The relentless itch

beginning, perhaps, as a little tickle, hardly noticeable.

Maybe you’re in an important meeting and you don’t want to fidget. Or maybe your hands are full. So you try to ignore it, but the sensation grows -- an irritating, niggling feeling that gradually occupies more and more of your attention.

Finally, you can’t take it any longer.

You have to scratch the itch.

Itching is as fundamental a sensation as pain and hunger, one we share with other creatures: “Every two-legged and four-legged animal itches and scratches,” says Dr. Gil Yosipovitch, a dermatologist at Wake Forest University Baptist Medical Center in Winston-Salem, N.C. Yet for such a seemingly simple sensation, it’s also surprisingly complicated.

Scientists have long wondered why pain -- for example, from scratching -- relieves an itch. They’ve searched for the nerves that send the itchy signal to the brain, and they’ve wondered what switches those nerves on and off.

And doctors and patients alike have wondered why the sensation can be so hard to expunge in those unfortunates who experience the extreme end of itching -- an itch that just won’t go away.

Today, a small group of dermatologists and neuroscientists are starting to look at the biological mechanisms that lie behind itching. As they do so, they are finding curious overlaps between itching and that different-seeming sensation, pain. Though sometimes pain is itching’s opposite, the latest findings are showing more and more similarities between the two.

And as they begin to understand the sensation’s biology, dermatologists -- including ones at the world’s only clinic dedicated entirely to the treatment of itch -- are developing new therapies for people who suffer the torment of chronically itchy hides.

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An unbearable sensation

For most people, itching is only a mild annoyance, relieved by a quick scratch or maybe some skin cream. For others, the itch stays, stays -- and stays.

“It starts like any other itch, like you’ve been bitten or something,” said David Hayes, a Los Angeles computer technician who has psoriasis, a noncontagious disease that causes skin inflammation, probably due to an overactive immune system. “But then it keeps on going. You’ve got to scratch it, and you’ve got to keep scratching until you’re almost bleeding before it stops.”

For people like Hayes with psoriasis, or for others with the skin allergy eczema, the sensation can be unbearable. “Itching is the worst thing,” says Susan Lipworth of Bloomfield Hills, Mich., who has had eczema for 13 years. “It never stops -- it never stops -- it wears you down.”

Lipworth, who is also a board member of the National Eczema Assn., a patient advocacy group, says that scratching becomes so automatic, she even does it while sleeping. “I’m waking my husband up with my scratching,” she says.

An estimated 4.5 million adult Americans have psoriasis and 9 million have eczema, according to the American Academy of Dermatology, most tolerating long-term itch that doesn’t go away with scratching. Burn patients, and people with certain kinds of nerve damage, also often have severe itching -- as can people with liver and kidney diseases and some who are infected with HIV, due to the infection itself and the medicines they must take.

Such itches can erode a person’s mental health, experts now say.

Many studies have found that people with severe itching from psoriasis, eczema and kidney dialysis are more likely to be depressed than others. In a 1998 study published in the British Journal of Dermatology, for example, researchers from the University of Western Ontario in Canada reported that almost 10% of 217 patients with psoriasis had had suicidal thoughts.

For many people, the itchiness also prevents them from sleeping. In a study in 2002, Yosipovitch found that 84% of 102 eczema patients had trouble falling asleep due to itching.

Lack of sleep is a particular problem in children with eczema. (The condition affects more children than adults.) A 1995 study, conducted at the Maelor Hospital in Wrexham, United Kingdom, estimated that preschoolers with eczema lost an average of two hours of sleep per night, and that the deficit led to behavioral problems at school.

Rebecca Litke, a professor at Cal State Northridge, has a 12-year-old daughter with eczema. “My daughter, for the first eight years rarely slept through the night,” she says. That meant that Litke rarely did, either. “It has been awful,” she said. “For years you’re functioning on three or four hours a night.”

Lack of sleep due to itching can affect people’s physical health, Yosipovitch says. “It affects even mortality,” he says. Last year, a group of scientists lead by Ronald L. Pisoni at the Arbor Research Collaborative for Health in Ann Arbor, Mich., completed a study of almost 19,000 people over eight years who had itching due to kidney dialysis. They found that moderate to severe itching resulted in a 17% higher chance of dying, mostly linked to lack of sleep.

