Meeting report Itching in the Nineties International Symposium on Itch: Basic and Clinical Aspects, Stockholm, Sweden, May 17-19, 1990 Jeffrey D. Bernhard, MD Worcester, Massachusetts Itch declared its independence from pain at a symposium held at the Karolinska Sjukhuset in Stockholm in May 1990. As conference organizer Osten Hagermark noted, itch has been treated as something of a "poor cousin" of pain "from a country that nobody cares much about." Although itch and pain are surely of a class in that both are modalities of nociception transmitted by small unmyelinated C fibers, evidence that itch is not just a variety of low-threshold pain was presented in force. Itch leads to the reflex or urge to scratch; pain leads to withdrawal. Itch occurs only in the skin; pain arises from deeper structures as well. Heat may stop itch but usually increases pain. Removal of the epidermis eliminates itch but causes pain. Analgesics, particularly opioids, relieve pain but often cause itch. In addition, as a variety of recent microstimulation and microneurographic experiments described by Erik Torebjork of Uppsala and Robert Tuckett and Herve Martin of Salt Lake City suggest, itch appears to be transmitted by a class of polymodal C nociceptors different from those that carry pain. For example, the magnitude of itch could be modulated by changes in the frequency of a stimulus delivered to peripheral nerve fibers in awake human subjects, but "the quality of itch did not change into pain at high frequencies," according to Torebjork. Similarly, Tuckett and Martin reported that only some polymodal C receptors subjected to stimulation by a variety of mechanical, temperature, and chemical stimuli responded to the classical itch-producing stimulus Mucuna pruriens. Although no one raised the issue, it could be argued that the historical vision of itch as a variety of pain has had a stultifying effect on research in the field and that thought-constricting terms such as nociceptor, which intellectually link itch to pain, From the Division of Dermatology, University of Massachusetts Medical Center. Reprints not available.
should be abandoned in favor of a more appropriate term such as itch receptor or knesmoreceptor (from the ancient Greek term for itch). (Although the anatomic existence of such a "receptor" remains to be clarified, the best working hypothesis at the moment is not new: the itch receptor resides at the free nerve endings of C fibers specialized to carry information about itch.) If this formulation seems at all too simple, it may be. Things got a bit ticklish when Patrick D. Wall of "gate-control" theory renown and the Cerebral Functions Research Group at University College, London, raised several objections to "the classical theory of hard-wired, dedicated, line-labelled, modality-specific sensory fibres" and argued in favor of "a more subtle system in which both peripheral and central analysis is involved." Although none of the dermatologists or cutaneous biologists denied the importance of the central nervous system in itch processing (or of gating mechanisms, for that matter), the discussion also made it clear that a meeting of the minds had yet to lead to an adequate model in which the central nervous system and labeled lines from the skin both would receive their due. In a talk entitled "Why Does Scratching Relieve Itching?" Wall noted that "we should examine itch from the vantage of changed peripheral excitation with central disinhibition" and scratch as a stimulus to restoration of central inhibition. The neural wiring of such an interaction may reside, at least in part, in large-diameter, low-threshold myelinated afferents that, when stimulated, "inhibit dorsal horn cells by both pre-synaptic and post-synaptic mechanisms. These afferents may be stimulated by scratching or by vibration or by low-level repetitive electrical stimulation, TENS (transcutaneous electrical nerve stimulation)," according to Wall. In addition to their local segmental inhibitory effects, such stimuli also could have a general placebo effect, he said. Along these lines Anders Ekblom, of the Karolinska Institute, reviewed the evidence for a beneficial effect of transcutaneous electrical nerve stimulation and acu-
