons that carry the signals up the spinal cord to the brain. The scientists, Santosh Mishra and Mark Hoon, engineered mice in which the gene for Nppb had been turned off. The mice could not, apparently, feel itch.

The media hype is evident. Nppb is not THE molecule responsible for itch. Several molecules are known to be involved in detecting itch in the first place, and we know many others must be involved in the signaling pathway.

What is remarkable, though, is that the scientists were able to define a model for how itch gets from the skin to the spinal cord.

Mishra and Hoon's model of how neurons carry the itch signal. (Fig 4G from their Science paper.)

We now know that there are at least two pinch points: the synapse across which Nppb carries the signal, and a second downstream synapse across which another molecule, GRP, sends the information to the next stage of neurons.

Blocking the receptors for Nppb or GRP would seem to be a prime candidate for an anti-itch therapy. 

But, of course, there are complications. Nppb was originally known because it is important in the heart, where it controls blood pressure. GRP controls digestion. The genetically engineered Nppb-free mice died early. (The scientists said so in their media interviews.) 

So you can’t just take a pill that blocks Nppb receptors everywhere. That would be a disaster.

But this kind of restriction on where a drug can act is well-known in pharmacology. That’s why, e.g., I can use the anti-pain Voltaren gel (diclofenac) safely by rubbing it into my joints, but diclofenac is known to be pretty toxic if you swallow it.

You can’t design an Nppb receptor-blocking topical cream, because the important synapses are in the spinal cord. A cream would only be effective on the surface.

But it might be possible to take a pill that blocks Nppb only in the spinal cord. I’m not sure how, but that’s what major pharma companies are paying their scientists the big bucks to find out. Maybe the receptors in the spinal cord are subtly different than those elsewhere in the body.

This is very exciting stuff. The massive question is whether the work applies to humans. I would expect it did. Mice and human immune systems are quite different, but our nervous systems are not. We most likely have an analog of Nppb that carries our itch signals.

Just to put this in context—the new work tells us substantially more about itch signaling than previous work in the field. I’d been aware of studies that had identified a class of itch neurons, or certain molecules important in detecting itch in the skin, but this research builds on those foundations in a big way.

Where to look for a surprise eczema cure to emerge

As I wrote in the previous post, the outlook is bleak for new eczema therapies that might qualify as a “cure.” On the fronts of barrier protection and repair and anti-inflammatories, nothing revolutionary is in the works apart from, perhaps, dupilumab, Regeneron’s antibody to IL-4. I can’t see anything emerging from research and entering and successfully exiting clinical trials for at least 25 years.

What might I have left out of this discussion? Where could a surprise come from?

Itch. Itch was the area that occurred to me. Imagine being able to break the itch-scratch cycle in eczema. You know what it’s like: your skin flares up and the itch becomes unbearable. You scratch to get relief. Sometimes you scratch in your sleep. Then your skin is torn up, which for a start can be embarrassing, but also often leads to infection. If there were no itch to begin with, eczema might never become anything more than a minor rash. Its impact on quality of life would be greatly minimized.

I believe we might see a convergence of two major trends that would result in a new anti-itch drug that patients could take in pill or cream form.

The first trend: In the past few years I have seen a number of papers describing newly identified neurons that transmit the sensation of itch, distinct from pain. The experiments were done on animals such as mice and cats; I don’t think these neurons have been found in people yet. But you can bet there are many scientists beavering away to be the first in the field.

Turning on or blocking neural receptors is what drugs do best. Think anesthetics. These itch neurons, if found in humans, are likely going to have receptors similar to those in other animals, and the search will be on to find drugs that block the receptors.

(You could also imagine a therapy using RNA interference to prevent neurons in the skin from making itch receptors in the first place.)

The second trend: scientists are developing powerful new techniques to speed the drug discovery process. While it does take around 15 years to take a new drug all the way through clinical trials to FDA approval, the path is shorter for “repurposed” drugs (such as Viagra, originally planned as a heart medication). The barrier is lower because the drug has already been proven nontoxic. Repurposed drugs have been approved as treatments for one condition but have side effects that, depending on your perspective, qualify as primary effects. There could well be an FDA-approved anti-itch drug out there already. It’s just being used to treat toenail fungus.

A company I am familiar with (I know the founders), SeaChange Pharmaceuticals, developed a rigorous way to search through databases of drugs and identify potential side effects or secondary uses, based on the chemistry of the protein targets for the drugs. (Wired magazine named SeaChange’s technology one of the top 10 breakthroughs of 2009.)

The idea would be that scientists would identify itch neurons in humans, and pin down the itch receptor; then somebody at Pfizer or Novartis or whatever would use a SeaChange-like technique to find FDA-approved drugs that block the receptor. Presto: no more itch. Conceivably this might happen within a decade.

Now, evidently these new drug discovery techniques could be applied in the areas of anti-inflammatories, or barrier repair. I think, though, that itch is a prime candidate for a surprise eczema “cure” because it’s likely that the itch sensation comes down to a single receptor. Blocking that receptor by a conventional drug will be a relatively simple task, compared to controlling inflammation without leaving the patient vulnerable to infection, or taking on the dubious task of compensating for a defective skin barrier in infants.

That’s my opinion.

San Diego eczema meeting: an intense experience

After you’ve been tormented by eczema your entire life, and always avoided talking about your embarrassing condition, and dealt with doctors whose solution is to prescribe more steroids and expect you to go away happy, what is it like to spend two days in the company of some of the world’s leading eczema experts, talking about nothing else?

