Cheyenne Bulle was 18 years old and at the end of her freshman year of college when, out of nowhere, she was struck by an unbearable itch.
"At first I thought it might be eczema, but it was much worse," she says.
"I wasn't allowed to take a hot shower, I couldn't focus on my school homework, I couldn't sleep because I had to scratch my bed for almost two hours. I would have to get up to wash because I would leave traces of blood on the sheets."
Cheyenne was diagnosed with prurigo nodularis (PN), a chronic inflammatory skin disease that translates as "itchy nodules".
This condition is one of many that cause chronic pruritus - which is medically defined as itching that lasts for more than six weeks.
Chronic itching is associated with dermatological disorders such as eczema, hives and psoriasis, but also with other health conditions such as chronic kidney disease, liver failure and lymphoma.
In some cases, chronic itching can last for years.
Sensation can lead to madness.
- Vitiligo: Skin changes that go from shame to acceptance
- Smallpox: What are the symptoms and how to prevent infection
- They reproduce on our face, clean our skin, but they are threatened with extinction
In Dante's Inferno, liars were condemned to the eighth circle of hell, where they felt "an unbearable attack of fierce itching which nothing could relieve".
It's something psoriasis sufferers can relate to, as the itching that comes with the condition has been compared to an attack of red ants.
Patients with a diseased liver would receive a transplant because they cannot cope with this sensation.
Some cancer patients stop taking the drugs that keep them alive because of the itching that the drug can cause.
"Studies have shown that chronic itching is just as debilitating as chronic pain, but I'd even argue that it's more than that," says Brian Kim, a clinician and neuroimmunologist at the Icahn School of Medicine at Mount Sinai in New York.
"With chronic pain, you have a dull aching sensation - it's like a six on a scale of 10 that doesn't go away - but you can sleep through it.
"Chronic itching is different because it doesn't give you peace at all. Sufferers stay up all night scratching. From that point of view, he knows how to make your life more difficult."
However, despite its prevalence, until recently scientists did not understand what causes chronic itching.
Acute pruritus, on the other hand, is relatively well understood.
If you are bitten by a mosquito, or come into contact with a stinging nettle, immune cells in the skin release histamines and other factors, which bind to small receptors on the surface of sensory nerves, causing them to activate and send an itch signal to the spinal cord and brain.
Although unpleasant, acute itching can be treated with antihistamines or topical steroids.
But antihistamines do not work on chronic itching.
As a result, there has been very little progress in the treatment of itch in the 360 years since itch was first medically defined.
One of the reasons for this is that scientists were convinced that itching was just a milder form of pain.
This misconception dates back to the early 1920s, when the Austrian-German psychologist Max von Frey pierced the skin of laboratory participants with tiny sharp objects called spicules.
He discovered that the initial sensation of pain is followed by a subsequent sensation of itching.
However, in 2007, scientists led by Zhou-Feng Shen of the University of Washington School of Medicine discovered a specialized itch receptor on a subset of neurons (nerve cells) in the spinal cord.
Mice without these receptors could not feel itch.
No matter how tickled or irritated they were, they didn't scratch.
And yet they felt pain normally.
In other words, the scientists found a bunch of neurons in the spinal cord that specifically transmitted the itch sensation to the brain.
Meanwhile, researchers discovered other receptors and neurons specialized for itch.
For example, g-protein-coupled receptors can be found on sensory neurons that cross the skin.
They project directly to the brain and appear to play a key role in the transmission of itch.
Meanwhile, in 2017, Brian Kim and colleagues at the Center for Itch and Sensory Disorders Studies at the University of Washington discovered that skin inflammation can cause immune cells to release chemical messengers called IL-4 and IL-13.
These chemicals, known as cytokines, also bind to sensory neurons in the skin, causing itching.
"One of the cool things about Brian Kim's work is that he found that not only did these molecules bind to the itch neurons, but they lowered the threshold for other molecules in the skin to activate the itch neurons, so they generally sensitized people with allergies to more they feel itchy," says Marlis Fassett, a professor of dermatology at the University of California, San Francisco.
