COVID-Pain: Acute and Late-Onset Painful Clinical Manifestations in COVID-19 - Molecular Mechanisms and Research Perspectives

Abstract

Although the respiratory manifestations of COVID-19 are predominant, signs and symptoms of an extra-pulmonary involvement are usually encompassed among the clinical picture of the disease. Several painful manifestations can occur during the acute phase but also as short- or long-term complications. Myalgia, joint pain, sore throat, abdominal pain, chest pain, and headache usually accompany respiratory symptoms, but they can also occur as isolated clinical findings or can be expressed regardless of the severity of COVID-19. On these premises, given the vast spectrum of clinical manifestations and the complexity of their pathogenesis, it would be more appropriate to refer to "COVID-pain", an umbrella term useful for encompassing all these clinical manifestations in a separate chapter of the disease. In this scenario, we addressed the topic from a molecular perspective, trying to provide explanations for the underlying pathophysiological processes. Consequently, this narrative review is aimed at dissecting the mechanisms of acute and chronic painful manifestations, summarizing fundamental concepts on the matter, controversies, current research gaps, and potential developments in this field.

Keywords: COVID-19; COVID-19 complications; COVID-pain; SARS-CoV-2.

Figure 1

Potential mechanisms of COVID-pain (SARS-CoV-2/COVID-19-induced pain). (A) ACE2/RAS pathway and the direct virus-induced damage. Within the RAS, the virus/receptor (ACE2) interaction involves unbalance of the ACE/Ang II/AT1R and the ACE2/Ang-(1–7)/MasR axes with down-regulation of ACE2 levels on cell surfaces, Ang-II accumulation, and impairment of the anti-nociceptive Ang-(1-7) pathway. Therefore, direct damage to sensory neurons and/or glial cells is produced. (B) Macrophage activation. Macrophages and other immune cells can stimulate the production of inflammatory mediators (eg, IL-1β, TNF, and bradykinins). These processes can facilitate the sensory cells injury and can lead to chronic pain through sensitization/activation processes. (C) The exuberant immune-mediated inflammation. It is mostly responsible for systemic damage and the triggering of long-COVID problems (including widespread myalgia and joint pain) via peripheral and central mechanisms. Disease-related and predisposing factors contribute to the determinism of the damage.