It’s pretty intense, I found out last weekend at the HOME (Harmonising Outcome Measures for Eczema) meeting in San Diego, California, where I and four other patient representatives helped clinicians and pharma reps from the US, UK, Germany, Japan, Brazil and other countries define how eczema severity should be characterized in clinical trials.

I’ll cover the technical details in a later post. Right now I just want to describe the experience.

I had been invited by Julie Block of the National Eczema Association. She introduced me to Gil Yosipovitch, Jon Hanifin and others. My initial feeling was one of awe. Many years ago I realized that scientists were actually studying itch and eczema when I read a New York Times article about Yosipovitch’s work. Now here I was on Saturday sitting with him and Block, eating fish tacos and getting my balding head sunburned.

And  then Hanifin walked by. He developed the original criteria, now used worldwide, for diagnosing eczema in the clinic. In the conference room, was that Eric Simpson of Oregon Health Sciences University? And Hywel Williams of the University of Nottingham, the UK leader in eczema research? It was surreal—the equivalent for a tennis fan, say, would be being in the same room as Roger Federer, Rafael Nadal, Andy Murray and the Williams sisters.

Also present along with me were several other patient representatives, three of whom either had eczema themselves and one who was the father of two affected children. Among them were Stephanie Merhand, founder of l’Assocation Francaise de l’Eczema (from Toulouse, France) and Rosemary Humphreys from the National Eczema Society (in the UK).

At first, it was a bit strange to meet people with whom you have nothing in common but a medical condition, but over the course of the two days I came to realize that it was not so much the eczema we shared but similar life experiences: the days and nights of itch, the social anguish.

During a short car ride, Tim Burton (a UK patient) and I traded stories about the various pharmaceuticals we’d inflicted on ourselves. It was hilarious. I’d given up on Protopic because it burned so badly. Tim uses it on his face. “It’s like holding your face to a three-burner fire for a couple weeks, but it eventually stops,” he said. Sounds like fun! I informed him that the best way to take prednisone was as an injection in the buttock.

In the working sessions I had cognitive dissonance hearing my condition discussed openly and unemotionally. I’ve spent nights tearing with my nails at scalp, my arms, my feet. I’ve endured, as anyone with chronic eczema does, the social pain of high school and university, the outings and activities missed, the relationships that never happened. Eczema is something that makes me want to hide in the basement. And here were people calmly displaying Powerpoint slides and droning on like it was a graduate seminar in statistics or comparative literature.

The jargon really was incredible. In casual conversation you were supposed to know what “xerosis,” “oedema,” “erythema,” and other words meant. You were supposed to be familiar with the acronyms for what seemed like fifty different clinical techniques. You were supposed to know the difference between “signs” and “symptoms,” which turned out not to be so clear-cut.

At one point I was asked what I thought about a topic they’d been discussing for fifteen minutes. I had to admit I hadn’t understood a word. It felt a bit like being a laboratory rat listening to scientists describe experiments they’d done on you.

That is why we patients were invited—to humanize things. “You might not realize it, but you are changing the tone of the session just by being here,” Roberto Takaoka, a dermatologist from Brazil, told me. Several of the presenters opened their talks by showing pictures of children or adult patients and reminding everyone that we were doing this for the patients. Apparently many doctors tend to “treat the disease, not the patient” and meetings without patients can become even more abstract and academic. Rosemary Humphreys told me that it she was on a crusade to get scientists to use the word “patient” instead of “subject”—“I’m a linguist and I know what the difference means,” she said.

At the same time, I remarked that we patients were treated as equals by the academics at this meeting. And everyone was committed and attentive and sincere. If anyone was checking their iPhone it was me. That says something.

As time went on, I realized that I was surrounded by some of the world’s top dermatologists and could get free consultations for myself and my kids just by asking. For example, if your daughter says that Cerave (a ceramide cream) is burning her cracked hands, you can get the clinical benefit of the cream by first rubbing her hands with olive or safflower oil, than applying Cerave, and then putting Vaseline on the cracks. And apparently 3M has a great new surgical tape that sticks to anything but doesn’t hurt the skin when you peel it off. You can use it like a Band-Aid on greasy skin.

It was sobering to know that after having gone to this meeting I now know as much as most people on Earth about the state of eczema therapy at the moment and in the near future. There are no miracle cures in the offing. But there are many intelligent, motivated doctors and scientists working on our behalf to make things better. Not as many as there should be, and they are not funded nearly well enough. We need to get involved to let them know how important this work is and to make sure they get the support they need.

Small study suggests anti-itch "hydrogel" effective

A small study of an anti-itch "hydrogel" conducted in North Carolina showed promising results, according to a report in the dermatology journal Cutis.

The hydrogel would be an alternative to topical steroids.

I couldn't find any information online about the active ingredient in the hydrogel, "Atapro" or R047-26 in the NIH database. Atapro is a product of Oculus Innovative Sciences, Inc. It would seem to make sense for a company to keep the active ingredient confidential in the early stages--maybe they will need to modify its chemical structure and they don't want their competitors to know what they're working with. But on the other hand, I was easily able to find out the structure of some of Anacor's compounds which are in phase 2 trials.

More than anything, this report reveals how little I know about clinical trials. The study only included 17 subjects, and I'd expect half of them to be controls, so only 8 people were using the product. About seven of the subjects experienced a decrease in itchiness over the trial period. The study would seem to be on the small end of "phase 1," in which the main point is to screen for safety. But there was no explicit mention of what phase the trial might be.