Fassett focused on another "itch cytokine," IL-31, which also activated neurons specialized for itch.
According to Fassett, the soon-to-be-published paper shows that, just like other itch cytokines, IL-31 also lowers the threshold of itch neurons, causing them to fire more often and more readily.
In a 2023 study, Fassett found that in addition to causing itching, IL-31 also reduced nearby inflammation so that the itching sensation gradually subsided.
Her team removed the gene in mice that codes for IL-31, then exposed the mice to house dust mites, a common allergen that causes itching.
As expected, the mites did not cause itching in mice lacking IL-31.
However, inflammation in that region skyrocketed.
"It's been known for 15 years now that when you inject IL-31 into the skin or cerebrospinal fluid of mice, the animal immediately starts scratching uncontrollably," Fassett says.
"But what remains the dilemma is that if you remove that itch cytokine, instead of inflammation in the tissue going down, it goes up. And that didn't make a lot of sense, because in most tissues where there's itching and inflammation together, you'd expect them to move together."
Neurons in the skin that are activated by IL-31 also appear to kill the immune response, which controls inflammation.
This finding is important because it means that anti-itch drugs that attack IL-31 may have side effects, causing inflammation to spiral out of control.
Watch the video: What happens when antibiotics stop working
Treatment of itching
Such drugs are already being worked on.
For example, nemolizumab, which targets the IL-31 receptor, recently completed Phase 2 and 3 clinical trials for the treatment of atopic dermatitis (AD), a form of eczema that causes inflammation, dryness, and itching of the skin.
People suffering from this debilitating condition can already get a prescription for dupilumab, a recently licensed drug that inhibits IL-4 and IL-13 receptors.
Other drugs such as EP262, abrocitinib and upadacitinib are also in phase 3 trials for the treatment of AD.
EP262 blocks the g-protein coupled receptor X2 (MRGPRX2), while abrocitinib and updacitinib affect the IL-4 and IL-13 pathways by inhibiting the JAK1 receptor.
Other conditions that cause itching may also benefit from new treatment methods.
For example, this year, Gil Josipovič, a professor of dermatology and physician at Miller University School of Medicine, worked with Brian Kim and others to complete two phase 3 trials for the use of dupilumab to treat PN, a condition Cheyenne suffers from.
After 24 weeks, 60 percent of participants who received dupilumab experienced a significant reduction in itching, compared to 18,4 percent of participants who received a placebo.
As a result, the FDA has now approved dupilumab for the treatment of patients with PN.
"PN is one of the most itchy conditions faced by dermatologists, and until recently there were no good treatment methods, so patients suffered a lot," says Josipovič.
"This is an interesting time for our patients. They feel like they finally have some hope.
"I've had many patients who were terribly distressed and unhappy, and they came to me and said, 'That drug changed my life.'"
Meanwhile, Brian Kim's new lab at the Icahn School of Medicine is testing difelikephalin for the treatment of paresthetic notalgia, a nerve disorder characterized by persistent itching in the upper back.
Difelikephalin is already approved by the FDA for the treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis.
However, in a phase 2 trial, it was also shown to be moderately effective in the treatment of paresthetic notalgia.
Together, these drugs offer hope that, until recently, was not there.
"I feel like myself again and I can continue to live life to the best of my ability," says Shajen, who was one of the participants in Josipovic's trial.
"Sometimes I get a little itchy, but just for 10 minutes, my quality of life is much better than it was," she says.
Although dupilumab does not cover all patients, more drugs are expected on the horizon.
"I believe that in the next five years we will be able to control most of these patients, so this is a very rewarding time for doctors like me who have been dealing with the suffering of these patients for so many years," says Josipovic.
Follow us on Facebook,Twitter i Viber. If you have a topic proposal for us, contact us at bbcnasrpskom@bbc.co.uk
Bonus video:
