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Clinical Updates

Gil Yosipovitch, MD

Chronic Itch

gil yosipovitch

Tuesday, July 03, 2007

Chronic itch (pruritus) is a common complaint in many inflammatory skin diseases, as well as in systemic diseases such as chronic kidney failure, chronic liver disease, HIV, and lymphoma. Chronic itch is defined as a prolonged itch that lasts more than 3 months. Chronic itch may continue when treatment stops, depending on the origin and state of the symptom.1

A recent clinical classification for chronic pruritus has been proposed by the International Forum for the Study of Itch (IFSI). It is divided into three major groups:

  1. The first group encompasses patients with skin diseases (pruritus on primary diseased skin). Acute secondary scratch lesions may or may not be present, such as those that often occur with excoriated atopic dermatitis, excoriated psoriasis, or scabies.
  2. Patients comprising the second group experience pruritus without any skin lesions (pruritus on primary non-diseased skin). Again, acute secondary scratch lesions may or may not be present.
  3. The third group of patients present with prominent, chronic scratch lesions (eg, prurigo nodularis, lichen amyloidosis, or lichen simplex) secondary to an underlying cause. The underlying origin may be a systemic disease (eg, uremic pruritus) or a skin disease that leads to massive scratch lesions.

Another well-known form of itch in chronic sufferers is intractable pruritus,1 which is an itch that cannot be treated in the generally accepted course of medical practice. It is important to acknowledge that such patients are encountered weekly in dermatology clinics and they do suffer. In such cases, a more holistic approach is required by an interdisciplinary team, with involvement of both patients and their families. It integrates pharmacologic and non-pharmacologic treatment with needed psychotherapy and rehabilitation.

Chronic itch induces a series of consistent physical and psychological changes that can significantly impair patients' quality of life such as difficulty sleeping, difficulty concentrating, decreased sexual desire and sexual function, agitation, and depression. In addition, eczematous lesions resulting from scratching can become secondarily infected, particularly in patients with atopic dermatitis. In the recent international Dialysis Outcomes and Practice Patterns Study (DOPPS), evaluating more than 18,000 patients on hemodialysis, pruritus was associated with a 17% higher mortality risk, an effect that was no longer significant after adjustment for measures of sleep quality. Another large cross-sectional study in Oslo consisting of 18,770 adult responders showed that more than 8% of the population reported that they suffered from itch, which was the most common cause of skin morbidity. Itch was also strongly associated with reporting poor general health.2

Chronic Itch and Chronic Pain

Chronic itch has many similarities to chronic pain. Both are unpleasant sensory experiences and consist of multidimensional phenomena, including sensory discriminative, cognitive, evaluative, affective, and motivational components. In most cases, chronic itch and pain result from an interaction between the brain and skin.3 Recent studies in patients with chronic itch demonstrate that repetitive painful stimuli, such as electrical, noxious heat pain, and scratching stimuli distal to an itchy stimuli, may be perceived as itch. Sensitization of nerve endings is a well-known mechanism of inflammatory pain. A similar mechanism occurs in chronic itch. Central sensitization in chronic itch is caused by sensitization of second-order neurons in the dorsal horn, thereby leading to increased sensitivity to itch. This increased sensitivity to itch is coined alloknesis (itchy skin) and can be observed when touch- or brush-evoked itch occurs around an itching site.4 This phenomenon is analogous to the better-known allodynia. Alloknesis is a prominent feature of atopic dermatitis3,5 and explains patients' complaints of severe pruritus associated with sweating, sudden changes in temperature, and dressing and undressing.

Sensitization of nerve endings is a well-known mechanism of inflammatory pain. A similar mechanism occurs in chronic itch. Central sensitization in chronic itch is caused by sensitization of second-order neurons in the dorsal horn, thereby leading to increased sensitivity to itch. This increased sensitivity to itch is coined alloknesis (itchy skin) and can be observed when touch- or brush-evoked itch occurs around an itching site.4 This phenomenon is analogous to the better known allodynia. Alloknesis, is a prominent feature of atopic dermatitis3,5and explains patients' complaints of severe pruritus associated with sweating, sudden changes in temperature, and dressing and undressing.