The study details are behind a paywall so I can't find out whether the author had any conflicts of interest. All in all, rather mysterious!

Hot pepper: the devil incarnate

After I eat food containing hot pepper, sweat beads my brow. Then, for a period lasting 30 minutes to a few hours later, I feel intensely itchy. I find cayenne is the worst--if I accidentally eat some during the day, I wake up scratching at night. But why?

In a recent post on the National Eczema Association website I explored allergy testing for eczema. Although onset is rapid, I wouldn't classify my reaction to hot pepper as an allergy. My symptoms are typical, except for the itchiness. And there is a well-known molecular explanation for how hot pepper gives you a burning, painful sensation, especially when you get some on your skin.

The active ingredient in pepper is a molecule called capsaicin. According to Wikipedia,

The burning and painful sensations associated with capsaicin result from its chemical interaction with sensory neurons. Capsaicin, as a member of the vanilloid family, binds to a receptor called the vanilloid receptor subtype 1 (VR1)... By binding to the VR1 receptor, the capsaicin molecule produces the same sensation that excessive heat or abrasive damage would cause, explaining why the spiciness of capsaicin is described as a burning sensation.

...Essentially, the body inflames tissues as if it has undergone a burn or abrasion and the resulting inflammation can cause tissue damage in cases of extreme exposure, as is the case for many substances that cause the body to trigger an inflammatory response.

I'd assume that when you eat hot pepper, you don't break down capsaicin; instead, most of it gets distributed all over your body, where it makes you feel hot, and triggers symptoms of inflammation. Great! The pepper-induced inflammation is likely generating signals in neurons that carry itch sensation to the brain.

But there's no explicit documentation of this in the scientific literature. When I searched for research connecting capsaicin and eczema on PubMed, the NIH archive, I found virtually nothing.

Instead, I was intrigued to discover on Wikipedia, PubMed, and the internet in general that capsaicin, far from being fingered as an evil trigger of eczema, is often touted as a TREATMENT for eczema. There are capsaicin-containing creams that you are supposed to rub on your skin to relieve itch. The theory, I guess, is that the burning pain overwhelms the itch neurons. I get that.

Unfortunately you're not supposed to rub capsaicin on open wounds. And with eczema, your skin always has open wounds. Even worse, the one clinical study I found showed that capsaicin cream relieved itch only for people who did not suffer from atopic dermatitis. Capsaicin appears to control itch that is caused by histamine; but chronic eczema itch is not caused by histamine, and so topical capsaicin does nothing for it.

In short, if you have eczema, hot pepper is not your friend, in any form. I love my hot sauce, but I can only look on it as a vice, not a virtue.

Scientists claim electroacupuncture relieves itch

"Electroacupuncture" is more effective than a common antihistamine pill for relieving allergic itch, researchers report in a small-scale study published recently in Allergy, the European Journal of Allergy and Clinical Immunology.

In electroacupuncture, two needles are inserted at classical acupuncture points, and a signal generator sends a low-frequency electrical current from one needle to the other. Whether electroacupuncture works is controversial.

The researchers, mostly Germans, led by Florian Pfab, a visiting professor at Harvard Medical School, compared electroacupuncture with the antihistamine cetirizine, and with placebo acupuncture and antihistamine, in a group of 20 patients. The patients had tested positive for type 1 hypersensitivity itch reaction to various allergens--and it was these allergens that the patients were skin-pricked with before the treatments. The scientists then asked the patients to rate how itchy they felt. The conclusion was that true  acupuncture applied during an itchy period was the most effective method. (They also tested acupuncture as a preventive measure before allergen prick--the effect was much weaker.)

Let's consider various aspects of the paper.

The very small group size. There were actually seven different subgroups out of 19 patients (one was dropped because he/she didn't feel itchy) so the subgroups were only two or three people apiece. That's way too small to produce definitive results.

Electroacupuncture is kinda weird. Were the researchers even performing it properly? I can't tell from the paper. They say they were using this device. It appears to have four separate channels--is that four separate pairs of electrodes? I used to be an electrical engineer [geek warning], and the way you set up a circuit is that one lead is the ground, and the other one is the signal. If you have four channels do you have one ground and three signals? Or four grounds and four signals? It would seem pretty dumb to connect more than one ground or signal to the body at the same time. Then you'd have current flowing all over your skin in an unpredictable pattern. I was once working in a lab where people were measuring the electrical activity of bird brains, and one of the postdoctoral researchers didn't even know what voltage was. So I'm not convinced these guys know what they're doing.

They're only treating allergic itch applied by a skin prick. If you're allergic to dust mites, you breathe it in and then you're itchy all over. You don't get chronic eczema from pinpoint contact with these allergens.

Beating antihistamine as an itch treatment for eczema doesn't mean much. In my experience antihistamines don't do anything to relieve itch.

So here's the killer: say they do know what they're doing, and the results are good. Is this a practical treatment method? I'd say no. It would only relieve the itch while the electroacupuncture was being done. The paper itself says so. Anyone with chronic eczema knows that you get it all over your body and you get it all the time. You can't just run off to the acupuncturist when the itch on your feet is driving you nuts, because ten minutes after the appointment, your scalp or the backs of your hands will be flaring up. You might as well pinch your skin, creating pain to dull the itch.

OK, I've been critical enough. It is interesting to see that acupuncture is being taken seriously, but scarce research funding should go to more useful projects.

Eczema is not the only rash

Eczema is not the only rash.

