Scratching the surface: The challenges of treating itching

Itching is poorly understood, but scientists are recognizing that this sensation may be more different from pain than previously thought.

By — Posted Jan. 21, 2008

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In the early days of his career, Gil Yosipovitch, MD, was an internist on call for hemodialysis patients. He discovered that, although they had obvious life-threatening medical needs associated with their kidney disease, they also commonly experienced a symptom that destroyed their quality of the life. They itched -- and it made them miserable.

"I saw how much these patients were suffering. In my opinion, they are like chronic pain sufferers. No sleep -- suffering, scratching all night," he said.

He is now a dermatologist and part of a cadre of physicians and scientists turning their attention to what causes itching and what can be done to alleviate the need to scratch. Dr. Yosipovitch, also a professor of dermatology, neurobiology and anatomy at Wake Forest University in Winston-Salem, N.C., founded the International Forum for the Study of Itch in 2005. The organization, which receives financial support from the National Institutes of Health, sponsored the fourth international meeting on this topic in San Francisco in September 2007.

Previously, "there were no itch meetings," he said. "Dermatologists won't go to pain meetings. Neuroscientists will never go to dermatology. Itch meetings combine all these people."

The scientific challenge he and others now face is significant. Itching has hundreds of causes from bug bites to the side effects of chemotherapy, but the amount of research money devoted to its study has long paled in comparison to pain. This circumstance arises, in part, because itching has generally been considered a lesser version of pain, although research is emerging to suggest that the relationship is far more complicated. Itch research could lead to a greater understanding of pain because, like sibling rivals, itch and pain may be closely intertwined at certain times, but very much separate at others.

"In the old days, it was thought itch was just a low level of pain transmitted along the same pain pathway. ... When the stimulus becomes stronger, it becomes painful. That doesn't make sense, and there has been some evidence suggesting that there may be a specific itch pathway," said Earl Carstens, PhD, professor in the section of neurobiology, physiology and behavior at the University of California, Davis. He was one of the organizers of the most recent itch meeting. "But there's still a lot of data out there that's not completely consistent with the idea that itch and pain are completely separate."

What is known is that the nerve fibers in the skin that make people itch are fewer in number than those that create pain, but they create this sensation over a larger area. Pain fibers tend to react quickly. Itch comes on more slowly. Pain fibers make people hurt in a focused way and lead them to protect the affected area to allow for healing. Itching leads to scratching. This act begets pain and more itching as the nerves become hypersensitive to the stimulus. Sometimes more nerves grow to respond to it.

Still, itch has been viewed as the lesser sensation in the basic science realm. It also has been a patient complaint that traditionally receives little respect, although anecdotal reports suggest patients suffer significantly.

"When you ask the patient, 'What bothers you more? Your bad heart disease or your rash?' -- they're going to say their rash," said Tim Berger, MD, chief of the dermatology clinics at the University of California, San Francisco. "I have patients who come in and say, 'My itching is so severe. If you don't help me, I'm going to have to kill myself.' " He is researching why itching becomes much more common with age.

And there is scientific literature documenting itching's significant impact on health, particularly if it is severe. A paper published in the March 2002 Pain documented the case of a patient who, over a year, scratched a hole through her skull to her brain. A case of shingles had left her feeling no pain -- but intense itching -- in the area, so she scratched. While hospitalized she had to have her hands bandaged or tied down to prevent further damage.

"There are other patients who have had severe self-injury from itch. This is not the only one," said Anne Louise Oaklander, MD, PhD, lead author on that case report and an associate professor of neurology at Harvard Medical School in Boston. "There have been certain areas of medicine not perceived as serious or worthy of legitimate medical attention. Unfortunately, itch has been one of these areas."

A truly distressing condition

Itch can even be deadly. A study in the December 2006 Nephrology Dialysis Transplantation found that 42% of hemodialysis patients had extreme pruritus and that this condition increased the risk of death by 17%, primarily because itching and the need to scratch disrupted sleep.

"People who itch chronically will tell you this is a terribly distressing disease," said Dr. Berger. "It has a huge impact on quality of life, and it's highly prevalent."