Treatment Strategies

Based on our increased understanding in recent years of chronic itch and its significant impact on patients' quality of life, it is imperative to treat chronic itch as a disease in its own right rather than a bothersome symptom similar to that proposed for chronic pain by the European Federation of IASP (International Association for the Study of Pain) Chapters.

The main goal in treating chronic itch is reduction of itch intensity. Although there are no general-purpose antipruritic drugs, recent findings of specific neural networks involved in itch transmission have led to novel therapeutic targets. These include inhibition of itch transmission in the central nervous system with anticonvulsants, antidepressants, and selective serotonin reuptake inhibitors (SSRI) as well as combined serotonin-norepinephrine reuptake inhibitors (SNRI).6 In addition, gabapentin may inhibit central itch pathways, as it does in pain. Several case series and small-scale studies have shown gabapentin to be effective in the treatment of itch, particularly neuropathic and chronic kidney disease-associated pruritus. For more localized chronic itch, topical agents that work directly at the site of application include local anesthetics, substance P depletors, such as capsaicin, and antinflammatories such as topical aspirin and salicylates.7,8

An imbalance of the endogenous opioidergic system has received recent attention in terms of the pathophysiology of pruritus per se, as well as in chronic pruritic conditions. Kappa agonists have shown promising results in phase III studies for chronic kidney disease-associated pruritus; however, they are as of yet not available in the market.9 Butorphanol, which is a kappa agonist and a mu antagonist, was reported to be an effective treatment for patients with chronic, severe intractable pruritus due to inflammatory skin and systemic diseases.10

Similar to chronic neuropathic pain, refractory cases of chronic itch often require the use of two agents with synergistic mechanisms of action.

Conclusion

Chronic itch is a major healthcare problem for millions of patients worldwide and needs to be addressed as a disease state rather than a mere symptom accompanying skin and systemic disease. Adopting such an approach will yield better outcomes for millions of itchy patients.

References

  1. Yosipovitch G, Greaves MW. Definitions of Itch. In: Yosipovitch G, Greaves MW, Fleischer AB, et al, eds. Itch: basic mechanisms and therapy. New York: Marcel Dekker; 2004:2.
  2. Dalgard F, Svensson A, Holm JO, et al. Self-reported skin morbidity among adults: associations with quality of life and general health in a Norwegian survey. J Investig Dermatol Symp Proc. 2004;9(2):120-5.
  3. Ikoma A, Steinhoff M, Stander S, et al. The neurobiology of itch. Nat Rev Neurosci. 2006;7(7):535-47.
  4. Schmelz M. Complex interactions between pain and itch. Pain. 2006;124(1-2):9-10.
  5. Heyer G, Ulmer FJ, Schmitz J, et al. Histamine-induced itch and alloknesis (itchy skin) in atopic eczema patients and controls. Acta Derm Venereol. 1995;75(5):348-52.
  6. Summey BT Jr, Yosipovitch G. Pharmacologic advances in the systemic treatment of itch. Dermatol Ther. 2005;18(4):328-32.
  7. Yosipovitch G. Pruritus: An Update. Current Problems in Dermatology. 2003;15:137-64.
  8. Yosipovitch G, Greaves MW, Schmelz M. Itch. Lancet. 2003;361(9358):690-4.
  9. Wikstrom B, Gellert R, Ladefoged SD, et al. Kappa-opioid system in uremic pruritus: multicenter, randomized, double-blind, placebo-controlled clinical studies. J Am Soc Nephrol. 2005;16(12):3742-3747.
  10. Dawn AG, Yosipovitch G. Butorphanol for treatment of intractable pruritus: a case series and review of the literature. Submitted for publication 2005.
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