Of course I know this, but last week I got a vivid reminder when both my kids came down with different rashes at the same time.

Shmoop had had a fever that peaked at 104F a few days before. Then, on the day before our planned trip to Lake Tahoe (naturally), he suddenly became itchy all over. Wherever he scratched, a red wheal appeared, with raised white welts. Soon he was covered head to toe in something that a cartoonist might have drawn to caricature a sick kid.

Voov, the one who has eczema, developed pinpoint dark red speckles on her arms and cheeks.

I made same-day appointments, took time off work, and drove the kids to the doctor. In the waiting room, as the kids played with toys they found there, I became aware once again that there is probably no better place than a pediatric waiting room to expose yourself to virulent pathogens.

Shmoop had the first appointment. The doctor looked him over and said that the rash was probably the result of his having a fever beforehand. Kids apparently are prone to getting rashes after fevers. Shmoop probably wasn't contagious...anymore. She prescribed Atarax (hydroxyzine HCl) as an anti-itch, and prednisolone if that didn't work. (We'd tried children's Benadryl without success.)

As I type this, I realize that I didn't check out all the side effects of Atarax. It's also used "for the short-term treatment of nervousness and tension that may occur with certain mental/mood disorders (e.g., anxiety, dementia)." It worked immediately to bring the rash down, which was great. It's also great that we got him off it asap. The idea of your kid being on a mood medication is disturbing.

Voov had the second appointment, with a different doctor. "That's hand, foot, and mouth," she announced confidently without even looking closely at the rash. As it turns out, it wasn't. Upon examining it, she said she didn't know what it was, but that Benadryl would probably work. And that kids get all kinds of rashes and this one didn't look like anything serious.

This sounded fine to me. I worry less than I should about things, to make up for my wife, Hidden B, worrying more than she should. Voov's rash did clear up, after briefly spreading to her face.

Through this experience I realized why people who see your eczema often react the way they do: avoid contact, pull their kids away from yours. They don't know what's causing the rash, or if it's contagious.

And neither do doctors. Pediatricians, especially, often have no idea why your kid is sick. And doctors in general often have no idea what is causing a skin problem for anyone, adult or child. The combination of kid & rash makes for maximum uncertainty. Eczema is not the only rash, nor the only rash of which doctors don't know the cause or cure. This is something we have to accept, difficult as it is, as the current state of medicine.

Habit reversal works for scalp itching

Training myself in habit-reversal, to replace compulsive scratching with more socially acceptable behavior, has not been easy.

It's hard because you have to be on all the time. You have to intercept those impulses to scratch before the action happens. Of course the goal is to make the behavior automatic, so you don't have to consciously think about it, but you do at the start.

And I fail all the time. I'll just discover my hand doing something it's not supposed to, and I'll have to yank it away. Fortunately the inventors of habit-reversal acknowledge that you'll fail. You just have to try your best.

I haven't quantified the results yet but I do see one significant improvement. I've been able to stop scratching my scalp, especially on the days that I wash my hair with shampoo (tar shampoo, naturally). Just a few weeks ago, my scalp was covered with dry skin and little scabs that I was picking at. It's annoying to feel itchy all the time, and everyone knows how embarrassing dandruff is.

But, in this completely unscientific experiment lacking any sort of control, I observe that I am hardly scratching my head at all any more. To some extent, I have broken the itch-scratch cycle for this specific behavior. And that's great.

However, elsewhere on my body, particularly the backs of my knees, I've got red and inflamed skin from scratching that I haven't brought under control. It's like a different type of itch, although there's certainly a psychological contribution.

My ability to implement habit-reversal is strongest in the morning. Later in the day--especially after I get back from work and the circus of getting the kids through bathtime and into bed begins--the stress mounts and I find myself scratching various places vigorously. (Not the scalp though.) I'd guess that's because whatever part of my brain I need to control scratching is busy thinking about how to keep the kids disciplined instead. Or it could just be that the urge to scratch gets brought on by stress, and there's little more stressful than fighting with your two- and five-year olds to brush their damn teeth and get into the tub and stop trying to drown your sister and stop whining and crying about how she's got your rubber dolphin, etc.

I need some stress-reduction technique--something more powerful than the beer I open after the kids are in bed.

Itch, and scratch relief, depends where it is on the body

A new study [media summary] by itch guru Gil Yosipovitch and colleagues at Wake Forest University has shown that the intensity of itch, and the pleasure of relieving it by scratching, depends on the precise location on the body that a standard itch stimulus is applied.

In standard studies of itch (and, one would presume, creams and ointments designed to relieve it) the usual site of focus has been the underside of the forearm. But Yosipovitch and colleagues, who compared itch on the forearm, the back (slightly to one side of the spine, near the middle) and the ankle, find that itch is sensed more intensely on both ankle and back, and the pleasure of scratching lasts longer on the ankle--even after the itch has dropped off--than on the forearm.

They used "cowhage spicules," which I think are akin to nettle spines, to cause the itch, and a standard laboratory scratching brush to relieve it in 18 volunteers. The paper, which is open-access, doesn't mention whether any of the volunteers had eczema. This matters, I think, because you'd expect eczema patients to perceive and respond to itch differently than "normal" people.

The authors, in their discussion section, speculate on why itch intensity and scratch relief differ across the body. They discuss various types of nerve fibers that might be responsible, but come to no conclusion. Really the paper just poses a question: why are these differences there? And we could expect, in following work, that they might narrow the answer down to the presence or absence of nerve types. It's clear that the mechanism of itch and relief is far from understood.

