Pain
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Neuropathic itch is clinically important but has received much less attention as compared to neuropathic pain. In the past decade, itch-specific pathways have been characterized on a cellular and molecular level, but their exact role in the pathophysiology of neuropathic itch is still unclear. Traditionally, mutually exclusive theories for itch such as labeled line, temporal/spatial pattern, or intensity theory have been proposed, and experimental studies in mice mainly favor the specificity theory of itch. ⋯ Rarefication of skin innervation in neuropathy could provide a "spatial contrast" discharge pattern, and axotomy could induce de novo expression of the itch-specific spinal neuropeptide, gastrin-releasing peptide, in primary afferent nociceptors, thereby modulating itch processing in the dorsal horn. Thus, clinical neuropathy may generate itch by changes in the spatial and temporal discharge patterns of nociceptors, hijacking the labeled line processing of itch and abandoning the canonical scheme of mutual exclusive itch theories. Moreover, the overlap between itch and pain symptoms in neuropathy patients complicates direct translation from animal experiments and, on a clinical level, necessitates collaboration between medical specialities, such as dermatologists, anesthesiologists, and neurologists.
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Quantitative sensory testing (QST) is a formal variant of a time-honoured clinical examination technique in neurology, the sensory examination. Prototypical QST profiles have been found in human surrogate models of peripheral sensitization, central sensitization, and deafferentation. Probabilistic sorting of individual patients to any combination of these profiles has been developed, and there is emerging evidence for the predictive value of such sensory profiles for treatment efficacy. ⋯ Several psychological factors had previously been found to be predictors of pain chronicity (catastrophizing, self-efficacy, and neuroticism). The relative importance of psychological vs sensory testing predictors has not been evaluated. It is likely that both will have differential roles in clinical practice.
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Chemotherapy-induced peripheral neuropathy (CIPN) is a major challenge, with increasing impact as oncological treatments, using potentially neurotoxic chemotherapy, improve cancer cure and survival. Acute CIPN occurs during chemotherapy, sometimes requiring dose reduction or cessation, impacting on survival. Around 30% of patients will still have CIPN a year, or more, after finishing chemotherapy. ⋯ Mechanisms are complex with changes in ion channels (sodium, potassium, and calcium), transient receptor potential channels, mitochondrial dysfunction, and immune cell interactions. Improved understanding is essential to advance CIPN management. On a positive note, there are many potential sites for modulation, with novel analgesic approaches.
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Peripheral neuropathy is the most common neurodegenerative disease affecting hundreds of millions of patients worldwide and is an important cause of chronic pain. Typical peripheral neuropathies are characterized by dysesthesias including numbness, crawling skin, a sensation of "pins and needles," and burning and stabbing pain. In addition, peripheral neuropathy can affect the motor and autonomic systems leading to symptoms such as weakness, constipation, and dysregulation of blood pressure. ⋯ Many neuropathies are due to degeneration of long axons; however, the mechanisms driving axon loss were unknown, and so no therapies are available to preserve vulnerable axons and prevent the development of peripheral neuropathy. With the recent identification of SARM1 as an injury-activated NADase enzyme that triggers axon degeneration, there is now a coherent picture emerging for the mechanism of axonal self-destruction. Here, we will present evidence that inhibiting the SARM1 pathway can prevent the development of peripheral neuropathy, describe the emerging mechanistic understanding of the axon degeneration program, and discuss how these mechanistic insights may be translated to the clinic for the prevention and treatment of peripheral neuropathy and other neurodegenerative disorders.
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This review expounds on types and properties of biomarkers for chronic pain, given a mechanistic model of processes underlying development of chronic pain. It covers advances in the field of developing biomarkers for chronic pain, while outlining the general principles of categorizing types of biomarkers driven by specific hypotheses regarding underlying mechanisms. Within this theoretical construct, example biomarkers are described and their properties expounded. We conclude that the field is advancing in important directions and the developed biomarkers have the potential of impacting both the science and the clinical practice regarding chronic pain.