If an itch is, at best, slightly annoying, and, at worst, causes a 17% higher chance of dying, it may make one wonder why our species evolved the bothersome sensation at all.

Itching exists for a reason, says Dr. Jeffrey Bernhard, a dermatologist at the University of Massachusetts Medical School in Worcester, Mass.: It helps one detect when an enemy is mounting an assault. The body’s first line of defense is the skin, and itch is the alarm that tells us when something (for example, a tick or other insect) has penetrated that first line.

Itching, in turn, triggers a desire to scratch, so the tick or other unwelcome guest can be pulled out.

Of course, if a tick has burrowed deeply, one may have to gouge out a big chunk of skin to fully remove the parasite. Under normal circumstances, such gouging would be painful.

Conveniently, with an itch, the brain rewires itself so that the normally painful sensation of rough scratching feels pleasurable. We still feel the pain, says Dr. Martin Schmelz, a professor in the Clinic for Anesthesiology and Intensive Care at the University of Heidelberg in Germany. But somehow, when it’s accompanied by itch, our brains don’t interpret it the same way -- they let us perceive the damage to our skin as pleasurable.

The cycle of itching and scratching is generally useful, Schmelz says. The problem arises when there are no insects. Or when the itch isn’t satisfied by scratching but is made even worse -- the case, unfortunately, for most people suffering from chronic itch.

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Seesaw of itch, scratch

Studying this interplay between itch and scratch has lead to some strange findings.

For healthy people, the relationship between pain and itch is like a well-balanced seesaw. Increasing pain (for example, by scratching) decreases itch. Decreasing pain (for example, by taking the painkiller morphine) increases itch.

But in chronically itchy people, the seesaw is off balance. In the best-understood cases -- some liver diseases such as cirrhosis -- the liver begins to produce chemicals called opioids, natural substances similar to morphine. Like those who take morphine, the sufferer begins to itch.

Scientists used to have a simple explanation for the seesaw relationship between itch and pain. Itch, they thought, was just a mild form of pain -- when pain nerves were slightly stimulated, it felt itchy, but when they were strongly stimulated, it felt painful.

That’s why scratching relieves itch, they thought -- the same nerves couldn’t transmit both itch and pain at the same time.

But in 1997, Schmelz discovered distinct nerve cells in the skin that respond to itchy stimuli, and itch researchers revised their theories. They now believe that the sensations of itch and pain travel along separate pathways.

In cases of chronic itching, though, things go wrong. Some of the nerves that would normally transmit pain start to send itch signals instead. A 2004 study led by Schmelz, for example, found that people with eczema perceived pinpricks and electric shocks as itchy, not painful.

“The nerves are acting wacky,” Yosipovitch says.

In such cases, scratching doesn’t make the itch go away -- in fact, over the long run it can make people even more sensitive to itchy sensations. Repeated damage to the skin makes it grow thicker and sprout even more itch nerves.

Yet it’s hard to avoid scratching in response to an itch -- even when you know you’re doing yourself no favors. “I consider it almost an addiction,” said Diana Cordio, a human resources assistant in San Mateo, who has psoriasis. “Scratching the itch -- you know that it’s not helping you in any way. But there were some times I would have to break down, and get [finger]nails to skin, or whatever was handy, like a hairbrush.”

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Therapies on the horizon

It has been only about a decade since dermatologists started studying itch specifically. As they’ve come to understand some of its biological mechanisms, this has opened the door on new therapies.

Opioids have turned out to play an important role. Although some of them, such as morphine, are itch-promoting, scientists now know that others are itch-reducing. One now-common treatment for people who itch because of liver disease is to prevent the body’s own itch-promoting opioids from working, using drugs such as naloxone or naltrexone (also used to treat morphine overdose and alcoholism). Patients experience less itch -- the downside is they also experience more pain. They often find this preferable.

“I tell you, if I scratch till it hurts, it’s actually relief when it hurts,” says Rita Kirshner, a retiree in Chicago who has itched due to a liver condition for more than eight years. She started taking naltrexone this year and says it has helped her somewhat. “Right now I feel fine, so it’s hard to even imagine what [the itch] feels like.”

