NEA and PeDRA wrap up their Eczema Counts project with new priorities for eczema research.
Published On: Sep 2, 2021
Last Updated On: Sep 28, 2022
Atopic dermatitis (AD) is well known for being an inflammatory disease associated with a reduced skin barrier and the greatest burdensome symptom, itch. However, physicians like Dr. Johnathan Silverberg, MD, PhD, MPH at George Washington University School of Medicine and Health Sciences paid attention when patients were describing their skin symptoms and heard words such as, “soreness, burning, stinging, painful, tingling, pricking, throbbing, biting and crawling sensation.” He realized patients were describing pain, not itch. To date very little research has been done on the processes underlying skin pain in AD.
Dr. Silverberg said, “I think part of why it has taken so long for research to start focusing on pain in AD stems from our understanding of the counter-effects of pain on itch.” Typically, in healthy skin, stimuli that cause pain (such as scratching) temporarily suppress itch.1 Dr. Silverberg said, “The field had assumed this to be true in AD as well, but it turns out to be far more complicated. Also, the pain experience is quite mixed in AD with patients reporting pain resulting from inflamed skin, scratching, fissures (cracks and wounds) and intolerance to skin exposure to irritants. This complexity has made pain more elusive for clinicians and even patients to appreciate.”
A key, but fundamental question that needed to be addressed in researching skin pain in AD was how many people with AD actually experience pain? In a recent study of 305 adolescent and adult patients with AD, 42.7% reported skin pain associated with their disease and many reported that their pain was associated with their itch, with scratching, or with both.2 Another study found that more than half of adult patients with AD reported skin pain and rated their pain a 6 out of 10 on a pain scale.3 In a third study of 602 adults with AD, 61% of patients reported experiencing skin pain with one-third experiencing pain once a week and 5% experiencing pain daily. In this study, pain intensity reached as high as 7 out of 10.4
Experiencing moderate to severe skin pain also correlated with reduced quality of life, poor sleep, mental health issues, and worse overall AD symptoms.2 Importantly, the researchers noted that for some patients skin pain did not associate with scratching or with skin wounds (e.g. visible scratch marks or skin cracks). Patients whose pain did not correlate with itch or evidence of scratching in this study used words to describe their pain that were indicative of neuropathic pain indicating possible nerve damage not associated with scratching.2 A follow-up investigation looking at itch and pain severity in adult AD patients over a period of four years showed that skin pain did not always correlate with itch and scratching over time.5 Dr. Silverberg said, “Patients with pain secondary to scratching report more soreness, whereas those with pain secondary to inflamed skin tend to report more burning and stinging.”
Some studies have looked at location of skin pain associated with AD; the results indicate that patient-reported pain seems to be worse on the palms, soles, and chest.6,7 Dr. Silverberg said, “AD patients with fissures (cracks or wounds) present on the hands and feet can experience excruciating pain.” Results from a study of 103 AD patients (age 5 years and older) worldwide, 78% reported pain together with itch, with the greatest degree of pain on the hands, around the mouth, and on the toes, which are also areas of the body with the highest number of sensory nerves.8 Buttocks, feet, legs, neck, fingers and forearms also were described as painful. Red, cracked, dry skin was most frequently described as “burning” and “stinging”.8 Tightness and tenderness were also used to describe pain in these areas. Pain seemed to be aggravated by sweat, warm temperatures, emotional stress, exposure to hot water, rubbing and wearing wool or synthetic clothing. Sometimes use of moisturizer or topical medication actually made pain worse.8
Studies to understand the science underlying pain in AD are in their infancy. Dr. Silverberg said, “We need mechanistic studies to understand how pain co-occurs with itch specifically in AD.” It has been suggested that a long-lasting inflammatory response from chronic AD lesions may sensitize the peripheral (nerves in the skin) and central (nerves in the spine leading to the brain) nervous system, which increases patients’ experience of pain.3
It is currently unknown whether the same nerves that convey the sensation of itch to the spine and up to the brain also act in the signaling of pain.9 Dr. Ethan Lerner, MD, PhD, of Massachusetts General Hospital said, “When people look at skin sensation, very rarely is it a pure itch or a pure pain. Different patients will have more of one than the other. The brain might be processing some of the same information differently with different signaling pathways involved.”