[It occurred to me later that maybe this research points to the need for different anti-itch treatments for different parts of the body. Whether they work or not, I can imagine companies claiming that various ointments and creams are optimized for your hands or whatever.]

More on habit-reversal for eczema treatment

After meeting Mei and CK Bridgett on Twitter I have done a little bit of research on the "habit-reversal" technique Bridgett is so keen on for eczema patients.

I like the idea very much. Through my entire life the only attitude I have gotten from doctors (GPs and dermatologists) about my eczema is that there's nothing you can do for the patient except prescribe topical corticosteroids. Nobody has ever addressed nervous or compulsive behavior, which is certainly a component.

In his website/book, Bridgett, a psychiatrist, refers to a number of the original papers on the habit-reversal technique. I printed them out and read them, and you can too.

Behavioural treatment of scratching in patients with atopic dermatitis (1986) 

A 17-patient study, finding that behavioral change (clenching hand into fist, or grasping an object) plus hydrocortisone cream improves skin quality twice as much as hydrocortisone cream alone (but did not affect bouts of intense itchiness).

The effect of combined topical steroids and habit-reversal treatment in patients with atopic dermatitis (1989) 

A 45-patient study, where behavior training (fist-clenching &/or pinching the itchy area to cause pain) + steroid reduced scratching by 90% compared with 75% for steroid alone.

Habit reversal: a turning point in the treatment of atopic dermatitis (1993)

A conversational speech by Peter Noren, very readable, in which he explains how parents can apply the technique to children. Noren rightly laments the poor attitude of many doctors and insists on a positive outlook by both doctor and patient, and deeper involvement by the doctor.

I have to say that these studies are pretty small in size. I wonder whether anyone's ever conducted a study of, say, 200 or 1000 patients, which would give you more confidence in the results. Soon I hope to conduct a very small study (one patient: me) and publish the results on this blog. What's stopping me? I have to get psyched up to make little marks on a piece of paper each time I scratch, and to poke my skin with my fingernail in public.

Last year I spoke to Martin Steinhoff about his plans for an integrated itch center at the University of California, San Francisco (where I work). At the time Steinhoff did not mention behavioral coaching, but I'd like to ask whether he would consider a psychiatrist or behavioral coach as an essential member of such a center.

"Me no like carrots"/Protein fragment could be target for treatment of eczema itch

Saturday--double swimming lessons again. We're getting dried off afterward, me and the two kids, and in the men's changing room they're getting some lessons in anatomy as a number of hirsute and moderately obese men shower. One of them lathers himself head to toe with soap. I kid you not, I have never seen someone so completely covered with suds, as if he'd been dipped like a sheep. What must it be like to be able to use soap like that without consequences? For me and Voov soap is something to be used sparingly if at all.

Voov, as you may know, has been on a restricted diet. For about a year or so she has eaten about eight things (others are allowed but not always available as organic produce--e.g. asparagus). So three weeks ago we were given the green light to start trying a small roster of new foods. The first candidate was carrots, which we chose for their nutritional punch. We were excited as we placed the first plate of chopped, boiled carrots in front of Voov. She picked up a piece and stuck it in her mouth.

"Me no like them. Me not eat them," she said.

And so it proved, after we offered them every day for two weeks: she doesn't like carrots. Fortunately she liked the next two items, apple and pork; we are on week two of pork and next week on to something else.

Hidden B went away last week to a veterinary conference and chose the opportunity to wean Voov off breastfeeding. That's two and a quarter years Voov has been breastfed (Hidden B is ecstatic to be able to eat dairy again) and I hope that her eczema and potential asthma are less severe because of it. I myself was fed on formula pretty much from birth. My mother says that that was what mothers were told to do in those days. I suspect but cannot prove that my food-related eczema has been nastier because of the formula--Hidden B tells me the opinion of doctors at her vet practice (now there's authority for you) is that it's better for kids to be exposed to tiny amounts of allergens through their mothers' milk, rather than be completely deprived of exposure and then hit all at once when they eat real food.

* * * 

I thought I would write a bit about a recent paper in the Journal of Neuroscience. Scientists at Yale and Johns Hopkins have found, in experiments with human volunteers, that BAM8-22, a common protein fragment found in the body can produce itch by a neural pathway independent of histamine.

Histamine is a small molecule that some foods (pickles, aged cheese, red wine) contain a lot of; it is also stored in white blood cells called mast cells that release it in response to food allergies. There are neurons with receptors for histamine, and these neurons send itch impulses to the central nervous system. This is why I scratch like a demented monkey after I eat Parmigiano-Reggiano.

But it is also known that there are other neural pathways for itch; researchers don't know many details yet. For this new paper, the scientists showed that when they poked volunteers' forearms with little plant spines coated with BAM8-22, the forearms got itchy, even if they had been rubbed with antihistamine cream beforehand.

The plant spines are called "cowhage spicules." Cowhage is famous for making people itchy, and it has tiny spines covered with an enzyme that triggers itch. A group of scientists has decided that cowhage spicules are the perfect instruments for applying chemicals that induce itch. Is that weird or what? Apparently if you autoclave (treat at high temperature & pressure) the spicules for an hour, the original enzyme is destroyed and the spicules don't make you itchy.

So the upshot of this new research is that BAM8-22 and the receptor it interacts with (its identity is known too) could be a major pathway by which chronic itch signals, like those that operate in eczema, are sent to the central nervous system. It's possible that pharmacologists may now search for drugs that inactivate the BAM8-22 receptor, and conduct clinical trials to find out whether the drugs relieve chronic itch. My guess is that such drugs could emerge in a decade or so, if a pharma company--or startup--decides that the pathway could be profitable.