Other opioid-linked drugs are in the works. Last year, Yosipovitch tested one called butorphanol that is known to decrease sensitivity to itch-promoting opioids and increase sensitivity to itch-reducing ones. Butorphanol stopped the itch for the five patients he tested, all of whom hadn’t been able to find relief any other way, he says.

In yet another opioid-related approach, Japanese researchers at Toray Industries Inc., in Kanagawa, developed a drug called TRK-820 that mimics the action of itch-reducing opioids. They have found that TRK-820 is effective in reducing scratching in mice with eczema. In 2005, an international study of 144 patients with itching due to kidney dialysis found that TRK-820 significantly decreased itchiness, allowing the patients to get two or three full nights of sleep a week, rather than the zero or one night they had been getting.

Toray Industries has completed Phase III clinical trials in Japan, and in November, they filed a new drug application for TRK-820 in Japan, the first step toward approving the drug for general use there. In the U.S., Phase III clinical trials are expected to begin later this year.

A different, nonopioid approach stems from the finding that pain and itch are often all scrambled up in chronic itch patients -- such as those eczema patients who find pinpricks itchy. Scientists asked: Might drugs used for pain help with itching too?

It has proven a successful approach, says Dr. Sonja Stander, who runs the Clinic for Neurodermatology in Munster, Germany -- the only clinic in the world that focuses specifically on treating itch. Patients from all over Europe and the world come to the clinic -- 500 to 700 a year since the clinic was established in 2002. With pocked and bloody hides they come, seeking relief for an itch that just won’t stop.

And they usually find it: “About 80 to 90% of the patients we can help,” Stander says.

She has used some pain drugs, including gabapentin (originally used to treat epilepsy), which seems to reduce the excitability of itch nerves. She’s also treated patients with capsaicin, the same substance that makes chile peppers spicy.

Initially, capsaicin cream burns when it’s smeared on the skin, but in fact it can help in a number of itchy conditions, Stander says, including psoriasis and the itching that often accompanies kidney dialysis. It does so by lowering levels of a chemical called “substance P” that allows sensory nerves in the skin to communicate with the brain. (The nerves detect the itch but can’t send the message to the brain.)

Stander’s itch clinic has been successfully treating some patients with another drug called aprepitant (Emend) that blocks substance P directly. And sometimes, she says, low doses of antidepressants such as paroxetine (Paxil) or mirtazapine (Remeron) can help.

No one knows quite why, but two pilot studies in the last five years have found that mirtazapine can relieve some people’s itching, particularly at night -- even in people who aren’t depressed.

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Getting to the source

Treating the itch itself is good, but it would be better to keep the itch-scratch cycle from spiraling out of control in the first place.

People with eczema, for example, sprout extra nerve endings where their skin is inflamed, making them more and more sensitive to itch as the years go by. A substance called nerve growth factor drives the nerves to sprout. It may be one key to stopping the runaway itching.

In a study published in February in the British Journal of Dermatology, scientists at Taisho Pharmaceutical Co. in Saitama, Japan, found that blocking nerve growth factor’s activity with drugs called AG879 and K252a reduced the amount that mice with eczema scratched themselves. Not only did the eczema not get worse, it actually decreased in severity over the duration of the study.

Human trials of AG879 or K252a aren’t planned yet, but Schmelz is hopeful that they will ultimately be helpful for itchy humans, not just mice.

As scientists continue to probe the complexities of itch and pain sensation, people with chronic itchiness keep a weather eye on the developments. Right now, say itch experts, doctors have no agent as good at treating itch as aspirin is at treating pain. Patients must do what they can to keep on going.

Cordio, whose psoriasis was diagnosed in 1998, has finally managed to clear up most of her skin. She had rough periods in the past: “I’ve been as much as 90% covered. Let me tell you, that’s not a fun way to be.”

She’s tried a variety of different medications, none of which were particularly effective. Recently, she’s started a new drug -- efalizumab (Raptiva), which interferes with the immune cells responsible for skin inflammation. “This was my lucky ticket,” she says. “This is the first time in all the years that I’ve had psoriasis that I’ve had this significant a clearing.”

There’s always a worry that her skin will flare up again. “I have a tendency to live in a cautious joy,” she says, “but I never know when [the itch] is going to come back.”

For now, though, “It’s a kind of freedom. There’s a freedom from the flare; there’s freedom from that constant burden of scratching.

“It is liberating,” she says, “when the itch is not there.”