As stated above, itching in healthy skin leads to scratching behavior which can result in pain that temporarily reduces the experience of itch. Studies of mice and rats have shown that spinal nerves receive pain input from peripheral nerve fibers (such as fibers reaching the dermis of the skin). Signals are the sent back to suppress the feeling of itch and scratching behavior.9 In AD, however, it seems that this neural process does not work properly. Studies are needed to understand the sequence of events – is it itch, scratching and then pain? Or is the pain associated with AD independent of itch? Dr. Gil Yosipovitch, MD at the University of Miami said, “It is clear that there is a component of pain in eczema that is related to inflammation and nerve sensitization that usually is accompanied by itch but can exist on its own.” He suggests psychosocial studies to help understand if patients experiencing pain derive less pleasure from scratching behavior than those not experiencing pain. These kinds of studies may inform how best to treat pain versus itch in AD because the treatment of pain in some cases may actually make itch worse.9
Most studies to date have not looked at how AD therapeutics impact skin pain. Dr. Silverberg said, “For now, it seems that the best approach is to treat the underlying inflammation and itch, which appears to secondarily reduce skin pain as well. We need studies specifically examining the optimal approaches to reducing skin pain in AD.”
For example, researchers have recently examined data from the dupilumab clinical trials (five separate clinical trials in which patients received placebo or dupilumab 300 mg every two weeks or once weekly with and without topical corticosteroids) and found that dupilumab reduced pain and discomfort starting early in treatment and lasting throughout the treatment.10 One of the newer oral JAK inhibitors pending FDA approval, baricitinib, was recently studied for its ability to reduce skin pain associated with AD in three Phase III clinical trials. This drug reduced skin pain severity by day two after initiating treatment.11 Targeting pain receptors by using gamma aminobutyric acid (GABA)-targeting drugs or antidepressants may also alleviate pain.12 In addition to these newer therapies, one study found that cool temperatures, use of moisturizers, reducing emotional stress, getting good sleep, exposing skin to a cool, wet towel, and topical steroid use relieved some of the burden of pain.7
Dr. Yosipovitch said, “Dermatologists need to be aware that pain sensations are part of the eczema and not unrelated. It is important to ask our patients about these sensations.” Patients also need to share if they are experiencing pain, as it has been reported that while the skin pain of AD can be intense, patients do not use pain medication more than those without AD.6 As patients think about their skin pain both with and without itching/scratching more information will be conveyed to physicians about how AD pain is experienced. Increased awareness of this burdensome symptom, and evaluation of pain endpoints in clinical trials for new AD therapies will go a long way toward better understanding and treating the pain associated with AD.
Take Home Points:
1. Vakharia PP, Chopra R, Sacotte R, et al. Burden of skin pain in atopic dermatitis. Ann Allergy Asthma Immunol. 2017;119(6):548-552 e543.
2. Huet F, Shourick J, Seite S, Taieb C, Misery L. Pain in Atopic Dermatitis: An Online Population-based Survey. Acta Derm Venereol. 2020;100(14):adv00198.
3. Silverberg JI, Gelfand JM, Margolis DJ, et al. Pain Is a Common and Burdensome Symptom of Atopic Dermatitis in United States Adults. J Allergy Clin Immunol Pract. 2019;7(8):2699-2706 e2697.
4. Hong MR, Lei D, Yousaf M, Chavda R, Gabriel S, Silverberg JI. A real-world study of the longitudinal course of skin pain in adult atopic dermatitis. J Am Acad Dermatol. 2021.
5. Fuxench ZCC. Pain in atopic dermatitis: it’s time we addressed this symptom further. Br J Dermatol. 2020;182(6):1326-1327.
6. Thyssen JP, Halling-Sonderby AS, Wu JJ, Egeberg A. Pain severity and use of analgesic medication in adults with atopic dermatitis: a cross-sectional study. Br J Dermatol. 2020;182(6):1430-1436.
7. Maarouf M, Kromenacker B, Capozza KL, et al. Pain and Itch Are Dual Burdens in Atopic Dermatitis. Dermatitis. 2018;29(5):278-281.
8. Andersen HH, Yosipovitch G, Arendt-Nielsen L. Pain inhibits itch, but not in atopic dermatitis? Ann Allergy Asthma Immunol. 2018;120(5):548-549.
9. Silverberg JI, Simpson EL, Guttman-Yassky E, et al. Dupilumab Significantly Modulates Pain and Discomfort in Patients With Atopic Dermatitis: A Post Hoc Analysis of 5 Randomized Clinical Trials. Dermatitis. 2020.
10. Thyssen JP, Buhl T, Fernandez-Penas P, et al. Baricitinib Rapidly Improves Skin Pain Resulting in Improved Quality of Life for Patients with Atopic Dermatitis: Analyses from BREEZE-AD1, 2, and 7. Dermatol Ther (Heidelb). 2021.
11. Elmariah SB. Adjunctive Management of Itch in Atopic Dermatitis. Dermatol Clin. 2017;35(3):373-394.