Franco Gemignani¹

^{Received: 31 July 2023 / Accepted: 15 November 2023 / Published online: 22 November 2023
© Fondazione Società Italiana di Neurologia 2023}

Fibromyalgia is a common condition characterized by widespread pain in association with a constellation of additional symptoms affecting various systems and organs. These features have been incorporated in the American College of Rheumatology (ACR) criteria [1]. The disease is usually well recognizable, and the clinical diagnosis based on
the ACR criteria is reliable, although no disease biomarkers have been identified, and the pathomechanisms remain unclear. In this regard, new perspectives have been disclosed, in recent years, by findings of functional and structural changes involving the nociceptive sensory system in fibromyalgia patients (review in [2]). The practical guidelines provided by the position statement of the Italian Society of Neurology-Neuropathic Pain Study Group (NPSG) [3] propose an innovative approach that integrates the traditional clinical assessment with new techniques investigating the sensory system in fibromyalgia, with the aim of refining the diagnostic workup, as well as
offering further insight into pathophysiology. An emerging point is that many fibromyalgia patients display decreased intraepidermal nerve fiber density on skin biopsy [2, 3], and other functional and/or structural signatures of small fiber involvement [2, 3]. Small fiber changes occurring in clinical contexts not consistent with small fiber neuropathy (SFN) have been categorized as small fiber pathology [4], and reported in association with various conditions, including Parkinson’s disease and amyotrophic lateral sclerosis [4]. Differently from other diseases associated with small fiber pathology, fibromyalgia has predominant painful manifestations; thus, small fiber changes may have a pathophysiological role, and not simply represent a laboratory finding of undetermined significance.

Fibromyalgia with small fiber pathology may have similarities with and should be differentiated from SFN, especially in SFN patients presenting with diffuse or multifocal pain symptoms. Differential diagnosis based on the ACR criteria might be not sufficient to discriminate between the two conditions. Widespread pain, the core element of the criteria, may be present in the nonlength dependent subtype of SFN (NLD-SFN). Also additional symptoms featuring the ACR criteria, such as fatigue, are quite common in SFN, and not strictly specific for fibromyalgia. Fibromyalgia and SFN are intuitively felt as different entities, and phenotypic differences are usually evident. Conceptually, fibromyalgia is identified as a condition of impaired processing of nociceptive inputs at the central level, with nociplastic pain, whereas SFN is underpinned by peripheral dysfunction of unmyelinated C fibers and thinly myelinated A-delta fibers, usually manifesting with neuropathic pain (or equivalents, such as dysesthesia). Nociplastic pain designates pain arising from altered nociception despite no clear evidence of nociceptive or neuropathic mechanisms, and is characterized by a regional rather than discrete distribution, with signs of pain hypersensitivity as possible clues for central sensitization [5]. Recent findings [2, 3] prospect a more complex scenario, showing that both peripheral and central mechanisms are variably involved in the pathophysiology of fibromyalgia, translating in a wide spectrum of sensory phenotypes, with possible mechanisms not restricted to nociplastic pain. On the other hand, a subset of patients with NLDSFN may have fibromyalgia-like presentation [6], and in some SFN patients, central sensitization might be driven by small fiber changes [2]. Overall, nociplastic pain and neuropathic pain represent still valid paradigms, as predominant endophenotypes of fibromyalgia and, respectively, of SFN, even considering clinical and mechanistic variability and overlap.

GKB-NON-2024-00189