Signs of progress in understanding it are starting to surface slowly. A paper published in the Aug. 9, 2007, Nature implicated the gastrin-releasing peptide receptor gene in communicating itch from the skin to the brain. Researchers created mice without this gene that reacted to pain, but not to substances that should have caused them to scratch. This gene is not believed to be the only one that creates this sensation, and the mice still scratched, although not as much. The hope is that understanding the underlying mechanisms will lead to the development of treatments that target itch directly.

"This is the first gene identified in the central nervous system for itching and provides hope for the design of drugs that could block this pathway," said Zhou-Feng Chen, PhD, lead author on that study and associate professor of anesthesiology at Washington University in St. Louis. "But there are definitely many genes that create itching, and we need to identify others."

This advance is important because patients currently have few options when it is not possible to remove the itch-producing culprit. Home remedies include oatmeal baths and skin lubricants. Antihistamines are the most common over-the-counter possibility. Still, many itches do not respond to them, although they can make sleep easier because they are sedating.

"Antihistamines work particularly well on hives, but most people aren't walking around with hives. They have eczema or psoriasis or itchy scalp or Hodgkin's or some nasty parasitic disease. That's why the antihistamines don't work very well," said Ethan Lerner, MD, PhD, associate professor of dermatology at Massachusetts General Hospital in Boston, who conducts research on this issue.

Opioid antagonists, selective serotonin reuptake inhibitors and epilepsy drugs are sometimes prescribed off-label for severe cases. Much like pain, itch can also have a psychiatric component, and cognitive behavioral therapy may help. Nalfurafine, the first selective kappa opioid receptor agonist to treat itch among hemodialysis patients, has been approved in Japan, and work is under way to get it approved in the U.S. as well as to discover other possibilities.

"We're very hopeful that we're going to find something that really works," said Nora V. Bergasa, MD, a gastroenterologist/hepatologist and deputy chief of medicine at Woodhull Medical and Mental Health Center in Brooklyn, N.Y.

More areas of research

Dr. Bergasa ran a clinical trial in which patients with liver disease who itched and received a placebo scratched less than those who received the drug that she had hoped would help them. She is now looking at whether the placebo effect can be harnessed for possible treatment applications. Other researchers are investigating the effect of scratching to determine if the essential element that makes this action work can be magnified to provide longer-term benefit.

"Scratching makes the neurons completely stop for five to 10 seconds and blocks itch," said Glenn Giesler, PhD, professor in the Dept. of Neuroscience at the University of Minnesota in Minneapolis. "If we understand the neurochemistry [of how scratch blocks itch], maybe we can make something that helps treat itch. Maybe we can come up with something that would lead to a drug that would help the millions of people who suffer from this problem."

Although work is starting to move forward, itch is a sensation for which many of the core scientific questions still need to be answered. Much research has been carried out in rats and mice, but there's disagreement over how good a model these animals may provide. They appear to itch in response to different stimuli than humans, but working with larger mammals gets expensive.

"Rodents are accessible and easier to work with. You can look at behavior in lots of animals at the same time, but the ultimate question is: If we discover pathways that we think are mediating itch in a rat or a mouse, how relevant is that to humans?" said Dr. Carstens.

Scientists also find it harder to create itch than pain in the study setting. The stimulus needs to be far more precise or it will suppress itch and cause pain instead. Measuring itching objectively is challenging -- although many researchers are trying to use scratching as a surrogate, and to devise patient questionnaires based on those that assess pain -- and some of the most basic aspects of this sensation are not understood.

"The curious thing about itching is why do we? What purpose does it serve? One can speculate that a brief episode of scratching may have its benefits, such as the removal of an irritant or the release of chemicals in the skin that promote healing. But prolonged scratching in response to chronic itching has no biological purpose. Clearly, the detrimental effects of scratching present an additional reason to unravel the mechanisms of itch," said Robert LaMotte, PhD, professor in the Dept. of Anesthesiology at Yale University in New Haven, Conn.

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Who's got the itch?

  • 300 million infested with scabies worldwide
  • 31.6 million Americans with eczema
  • 17.8 million Americans with atopic dermatitis
  • 32.4 million visits to American dermatologists for skin rash
  • 12.5 million visits to American primary care and other medical specialists for skin rash

Sources: Lancet Infectious Diseases, December 2006; Dermatitis, August 2007; National Ambulatory Medical Care Survey

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External links

4th International Workshop for the Study of Itch, San Francisco, Sept. 9-11, 2007 (link)

"A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord," Nature, Aug. 9, 2007 (link)

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