Scientists: We want you to stop the itch

On Twitter I heard about this survey that the University of Nottingham is doing. You can do it too!...it's not exactly a big investment of effort. They ask you what you would like to learn from eczema research. I'd assume that they are hoping to get some interesting questions, like "how do food allergies develop in children aged 1-3" or "what are the genetic defects in structural proteins in the skin that are most strongly linked to adult eczema."

As a relatively well-educated guy with an interest in eczema, I was interested to step outside my skin, so to speak, and watch as I entered in my questions in the survey--I didn't think too hard, so they were my knee-jerk reactions, what I want to know at a primal level:

1. how can I stop scratching?
2. how can I stop scratching at night?
3. how can I stop my scratched skin from getting infected?

Not exactly PhD material, eh?

But I think this illustrates what patients want from researchers. We are not interested in the science. We want results. And there's basically one thing we want: we want the itch to stop. If the itch stops, the scratching stops, and then there's much less risk of infection. So our challenge to researchers is "figure out what's causing the itch in eczema. Then figure out how to stop it."

I do have to say that eczema is a fascinating condition, though, when you start to read the scientific literature. I just wish my interest in it was purely intellectual.

Julie Block at the NEA asked me to write a brief research summary for the next e-newsletter, about a new discovery in itch pathways. When the newsletter comes out I'll comment on it.

Managing eczema on your scalp

Scalp eczema doesn’t get much press, but a lot of us live with the problem every day. Me, for example: I own virtually no dark-colored tops, because a snow of skin flakes shows up within seconds. I comb my hair, or what’s left of it (hey, I’m a 40-year-old man) not to straighten tangles, but to clear up any rogue scabs. And I’ve had to develop my own regimen for scalp care because nobody ever handed me a pamphlet.

Eczema on your scalp is the same as it is everywhere else, except for two complications.

1. most people have hair on their heads, which makes it difficult and unsightly to apply thick creams and ointments
2. it’s right out in the open where everyone can see. You can hide it only with long hair, and long hair makes it difficult to treat the scalp.

So how should we treat it? Pretty much as we do “normal” eczema. You have to clear up infection with antiseptics; reduce the inflammation; and moisturize as much as possible. And any concerns about how your hair looks are secondary. You’re not Fabio or Catherine Zeta-Jones, so get over it.

I keep my hair very short. I use a #2 buzzer on my head. I can get away with this because I’m a man in a job where hairstyle doesn’t matter. The #2 keeps my hair short enough that I can apply steroid creams or ointments but long enough that other people can’t see my sores or scabs easily.

Steroid ointments (say, fluocinonide 0.05%, my “strong” option) come with warnings about folliculitis. You’d think this would be a problem on the scalp, but I haven’t found it to be. I try to use it sparingly, though.

Many shampoos and conditioners brag about their moisturizing properties, but they refer to what they do for your hair, not your scalp. In my experience, both shampoos and conditioners have detergents that dry out my scalp to a painful degree, and fragrances that irritate it. What to do?

Go fragrance-free, for a start. Or as fragrance-free as you can; medicated shampoos seem all to come with masking fragrances to hide their smell. Options that I’m aware of are coal tar (say, T-Gel, Zetar, Polytar); zinc pyrithione (e.g. Head and Shoulders, Selsun Blue); and iodine (Betadine). I spent several years in the UK where Betadine is available as a shampoo. I haven’t seen it as a shampoo in North America, but Hidden B, who’s a veterinarian, has a bottle of it that she uses on dogs.

Let’s tackle these one at a time, and ignore any qualms about weird smells.

Zinc pyrithione (http://en.wikipedia.org/wiki/Zinc_pyrithione) is an antimicrobial that kills bacteria and fungi. It doesn’t work for me. This is probably because my primary problem is in the skin barrier, not a secondary infection. I may also have infections that it does or doesn’t clear up.

I remember Betadine being relatively pleasant, and leaving terrible brown stains on everything. I think it worked well because it didn’t have a very strong detergent component, and was much more a medical than a cosmetic product. I’m all in favor of this. Hey, maybe I should borrow some from Hidden B. Again, the active ingredient in Betadine is iodine, because it’s a broad-spectrum antimicrobial.

Coal tar works for me, but only in the strongest formulation. I use T-Gel Extra Strength and Polytar. In the past these have been difficult to find where I live in California, and I have bought them online from a Canadian source, but recently I’ve seen tar shampoos on the shelf in pharmacies here.

Coal tar’s a bit of an oddity. It is not a pure substance that can be easily quantified. It is a mixture of apparently up to 20,000 organic compounds, and it’s a traditional treatment for scaling skin diseases that reduces inflammation and itch and kills microbes. Which of the 20,000 compounds are doing what is anyone’s guess, and there have occasionally been claims that coal tar causes cancer. I don’t take these seriously because there has never been a conclusive study and if there were a large risk we’d know about it by now. (See a recent study here.) I think that it matters very much which brand of coal tar you use, because different brands are probably from different sources and contain different stuff.

What I DO take seriously is the increased sensitivity to UV that comes with using tar shampoo. The days I use it, I often find I get lightly sunburned on my face. Sunburn = cancer risk. So if I were going to spend a day outside, I’d be careful not to use tar shampoo that morning.

