CHICAGO Neuroimaging of patients with atopic dermatitis has shown that different areas of the brain are activated in the itch versus scratch cycles.
The findings provide insight into the the role of peripheral and central neural sensitization of nerve fibers in contributing to atopic dermatitis itch. The findings also support the growing interest in drugs that act as antipruritics to reduce central sensitization, Dr. Gil Yosipovitch said.
Using arterial spin labeling-based functional MRI, Dr. Yosipovitch and colleagues at Wake Forest University, Winston-Salem, N.C., showed that the anterior cingulate cortex and dorsolateral prefrontal cortex are highly activated in patients with atopic dermatitis, but are not activated in healthy subjects when itch is induced. The activity in these cortices is also significantly correlated to itch intensity and disease severity scores in atopic dermatitis, according to unpublished data.
Curious about brain processing during scratching, the investigators, in another study, exposed 13 healthy subjects to a scratching stimulus. They found that repetitive scratching activates areas in the brain not activated in itch, most notably the secondary somatosensory cortex (J. Invest. Dermatol. 2008;128:180611). They also found significant activity in the cerebellum, which may be involved in coordinating the itch-scratch cycle.
What was more striking was a robust deactivation of the anterior cingulate cortex, which is involved in the unpleasant sensation of itch and thus may explain why scratching is so pleasurable, said Dr. Yosipovitch. Furthermore, there was a significant correlation between perceived scratching intensity and bilateral deactivation of the cingulate cortex.
"There is a hypersensitization of the nerve fibers in chronic itch; the nerve fibers are acting wacky," he said. "So when you give a painful stimulus instead of it being perceived as pain, it actually aggravates itch. It's very similar to patients with chronic pain, who when you induce an itchy state, it is perceived as pain.
"Now you can understand why one of my treatments of itch is reduction of central sensitization," he said at the American Academy of Dermatology's Academy 2008 meeting
Drugs targeting this mechanism include selective noradrenergic reuptake inhibitors such as mirtazapine, neuroleptics, and kappa opioids.
Butorphanol is an approved kappa agonist and mu-receptor antagonist analgesic that is available in injectable and intranasal spray formulations, he said. Butorphanol nasal spray is very effective in treating patients with chronic, intractable itch that affects their sleep and quality of life.
"I don't want to send the wrong message that this is a first-line drug for itch, but I'm quite sure we all have these patients and sometimes it's worth a try," he said.
Dr. Yosipovitch also uses 15 mg of mirtazapine (Remeron) at bedtime for intractable itch in patients aged 10 years and older, almost half of whom report a significant improvement in sleep and quality of life. The antidepressant is not addictive, but weight gain can occur.
He suggested that the immunosuppressant azathioprine (Imuran), which is used to prevent kidney transplant rejection and to treat severe rheumatoid arthritis, is underutilized in the United States for atopic dermatitis. He acknowledged concerns about the increased risk of lymphoma associated with azathioprine therapy, but said this is unlikely with short-term use of 1 year or less at a dosage of 1 mg/kg.
In a double-blind, randomized trial conducted in the United Kingdom in 63 patients who had moderate to severe atopic eczema despite having received optimum topical therapy, azathioprine dosed by thiopurine methyltransferase (TPMT) was well tolerated; however, two patients developed drug hypersensitivity (Lancet 2006;367:83946). At week 12, there was a 37% improvement in mean disease activity with azathioprine, compared with a 20% improvement with placebo. Significant improvements in itch, area of involvement, and quality of life were also observed.
Although the psoriasis biologic therapiesefalizumab, alefacept, and rituximabare being studied for atopic dermatitis, Dr. Yosipovitch said he is not convinced at this point of their efficacy.
Dr. Yosipovitch, known as "Dr. Itch" to his patients, is fond of the old-fashioned remedy of double-layer wet pajamas in which a moist wet-wrap dressing is covered by a layer of dry pajamas. A Korean study in 10 patients with severe atopic dermatitis confirmed that wet-wrap dressings were associated with clinical improvement and recovery of the epidermal barrier (J. Eur. Acad. Dermatol. Venereol. 2007;21:13608).
Dr. Yosipovitch disclosed that he has been on the advisory board of, been a consultant for, or received research grant support from, Acologix Inc., Cara Therapeutics, Taisho Pharmaceutical Co., Stiefel Laboratories Inc., UCB Pharma, Connetics Corp., and the National Eczema Association.
A robust deactivation of the anterior cingulate cortex may explain why scratching is so pleasurable. DR. YOSIPOVITCH