Skin Matters: Identifying Pain Mechanisms and Predicting Treatment Outcomes

Mye om huden relatert til smerte og nevropati! Mest relatert til biopsi, men mye kan knyttes til behandling også. Spesielt ved hemming av TRPV1.

This data has led to new insights into the potential pain mechanisms for various pain conditions including neuropathic pain (from small fiber neuropathies) and Complex Regional Pain Syndrome. The somatosensory neurons that innervate our skin constantly update our brains on the objects and environmental factors that surround us. Cutaneous sensory neurons expressing nociceptive receptors such as transient receptor potential vanilloid 1 channels and voltage-gated sodium channels are critical for pain transmission. Epidermal cells (such as keratinocytes, Langerhans cells, and Merkel cells) express sensor proteins and neuropeptides; these regulate the neuroimmunocutaneous system and participate in nociception and neurogenic inflammation.

The skin has homeostatic and immunologic barrier functions, but acts as a complex sensory organ as well [1]. The somatosensory neurons that innervate our skin constantly update our brains on the objects and environmental factors that surround us [2]. The neuroimmunocutaneous system (NICS) is responsible for the cutaneous sensations of touch, pressure, temperature, and pain. This sensory transduction occurs via primary afferent nerves following reciprocated signals between neuronal and nonneuronal skin cells of the NICS [1]. New data concerning peripheral pain mechanisms from within the skin have led to new insight into the potential pain mechanisms for various pain conditions including neuropathic pain syndromes such as diabetic neuropathy and Complex Regional Pain Syndrome.

In pain and neurogenic inflammation, TRPV1 is coexpressed on TRPA1-expressing sensory nerves; both integrate a variety of noxious stimuli [4]. Complex signaling pathways between cells of the NICS, such as keratinocytes, TRPV1-expressing nociceptors, and macrophages, lead to the release of neural growth factor (NGF), prostaglandins, opioids, proinflammatory cytokines, and chemokines [1]. These lead to sensitisation of the peripheral nerves by upregulating ionic channels and by inducing further spinal cord cytokine release [8].

2. Small Fiber Neuropathy (SFN)
Neuropathic pain arises as a direct consequence of a lesion or disease of the somatosensory system; it affects about 7% of the general population [10, 11].

Small fiber neuropathy is a neuropathy of the small nonmyelinated fibers and myelinated A delta fibers. Neuropathic pain occurs from small fiber neuropathy; small fiber neuropathy is caused by a wide variety of acquired and genetic disorders [12], many of which are treatable [13].

Diabetes mellitus is the most frequent underlying cause of SFN [14]. Other causes include toxic (e.g., alcohol), metabolic, immune-mediated, infectious, and hereditary causes.

About 60% of patients describe the painful sensation as spontaneous (burning, sunburn-like, paroxysmal, pruritic, and deep), with worsening at rest or during the night [12]; the sensation can be associated with thermal evoked pain (cold or warm) with or without allodynia, a painful response to a normally innocuous stimulus, and hyperalgesia, an increased response to a painful stimulus [12]. In addition there are negative sensory symptoms (thermal and pinprick hypoesthesia) that reflect peripheral deafferentation [19]. Sensation of cold feet is reported, though warm to touch. Thermal hypoesthesia with or without pinprick hypoesthesia has been detected in 40% of patients [20]; hyperalgesia and aftersensation have been detected in 10–20% of patients [12, 20].

2.3. Complex Regional Pain Syndrome (CRPS)
CRPS is a syndrome characterized by a continuing (spontaneous and/or evoked) regional pain, that is, seemingly disproportionate in time or degree to the usual course of any known trauma or other lesion [23]. The pain is regional (not in a specific nerve territory or dermatome); it usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings. It has signs of central sensitisation such as allodynia and hyperalgesia. The syndrome shows variable progression over time [23].

Accumulating experimental and clinical evidence supports the hypothesis that Complex Regional Pain Syndrome type I (CRPS-I) might indeed be a small fiber neuropathy [25]. Most post-traumatic inflammatory changes observed in CRPS are mediated by two peptides, CGRP and substance P [26]. The activation of cutaneous nociceptors can induce retrograde depolarisation of small-diameter primary afferents, causing release of neuropeptides such as substance P and CGRP from sensory terminals in the skin.

A specific diagnostic test for small fiber neuropathy is a skin biopsy; this includes a count of the intraepidermal small nerve fibers (IENF) that cross the basal membrane. The loss of IENF can be reliably measured and is currently used to diagnose small fiber neuropathy (SFN) [17].

Skin biopsy is much less invasive and more practical than peripheral nerve biopsy. It is a safe and reliable tool for investigating nociceptive fibers in human epidermis and dermis [29]. It can be performed at any site of the body, with a disposable punch, using a sterile technique, and under local anesthesia (Figure 2) [29].

A recent study assessed the usefulness of skin biopsy in the assessment of 145 patients with suspected SFN [21]. In 59% of patients skin biopsy was abnormal in at least one site [21]. Patients with confirmed SFN were significantly more likely to have pain; they were more than twice as likely to respond to standard neuropathic pain medications [21]. A positive response to neuropathic pain medications was seen in 84% of patients with an abnormal skin biopsy compared to only 42% of those with a normal biopsy [21]. Skin biopsy has a relatively high yield in patients with sensory symptoms with no findings of mixed fiber neuropathy on clinical examination or on nerve conduction studies [21].

Along with neuronal and immunological systems, the skin plays a critical role in sensory transduction [1]. Further direct targeting of the skin with topical agents should be considered. The interaction of TRPV1 and TRPA1 channels in the skin in painful conditions needs further exploration. Second generation TRPV1 antagonists (without on-target side effects of hyperthermia and burn risk) are under development [6].

In Pain Medicine, the skin does indeed matter!

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