Research designs considerations for chronic pain prevention clinical trials: IMMPACT recommendations

Although certain risk factors can identify individuals who aremost likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACTmeeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses.We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, inmany instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials

Clinical presentation, management, and pathophysiology of neuropathic itch

Unlike conventional itch, neuropathic itch develops in normal skin from excess peripheral firing or dampened central inhibition of itch pathway neurons. Neuropathic itch is a symptom of the same central and peripheral nervous system disorders that cause neuropathic pain, such as sensory polyneuropathy, radiculopathy, herpes zoster, stroke, or multiple sclerosis, and lesion location affects symptoms more than aetiology. The causes of neuropathic itch are heterogeneous, and thus diagnosis is based primarily on recognising characteristic, disease-specific clinical presentations. However, the diagnosis of neuropathic itch is challenging, different subforms exist (eg, focal vs widespread, peripheral vs central), and the mechanisms of neuropathic itch are poorly understood, resulting in reduced treatment availability. Currently available strategies include treating or preventing causal diseases, such as diabetes or herpes zoster, and topical or systemic medications that calm excess neuronal firing. Discovery of itch mediators such as gastrin releasing peptide, receptors (eg, neurokinin-1), and pathways (eg, Janus kinases) might encourage much needed new research into targeted treatments of neuropathic itch. ? 2018 Elsevier LtdNational Institutes of Health, Deutsche ForschungsgemeinschaftScopu

Neuropathic itch

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. By contrast, results in humans also suggest a role for spatial and temporal patterns in neuropathic 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.Scopu

Peripheral Neuropathy Evaluations of Patients With Prolonged Long COVID

BACKGROUND AND OBJECTIVES: Recovery from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection appears exponential, leaving a tail of patients reporting various long COVID symptoms including unexplained fatigue/exertional intolerance and dysautonomic and sensory concerns. Indirect evidence links long COVID to incident polyneuropathy affecting the small-fiber (sensory/autonomic) axons. METHODS: We analyzed cross-sectional and longitudinal data from patients with World Health Organization (WHO)-defined long COVID without prior neuropathy history or risks who were referred for peripheral neuropathy evaluations. We captured standardized symptoms, examinations, objective neurodiagnostic test results, and outcomes, tracking participants for 1.4 years on average. RESULTS: Among 17 patients (mean age 43.3 years, 69% female, 94% Caucasian, and 19% Latino), 59% had ≥1 test interpretation confirming neuropathy. These included 63% (10/16) of skin biopsies, 17% (2/12) of electrodiagnostic tests and 50% (4/8) of autonomic function tests. One patient was diagnosed with critical illness axonal neuropathy and another with multifocal demyelinating neuropathy 3 weeks after mild COVID, and ≥10 received small-fiber neuropathy diagnoses. Longitudinal improvement averaged 52%, although none reported complete resolution. For treatment, 65% (11/17) received immunotherapies (corticosteroids and/or IV immunoglobulins). DISCUSSION: Among evaluated patients with long COVID, prolonged, often disabling, small-fiber neuropathy after mild SARS-CoV-2 was most common, beginning within 1 month of COVID-19 onset. Various evidence suggested infection-triggered immune dysregulation as a common mechanism. Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology

Acute monophasic erythromelalgia pain in five children diagnosed as small-fiber neuropathy.

The small-fiber polyneuropathies (SFN) are a class of diseases in which the small thin myelinated (Aδ) and/or unmyelinated (C) fibers within peripheral nerves malfunction and can degenerate. SFN usually begins in the farthest, most-vulnerable axons, so distal neuropathic pain and symptoms from microvascular dysregulation are common. It is well known in adults, e.g. from diabetes, human immunodeficiency virus, or neurotoxins, but considered extremely rare in children, linked mostly with pathogenic genetic variants in voltage-gated sodium channels. However, increasing evidence suggests that pediatric SFN is not rare, and that dysimmunity is the most common cause. Because most pediatric neurologists are unfamiliar with SFN, we report the diagnosis and management of 5 Swiss children, aged 6-11y, who presented with severe paroxysmal burning pain in the hands and feet temporarily relieved by cooling-the erythromelalgia presentation. Medical evaluations revealed autoimmune diseases in 3 families and 3/5 had preceding or concomitant infections. The standard diagnostic test (PGP9.5-immunolabeled lower-leg skin biopsy) confirmed SFN diagnoses in 3/4, and autonomic function testing (AFT) was abnormal in 2/3. Blood testing for etiology was unrevealing, including genetic testing in 3. Paracetamol and ibuprofen were ineffective. Two children responded to gabapentin plus mexiletine, one to carbamazepine, two to mexiletine plus immunotherapy (methylprednisolone/IVIg). All recovered within 6 months, remaining well for years. These monophasic tempos and therapeutic responses are most consistent with acute post-infectious immune-mediated causality akin to Guillain-Barré large-fiber polyneuropathy. Skin biopsy and AFT for SFN, neuropathic-pain medications and immunotherapy should be considered for acute sporadic pediatric erythromelalgia