In this case series, we describe, for the first time, a group of patients with chronic oncological pain, requiring management by a palliative care team, in which severe SARS-CoV-2 infection resulted in a temporary decrease of pain perception. It should be noted that despite optimal treatment, pain was insufficiently controlled in all cases before the infection. Patient 1 suffered from medullary compression at D2 due to probable perivertebral metastasis associated with bone lysis; patient 2 suffered from painful rib metastases; and patient 3 suffered from neoplastic infiltration of the rectum from a bladder adenocarcinoma. Based on these results, we hypothesize that acute SARS-CoV-2 infection could have modulated pain perception starting within the first few days after the onset of COVID-19 symptoms. It should be specified that none of the patients had impaired cognitive function that could have compromised their evaluation of pain.
Interestingly, none of the patients complained of dyspnea at the moment of hospitalization; moreover, the reappearance of pain in patient 3 coincided with recovery from COVID-19 and de novo onset of dyspnea.
Modulation of nociceptive pain perception is not a known neurological manifestation of this proteiform disease. Instead, several articles have shown that the specific context of the COVID-19 pandemic can contribute to chronification and worsening of pain.[8,12] Different factors have been suggested to explain this phenomenon, mainly social, emotional, psychological, and neuropsychiatric. However, our observation suggests that another COVID-19–related mechanism may be involved in pain perception modulation. Animal models support our clinical observations: SARS-CoV-2 spike protein can interfere with pain signaling by interruption of the vascular endothelial growth factor-A/neuropilin-1 signaling pathway. Thus, this interference could result in pain reduction in animal models of neuropathic pain.[14,21] It should be noted however that the underlying mechanisms of neuropathic pain are different from the nociceptive pain experienced by the 3 patients described in this case series and therefore cannot be completely explained by the alteration of the vascular endothelial growth factor/neuropilin-1 signaling pathway.
Taken together, we believe that this case series suggests that SARS-CoV-2 infection may acutely modulate chronic pain perception. Aside from our seminal observation, only 1 anecdotal case of COVID-19–associated pain reduction was reported by the lay press.
It would be tempting to advocate for a single pathogenetic hypothesis for the now well-known asymptomatic hypoxemia and pain blunting. As we have previously suggested, one can hypothesize that a common, virus-mediated dysfunction of a focal cortical region, the insula, can explain both asymptomatic hypoxemia and decreased pain perception. This could result from either a direct (propagation of SARS-CoV-2 from the nose to the cortex, in particular the insula) or indirect insult (central nervous system [CNS] penetration of inflammatory cytokines in patients with preexisting vessel fragility), as supported by neuroimaging findings of patient 3 showing a bilateral vertebral artery gadolinium enhancement, suggestive of SARS-CoV-2–mediated endotheliitis.[1,6]
Indeed, the insula, in particular its mid and anterior areas, plays a pivotal role in interoception by linking awareness of body signals, such as breathing and pain, to the conscious experience of human emotions.[9,16,23] More specifically, insular lesions are associated with reduced sensitivity to the perception of unpleasantness stemming from both dyspnea and pain, and an altered insular activity has been demonstrated in chronic pain syndromes, eg, temporomandibular joint and fibromyalgia.[2–4,10,11,18,23] The insula is also known to respond to chemesthetic stimulations. Chemesthetic sensations can indeed arise from the activation of somatosensory receptors and interact with the same neural pathways that transduce pain. Interestingly, COVID-19 can reduce oral chemestesis. It is worth noticing that the brain possesses one of the highest expressions of the SARS-CoV-2 cell receptor gene ACE2 of any other organ.[5,13] Moreover, the insula could provide an ideal substrate for SARS-CoV-2 because of its high expression of genes correlated with the SARS-CoV-2 entry factors ACE2/TMPRSS2.
Neuropathological findings in patient 2, the only patient in our case series on whom an autopsy was performed, showed no morphological lesions related to SARS-CoV-2 infection. It is worth noticing that only a few studies have demonstrated the presence of SARS-CoV-2 in brain tissues, and findings of brain autopsies are not unequivocal. Akin to SARS-CoV-2–related encephalopathy, modulation of pain perception could, on the other hand, result from a brain alteration of systemic (inflammatory) origin of which the vascular changes visible in the MRI of patient 2 could be an indication. The fact that pain perception modulation was associated with signs and symptoms of encephalopathy (patients 1 and 2) suggest a possible pathophysiological mechanism related to CNS pain processing interference.
In 2 of our 3 patients (patient 2 died too soon), as well as in the patient described in our previous article, recovery from COVID-19 was associated with a progressive return to baseline pain, further suggesting that the pain-free "honeymoon period" could be attributed to a temporary dysfunction of brain region(s) implicated in pain processing.
A possible effect of SARS-CoV-2 on the peripheral pain pathways should, however, also be considered. Akin to what has been discussed about the CNS, this effect can either be direct (indeed the human dorsal root ganglia sensory neurons express the ACE-2 receptor) or indirect (immuno-mediated).[19,24]
In conclusion, our case series supports the hypothesis that SARS-CoV-2 acute infection can trigger modulation of pain perception. As in asymptomatic hypoxia, dysfunction of the insula could potentially play a pivotal role in this phenomenon. We believe that this pivotal case series can shed a new light on COVID-19 and can likely provide insights into chronic pain pathogenesis. Further studies are needed to evaluate the prevalence of COVID-19–associated pain modulation in different cohorts of patients, its association with silent hypoxemia or encephalopathy, and finally to ascertain whether indeed SARS-CoV-2 has a tropism for the insula.
The study was approved by the Cantonal Research Ethics Committee of Geneva; protocol number 2020–01752.
Pain. 2022;163(6):1019-1022. © 2022 Lippincott Williams & Wilkins