The more I learn about eczema, though, the more I understand that we might not want to use a strong antiseptic on our head too much. We probably have a flora of beneficial bacteria and fungi living on our scalps, and we ought to keep them healthy while killing off the S. aureus etc. that cause us so much grief.

Lastly, for moisturizing: every morning, and after I shower (which I do not do every day), I rub jojoba oil into my scalp. Jojoba’s a very light oil, and it doesn’t make my head too greasy. I think grapeseed or walnut oil would also do the job, but olive oil would be too heavy. Sometimes, when I have really dry skin, I have resorted to rubbing Eucerin into my scalp, but this is a bit gross.

What are your solutions to cooling itch and moisturizing on your scalp? I’d be interested to hear them.

Yosipovitch on itch clinics

Last Thursday I spoke to Gil Yosipovitch, an eminent dermatologist and itch expert at Wake Forest University. I called him because Martin Steinhoff said Yosipovitch ran the only itch clinic in the United States, and I wanted to learn how such a clinic operates.

The only problem: Yosipovitch does not run an itch clinic. There are NO itch clinics in the United States. "I very much believe it's the future and there should be many of them," he says. He's happy that Steinhoff is establishing one. The centers in Germany are the model; apparently a colleague is also starting one in Singapore.

Y believes there are a couple barriers to itch clinics getting started in the US. The major one is insurance companies and the current system for reimbursement; doctors have much more incentive to do basic treatment like wart removal than they do to care for patients with chronic conditions who require regular monitoring. Also, he says, to establish a clinic, a department chair (at a hospital or university) has to put money into it. That means leadership, and no-one except for Steinhoff has shown that leadership.

Y says that he likes Steinhoff's plan of directing a clinic with a number of resident doctors and a nurse practitioner who keeps in touch with patients through an online forum. In fact, Y himself once ran such a forum, called "Living with Itch" (if I understand correctly, it got folded into the International Forum for the Study of Itch website, but I can't find a link to old postings). The problem was that the site, on which patients shared their "anguish, frustration, and practical ideas," was quickly "hacked," in Y's words--possibly not hacked, but overwhelmed with spam from quacks advertising miracle cures like some garlic diet. So the forum became useless and was abandoned. Y thinks an online patient forum could work if someone was dedicated to the web technology side, and ensuring that only authorized patients could use it. (Also, there are "HIPAA," or medical privacy, issues, he says; presumably his former site managed to solve them.)

A point Y insisted on making was that itch should be treated as a disease, not a symptom. It's a major issue. He sees many parallels between itch and pain; itch is now where chronic pain was thirty years ago.

Y also thinks that eczema patients should look to psoriasis as a disease whose patients have been successful in setting up support groups and activism for funding. "But [itch clinics] needsencouragement from the upper levels," he says, meaning the NIH and legislators who have the power to make insurance companies change the incentive model.

Y is a fan of the National Eczema Association. "They're providing a lot of support to atopics," he says. He was able to leverage a small NEA grant into a large NIH one (that's how science funding works--a granting agency will only give you money if someone else has already given you money). I suppose I should be happy that he likes the NEA. He said he only decided to talk to me because I was raising money for them.

In my next post I'll talk about Y's position on alternative medicine. My next post, by the way, may be my last for some time. I need to resolve this trouble I've been having with my neck, and the less time I spend at a computer the better, for the moment.

Up next, Gil Yosipovitch

Today I spoke with Gil Yosipovitch on the phone--he was at his home in North Carolina. It was a good conversation and I learned quite a bit that I will share with you in the near future. I'll be considering it in two parts: one about traditional Western medicine and one about Gil's opinion of alternative methods, which might surprise you. He is concerned that I not misrepresent his views on that subject so I'll be running his quotes by him first.

I wish I could write more today but recently I have been short of time. (My physiotherapist has given me home exercises to do that take the time I'd set aside for blogging.) Best regards to all.

The "itch receptor"

Another thing for me to be excited about: this Thursday, I get to talk to Gil Yosipovitch, the "Godfather of Itch," who runs a clinic at Wake Forest University and founded the International Forum for the Study of Itch. (I made him an offer he couldn't refuse.) If you have any questions for him, please ask and I will pass them along. Myself, I just want to get an idea of how his clinic operates, and find out why there aren't more of them.

Also, whether he envisions any pharmaceutical cures for itch appearing soon. Martin Steinhoff scribbled a list of possible targets in the itch pathway that one might like to shut down to reduce or eliminate itch. Here's what he wrote down, before I distracted him with another question:

• GABA
• GRP
• Proteases

The "GRP" rang a bell in my memory so I looked it up. It stands for "gastrin-releasing peptide," whatever that is. What's important is that in 2007, two scientists at Washington University in St. Louis discovered that a receptor for GRP is a major gate for itch nerve impulses in the spinal cord, at least in mice. (And basic neurology isn't different in mice and humans.) I could be wrong, but I think that GRP receptor is still the prime suspect.

The scientists were able to do their experiments because they had developed a strain of mice without GRP receptors. These mice were much less likely to scratch themselves when their skin was injected with substances known to induce itch. And in normal mice, a compound that inhibits GRP receptors greatly reduced scratching behavior.

This isn't exactly breaking news, but it is good for me to know as I explore "itch centers" in the US and around the world.

* * * 

A wee  bit of business news: a small company in Seattle, recently acquired by Bristol-Myers Squibb, is developing an anti-IL-31 antibody which is now in preclinical trials for atopic dermatitis. (Now, what does IL-31 do? I always get confused by these IL-X things. It is apparently produced by Th2 cells and has something to do with inflammation.