310 Bernhard puncture in both experimental and clinical pruritus. Several speakers covered the chemical aspects of itch. Osten Hagermark reviewed his seminal work on histamine, serotonin, and prostaglandins and speculated on the possible existence of pruritogenic cytokines. His experiments, however, have not yet succeeded in demonstrating their existence. J. C. Foreman, of University College, London, discussed neurogenic inflammation and itch. C fibers contain a variety of neuropeptides, including substance P, somatostatin, neurokinin A, and calcitonin gene-related peptide. We know that substance P is directly involved in the spreading vasodilatory flare of the triple response. Substance P also leads to plasma extravasation. It and other neuropeptides can be expected to contribute to inflammatory responses in the skin when some types of afferent sensory nerves are stimulated antidromically, that is, in a retrograde direction opposite from that in which they ordinarily convey impulses. Foreman also concluded that "the C-fibres conveying pain appear to be separate from those conveying itch." (Observe the tentative declaration of independence from pain again here: pain and itch "appear" to be members of the same commonwealth of C fiber-mediated sensations, pay appropriate homage to the central nervous system, but still are separate entities.) Bruce Lynn, also of University College, London, then described the dramatic effect that capsaicin has in depleting substance P and causing "a long-lasting and selective depression in the functioning of C-polymodal nociceptors." Here again, itch and pain appear to be affected in concert, but that does not prove that the sensations are not separate modalities. On the contrary, one could assume that different itch and pain C fibers are both sensitive to capsaicin. Further, there is clinical· evidence that links substance Pcontaining fibers to itchy skin. In a poster presentation, Joanna Wallengren described promising results with topical capsaicin treatment of notalgia paresthetica. Lars Tesenius of Stockholm, E. Weihe of Mainz, and 6. Hagermark reviewed the current status of opioid peptides and itch. Circumstantial evidence for their involvement in itching, perhaps even as transmitters of the itch sensation, continues to mount. Aquagenic pruritus was reviewed by Malcolm Greaves of London, cholestatic pruritus by Gerard Murphy of London, and uremic pruritus by Mona Stahle-Backdahl of Stockholm. One of the most interesting observations reported by Stahle-Backdahl
Journal of the American Academy of Dermatology
was the presence of nerve fibers and terminals sprouting throughout the layers of the epidermis of patients with uremic pruritus. These were detected by immunohistochemical staining for a new marker called neuron-specific enolase. Barbara Gilchrest of Boston discussed itching in the elderly and phototherapeutic treatment of pruritus of various types. Perhaps the most controversial discussions at the symposium centered about the role of histamine, if there is one, in atopic dermatitis and the use of sedating versus nonsedating antihistamines in its treatment. Sam Shuster of Newcastle-upon-Tyne reiterated the central dogma on this question, namely, that any beneficial effect of antihistamines in reducing the itch of atopic dermatitis is due to their sedative effect and not their specific antihistamine effect. John Gibson of Buffalo fearlessly picked up the gauntlet, arguing that virtually all studies in this area are flawed in one way or another. He reviewed data from studies in which the so-called nonsedative (he prefers to call them "low-sedative") antihistamines did seem to have a beneficial effect on atopic dermatitis and suggested that subgroups of patients may respond to such agents. He questioned the reliability of cross-over trails in atopic dermatitis, which may be hurt by order effects and by insufficient treatment periods. Perhaps more tests with techniques to measure scratching, as described by Shuster and by J. A. Savin of Edinburgh, will help to settle the issue some day. A microcomputer-based portable data logger for itching, as described by Wahlgren and colleagues of the Stockholm group, is sure to be helpful in future studies as well. Or perhaps someone will discover an H s receptor or a molecular aberration in the HI receptor of patients with atopic eczema; such a finding might help all of the conflicting data and opinions fall neatly into a comprehensive theory. Near the session's end, there was some discussion about whether the long-standing definition of itch as "a sensation that produces the desire to scratch" requires revision. I, for one, think not. Professor Wall, however, suggested that "a Karolinska itch inventory," analogous to the McGill Pain Questionnaire, be created in honor of the Karolinska Hospital's 50th Anniversary and named Kitch. Alas, he had been anticipated by such an instrument under development at the University of Massachusetts in Worcester, called Witch. Abstracts from the Itch Symposium have been published in Skin Pharmacology 1989;2(4):217-35.