Skin matters! The role of keratinocytes in nociception: a rational argument for the development of topical analgesics

Jan M Keppel Hesselink,1 David J Kopsky,2 Arun K Bhaskar3 1Institute for Neuropathic Pain, Bosch en Duin, the Netherlands; 2Institute for Neuropathic Pain, Vespuccistraat 64-III, Amsterdam, the Netherlands; 3Pain management Centre, Charing Cross Hospital Imperial Healthcare NHS Trust, London, United Kingdom Abstract: Treatment of neuropathic pain using topical formulations is still in its infancy. Only few topical analgesic formulations have become available for clinical use, and among these, analgesic creams are still rare. This is unfortunate because analgesic creams offer a number of advantages over patches, such as convenience, ease of adapting the frequency of application, and dose, and “rubbing cream where it hurts” involves the patient much more in the therapeutic process compared to patches and other localized treatment modalities. Although the literature supporting the efficacy and safety of analgesic creams (mostly compounded) is growing since the last decade, most pain physicians have not yet noticed and appreciated the therapeutic potential and clinical value of these creams. This is most probably due to a prejudice that topical application should need to act transdermally, more or less as a slow-release formulation, such as in patches delivering opioids. We will discuss this prejudice and show that there are multiple important targets in the skin to be reached by topical analgesic or anti-inflammatory compounds, and that the keratinocyte is one of those targets. By specifically targeting the keratinocyte, analgesia seems possible, effective, and safe, and thus topical analgesic creams may hold promise as a novel treatment modality for neuropathic pain. Keywords: topical, keratinocyte, transdermal delivery, analgesics, neuropathic pain, peripheral sensitizatio