Gil Yosipovitch, MD, is a professor and Stiefel Chair of Medical Dermatology at the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery and director of Miami Itch Center of the University of Miami Miller School of Medicine in Miami, FL. As part of our ongoing series into pain in atopic dermatitis (AD), Dr Yosipovitch spoke about the relationship of pain and AD, how to consider pain in these patients, and what therapies may be successful in treating AD-related pain.
What is the relationship between pain and AD?
The same small, unmyelinated fibers that transmit itch may also be able to transmit pain. In nerve activity, there is a lot of crosstalk between inflammation and the cytokines, and it is thought that this component of pain is part of the same inflammation that causes itching. Therefore, the pain is not just in the skin but also centrally mediated. We have done studies on brain imaging of patients who have atopic eczema. They have areas in the brain where pain is highly activated, and the center of neurosensitization is in the anterior cingulate cortex. When itching is induced, these areas are highly activated in patients with AD.1
Further, I want to emphasize that there is a peripheral inflammatory effect that goes up to the brain. That is why it is not surprising that there seems to be so much interrelationship between both itch and pain. In 2009, we looked at validated itch questionnaires, which revealed that pain is experienced by almost 60% of the patients with atopic eczema.2 Silverberg et al published in 2019 and 2017 that pain is a very important component of AD.3,4
There seem to be a number of similarities and correlations between itch and pain in these patients, but the main component of this etiology is neurosensitization. Examples of neural sensitization phenomena in daily life activities is when patients tell you that when they dress up they feel the clothing cause their skin to burn and itch or when the temperature changes they feel the skin is burning and itchy. If someone without AD were to put clothing—even a sweater—they do not itch or feel burning sensation.
What hasn’t the literature explored the relationship between pain and AD?
Characterization of AD-related pain is an issue that has not been reported enough. Most of the complaints are about a burning sensation, rather than very sharp aches. Additional research is needed to understand why pain-related inflammation is prevalent in atopic eczema.
In 2017, we published a study in Pain regarding sensory testing of the neurosensitization of atopic eczema.5 This is the most advanced research done on the sensory aspects of this disease. We showed that there is a mechanical pain sensitivity in these patients; their nerves are overactivated, causing itch as well as pain. As dermatologists, we have been trained to always acknowledge only itch or only pain. However, pain and itch can live together in diseases, as is the case with atopic eczema. In addition, we showed in a 2018 study that sensory complaints are very common in inflammatory pruritus.6 These complaints were even more common than in neuropathies that cause itch, and they require more large-scale studies to further characterize the sensations.6
How should pain be considered in evaluating a patient with AD?
At my itch center, I see many patients with atopic eczema who experience chronic itch. Of those who have experienced itching, many have also dealt with pain. The key point here is to understand that pain could be associated with this itch. Dermatologists know itch is part of AD, but we need to remember that the evidence suggests pain is a component of the disease process as well. We recognize that the most bothersome and main symptom to treat in AD is still going to be itch, but acknowledging and addressing pain is important if the patient reports it as a symptom.
The general thought is that if we address the itch, then the pain will subside as well. Unfortunately, the approved advanced therapies for atopic eczema do not have sufficient data to determine if that holds true. Previous studies only focused on the changes in itch since that is the hallmark symptom of the disease. Current and future studies into advanced therapies are beginning to track the changes in AD-related pain without the use of additional therapies.
What do we need to research to better understand pain in AD?
We need to explore if AD-related pain is a marker of more acute or long-term disease. I will give you an example: there are patients who have atopic eczema and their external inflammation is not severe, but the burning sensation and itch are way above what we see in the skin. If we examine these cases further and find that there is more burning sensation with itch, should we target a bit differently? That would be an interesting question, but at the moment, I do not think that we have any data to suggest that. It also would be interesting to see is there a subpopulation that is more susceptible to pain. For example, in African Americans, prurigo nodularis is more common in AD. Prurigo nodularis has also a component of pain and direct damage to nerve fibers.
What therapies may be useful in treating AD-related pain?
Some of the topical treatments that work on itch may work on the pain, especially if they target the nerves. In my practice, when I have a patient who has that pain, I compound a regimen that contains peripheral nerve inhibitors, such as a formulation called ketamine lidocaine amitriptyline, which numbs the nerves. Transient receptor potential (TRP) ion channels have been shown to be involved in both itch and pain. Therefore, if we numb these TRP channels or develop topicals that work on the neural system that could inhibit them, we theoretically could enable patients to have less pain and itch.
Another option is to give drugs that target central nervous system including the brain to reduce that sensitivity. GABAergic (γ-aminobutyric acid-mediated) drugs, such as gabapentin and pregabalin. I have also used mirtazapine a tetracyclic anti depressant that has an effect on neurosensitization in pain and itch, and these options may help patients to sleep better.
Additionally, we understand that scratching can help reduce the itch in a way. For example, when you have an instinct-like reaction to a mosquito, you immediately scratch. In comparison, patients with AD can scratch themselves sometimes until they bleed, never relieving that itch but creating another source of pain. It would be helpful in creating a better care plan for a dermatologist to address this by understanding all of the complexities of itch, including the involved nerves.
The worst thing we can do is to tell the patient to stop scratching. That is easy to say, but the patient simply cannot just do that. It is important that you have the capability of understanding the complaints of itch and pain first and the explain to the patients that these phenomena are a part of atopic eczema. It is possible to be more attentive to these symptoms by addressing them with various drugs while we await an advanced therapy that works on them all.
What pearls of wisdom can you offer regarding pain in AD?
Ask about pain and learn about the neurosensitization phenomena. Do not dismiss a patient if they tell you they have pain with an itch. When I was a resident almost 25 years ago, I was taught that if you have itch and pain, then the patient has some psychiatric issues. Now as we research more into the relationship between itch and pain, that is clearly not the case in atopic eczema.
References
1. Ishiuji Y, Coghill RC, Patel TS, Oshiro Y, Kraft RA, Yosipovitch G. Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis. Br J Dermatol. 2009;161(5):1072-1080. doi:10.1111/j.1365-2133.2009.09308.x.
2. Dawn A, Papoi ADP, Chan YH, Rapp SR, Rassette N, Yosipovitch G. Itch characteristics in atopic dermatitis: results of a web-based questionnaire. Br J Dermatol. 2009;160(3):642-644. doi:10.1111/j.1365-2133.2008.08941.x.
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.e7. doi:10.1016/j.jaip.2019.05.055
4. Vakharia PP, Chopra R, Sacotte R, et al. Burden of skin pain in atopic dermatitis. Ann Allergy Asthma Immunol. 2017;119(6):548-552.e3. doi:10.1016/j.anai.2017.09.076
5. Andersen HH, Elberling J, Sølvsten H, Yosipovitch G, Arendt-Nielsen L. Nonhistaminergic and mechanical itch sensitization in atopic dermatitis. Pain. 2017;158(9):1780-1791. doi:10.1097/j.pain.0000000000000980
6. Rosen JD, Fostini AC, Chan YH, Nattkemper LA, Yosipovitch G. Cross-sectional study of clinical distinctions between neuropathic and inflammatory pruritus. J Am Acad Dermatol. 2018;79(6):1143-1144. doi:10.1016/j.jaad.2018.05.1236
