A mechanistic understanding of the relationship between skin innervation and chemotherapy-induced neuropathic pain

Abstract

Neuropathic pain is a frequent complication of chemotherapy-induced peripheral neurotoxicity (CIPN). Chemotherapy-induced peripheral neuropathies may serve as a model to study mechanisms of neuropathic pain, since several other common causes of peripheral neuropathy like painful diabetic neuropathy may be due to both neuropathic and non-neuropathic pain mechanisms like ischemia and inflammation. Experimental studies are ideally suited to study changes in morphology, phenotype and electrophysiologic characteristics of primary afferent neurons that are affected by chemotherapy and to correlate these changes to behaviors reflective of evoked pain, mainly hyperalgesia and allodynia. However, hyperalgesia and allodynia may only represent one aspect of human pain, i.e., the sensory-discriminative component, while patients with CIPN often describe their pain using words like annoying, tiring and dreadful, which are affective-emotional descriptors that cannot be tested in experimental animals. To understand why some patients with CIPN develop neuropathic pain and others not, and which are the components of neuropathic pain that they are experiencing, experimental and clinical pain research should be combined. Emerging evidence suggests that changes in subsets of primary afferent nerve fibers may contribute to specific aspects of neuropathic pain in both preclinical models and in patients with CIPN. In addition, the role of cutaneous neuroimmune interactions is considered. Since obtaining dorsal root ganglia and peripheral nerves in patients is problematic, analyses performed on skin biopsies from preclinical models as well as patients provide an opportunity to study changes in primary afferent nerve fibers and to associate these changes to human pain. In addition, other biomarkers of small fiber damage in CIPN, like corneal confocal microscope and quantitative sensory testing, may be considered.

Exercise intervention for the management of chemotherapy-induced peripheral neuropathy: a systematic review and network meta-analysis

“…In diagnosing peripheral neuropathy, electromyography and nerve conduction velocity discern nerve fiber types ( 51 ). Nerve conduction studies (NCS) are suitable for detecting large fiber neuropathy but are often normal in small fiber neuropathy (SFN) and CIPN ( 52 , 53 ). SFN can be diagnosed by skin biopsy in addition to symptom assessment ( 53–55 ).…”

“…Nerve conduction studies (NCS) are suitable for detecting large fiber neuropathy but are often normal in small fiber neuropathy (SFN) and CIPN ( 52 , 53 ). SFN can be diagnosed by skin biopsy in addition to symptom assessment ( 53–55 ). Definitive diagnostic methods for CIPN have not been established due to diverse mechanisms and inconsistency between subjective symptoms and neurophysiological testing, and invasive skin biopsy has limited its use in oncology ( 10 , 52 , 53 , 55 ).…”

“…SFN can be diagnosed by skin biopsy in addition to symptom assessment ( 53–55 ). Definitive diagnostic methods for CIPN have not been established due to diverse mechanisms and inconsistency between subjective symptoms and neurophysiological testing, and invasive skin biopsy has limited its use in oncology ( 10 , 52 , 53 , 55 ). Although the mechanism and symptoms of CIPN vary by anticancer drug, CIPN is characterized mainly by sensory nerve fiber damage ( 1 , 9 , 10 ).…”

Rehabilitation of Peripheral Neuropathies: From Lexical Analysis of the Literature to Identification of Clinical Protocols

“…In addition to the complex classification of PNDs, the clinical presentation is not always clear, and the symptoms and their severity can be variegated. In cases of sensory involvement, neuropathic pain, allodynia, hypoesthesia, and sometimes itch may be present [ 21 ]. In motor involvement, a strength deficit and difficulties in motor tasks are present [ 22 ].…”

Editorial: Insights in neuropathic pain: 2022

“…The subsequent review by Meregalli et al focuses on the involvement of skin innervation in chemotherapy-induced neuropathic pain ( 6 ). Neuropathic pain is a common neurological complication of chemotherapy-induced peripheral neurotoxicity (CIPN).…”