Steinhoff's 2006 itch review fascinating, useful

So in advance of meeting Martin Steinhoff, I've been reading a couple of his review papers on itch research. I am well used to reading scientific papers--the slog through the jargon and hard-to-grasp concepts. It's liberating to read a paper about a subject that touches you personally, instead of one about some anonymous molecule with an acronym like ADF46-PGL (I made that up) that is somehow linked to something that might be useful to someone someday. With Steinhoff's itch reviews, there's a fair amount of jargon, yes, but I can relate to virtually every paragraph, and I pay attention because I hope to learn tips that I can apply to my daily life. For example:

Recent results suggest that noxious heat stimuli and scratching produce a stronger itch inhibition than do noxious cold stimuli.

I've always found that a cold pack from the freezer helped kill an itch, at least for a while. Maybe I'll try a hot pack next time.

The main point I take away from the review I've just finished is that itch research is unfortunately far from being able to produce a good target for anti-itch drugs. Decades, maybe--although that review is from 2006, so the current state-of-the-art may be much further ahead; you never know. There's always the hope that an already-approved drug might turn out to have a beneficial side effect against itch. Certainly, one thing that's been discovered is that pain inhibits itch--this was discovered partly because painkiller drugs tend to make people itchy.

A major recent development is that scientists have identified specific neurons that carry itch from the skin to the spinal cord and then to the thalamus in the brain. Some of these neurons are called "histamine-sensitive itch fibers," or "pruriceptors," although there must be other itch fibers because there are many more molecules besides histamine that have been shown to induce itch.

This diversity of primary afferent "itch fibers" would nicely fit to the different submodalities of pruritis ("itch quality") observed in patients.

Exactly! Um...that is, I know I experience different kinds of itch. There's the tickly kind, like when an ant is crawling on my neck; there's a distinct itch I get from a small, active patch of eczema, on my foot, say; and there's the full-on-paroxysm that I occasionally wake up with after I've had the poor judgement to drink eggnog or eat something laced with cayenne pepper. And there are others.

As I just mentioned, there are many more itch-inducing molecules besides histamine. Steinhoff thinks that researchers have focused too much on histamine. Table 1 lists 16 different types of molecules (he calls it the "itching army") that represent the major culprits. In eczema, acetylcholine and mu-opioids appear to be more significant than the other molecules.

On to the next review, which has more gems, I'm sure.

The itch roundtable

When I heard back in December about the NIAMS (division of the NIH) itch roundtable--a discussion that involved the NEA's CEO Julie Block, a number of NIAMS directors, and a larger number of active itch researchers--I was excited that the meeting summary would be made public. I don't know why it is, but in the media you hear about eczema much more from the allergy perspective, or as if it's a cosmetic issue with dry skin, rather than the reality for a lot of us: chronic itch. If we could control the itch, we'd be less at risk of infection, we wouldn't prolong our flares, and possibly most importantly, we'd have more self-respect.

It's hard to feel like you're a grown-up when your self-control in this one dimension is no better than a three-year-old's.

The summary of the itch roundtable was recently put online (at the link above). I got there by following a link in the email the NEA sent all its members. At the end of the summary there's a long list of the participants. I plan to check out what research they're all doing.

Two things jumped out at me from the summary. The first thing is that itch research is building on the much more established field of pain research. It appears well-known that certain types of pain can inhibit itch. (And, in fact, that the same type of neuron carries both impulses.) As an eczema patient I know this very well first-hand. In fact, sometimes scratching feels good precisely because it hurts, and seems to spread a cool blanket of pain over the burning itch.

I've got a rather silly story to relate about this. When I was a teenager I discovered this pain-itch connection, and I happened to have an itchy scalp at the time. I found that a good way to relieve the itch was to pull out small clumps of hair. Ouch! you say. Ouch is right. Felt great. I did this for about a week.

The problem was that I then developed an extremely nasty case of something like eczema herpeticum--little fluid-filled blisters that spread all over my body and threatened to leave me looking sandblasted for life. Fortunately my parents took me to a doctor who prescribed some magical cream that completely reversed the infection. I have no idea what the cream was, only that it worked, and that my parents said it was "very strong." It must have been an antibiotic of some kind.

Dr. Sib, if she still reads this blog--will remember this episode. During the recovery period, I drove her crazy by picking at my scabs.

So don't try that at home.

The second thing that jumped out at me from the summary was that, although mice are the standard laboratory model animal for many human diseases, there are several key reasons why itch in mice and humans is substantially different at the molecular level and at the level of the skin as an organ. Therefore, it's unlikely that a mouse model will be developed for human itch. To quote NIAMS:

• Itch- and pain-specific neurons and receptors identified in mouse models may not have the same distinct functions in humans.
• Structural differences in mouse and human epidermis may create differences in itch transduction, and downstream cellular activity (e.g., protease production).
• Overexpression of many cytokines in mice will induce non-specific itch, whereas the itch mechanisms in humans appear to be more complex.
• Current mouse models correspond to acute itch, whereas clinical itch tends to be chronic.
• Linking itch mechanisms from animal models to the spectrum of itch descriptions in human patient populations can be challenging, because some behaviors in animal models, such as scratching, licking, and biting that are attributed to the condition may be unrelated to it.

These complications with animal models will slow itch research. But pain research has faced similar hurdles, and is more advanced as a field, so we can hope the scientists can piggyback their work on existing pain research.