Analgesia During COVID-19 Infection, a Case Report and Review of the Literature

Introduction

The COVID-19 pandemic was primary characterized with an acute respiratory syndrome, however neurological complications such as anosmia, headaches and others are common [1-3]. However, transient hypoalgesia or analgesia during a SARS-CoV-2 infection are hardly ever reported [3]. We described a woman disabled by a chronic painful dermatomyositis refractory to therapy who developed a generalized anesthesia during a SARS‐CoV‐2 infection that slowly resolved months after the resolution of the viral illness. We also discuss the meager literature about COVID-19-related analgesia in other painful disorders.

Clinical Presentation

A 44-year-old female with chronic painful dermatomyositis who presented herself into the Emergency Department one morning when she woke up with no more diffuse body achiness, but with anosmia and ageusia. She tested positive for SARS‐CoV‐2. She denied symptoms of upper respiratory infection, cough, dyspnea, fever, chills, chest pain, abdominal pain, nausea, vomiting, diarrhea, and headaches. Her painful dermatomyositis was characterized by a diffuse myalgias affecting her body, especially upper and lower limbs. She was refractory to several analgesic medications including gabapentin, pregabalin, tricyclics, and baclofen. Her general and neurological examination was unremarkable, except for a sensory exam that revealed absent pinprick and temperature loss in upper extremities. Lab was unremarkable for anti-acetylcholine antibodies and anti-MUSK antibodies, myositis-related antibodies, paraneoplastic panel, CK/Aldolase, CRP, complete metabolic and rheumatic panel. Brain imaging was deemed unnecessary. The generalized analgesia, anosmia and ageusia started to dissipate into the third month post infection period with resumption of myalgias and for the fifth month she was back to the pre-infection state.

Discussion

We describe a woman with a chronic painful dermatomyositis who became pain free during COVID-19 illness and postinfectio period. This represents the first woman with blunting in pain during a SARS-CoV-2 infection. There are six prior cases in English, all men and refractory to pain therapy with a significant pain improvement during a COVID-19 infection.

The first case, a 49-years old male with refractory neuropathic pain in his legs, especially at night, caused by a motor vehicle accident with multiple vertebral fractures, who experienced a dramatic pain improvement during COVID infection that present with headaches and fatigue; as the infection resolved his pain resumed [4]. The second case was a 70-years-old male chronic refractory back pain that resolved during a COVID infection that required hospitalization due to severe hypoxia, but with no discomfort or dyspnea. His refractory chronic back pain resolved during the viral infections. His clinical features resumed a month later [5]. A case series of three terminal cancer patients refractory to pain therapy developed analgesia or hypoalgesia surrounding a COVID infection: a 84-yearold- male with a neuroendocrine carcinoma and severe lumbar pain due to peri-vertebral bone metastasis who did not required any longer opioids during the viral infection; a 68-year-old-man with chest pain related to bilateral rib metastases who became pain free during a COVID 19 infection with fever and coughing and a 67-year-old man with bladder adenocarcinoma with neoplastic infiltration of the rectum with excruciating pain, especially while defecating. During COVID illness he developed coughing, fatigue, fever and hypoxemia, however his pain dramatically resolved only having minimal pain while defecating. A month later his rectal pain reappeared as his viral infection cleared. All died soon after, but none had serious cognitive issues to invalidate their pain self-report [1]. The last case was a 48-year-old man who during a COVID illness with mild flu-symptoms, severe anosmia, ageusia and bilateral leg sensory loss had no pain after a right knee surgery, even during physical therapy. The COVID-illness lasted a month, but most of his neurological symptoms continued progressively resolving after a year [6]. The intraepithelial nerve density displayed a reduction of nerve fibers in the distal leg skin. Table 1 showed summary of all these cases.

Table 1: Main features of patients with COVID-related analgesia.

It is unknown how SARS-CoV-2 infection modulated pain perception during the COVID-19 illness. The SARS-CoV-2 Spike glycoprotein (S-glycoprotein) binds to the Angiotensin-Converting Enzyme 2 (ACE2) protein, a noci-receptor located at the dorsal root ganglia. When viruses get access into the sensory neuron via the ACE2 receptor ends harming their axons, as shown in the last case where a decrement in intraepidermal nerve fibers density was reported [6].

An alternative door for SARS-CoV-2 virus is throughout the Neuropilin NRP1, also known as vascular endothelial cell growth factor 165 receptor [VEGF165R] [7]. When the viral spike interact with the NRP1 protein causes the virus to get access into the cell. In animal models the SARS-CoV-2 spike protein might interfere with pain signaling while interrupting the vascular endothelial growth factor-A [VEGF] /neuropilin-1 [NRP-1] signal pathway and diminishing or preventing the pain sensation. The VEGF has a pronociceptive effect making sensory neurons to fire. In an animal study when VEGF was applied on the paw induced pain in 24 hours, but that painful response was blocked when VEGF and viral spike were used together. NRP1 is a cofactor for the ACE2 receptor and co-work with the ACE2 in modulation of pain [4,8-13].

Conclusion

This case in conjunction with six prior cases suggests that SARSCoV- 2 infection may acutely and sub-acutely modulate chronic pain. Therefore, a high index of suspiciousness for COVID-19 infection should be maintained in any case of an acute and unexplained resolution of chronic pain, regardless if patient is symptomatic for COVID 19 infection.

Study Funding

No targeted funding reported.

Disclosures

The authors report no disclosures relevant to the manuscript.

Acknowledgements

None.

Conflicts of Interest

None.

References

• Lisa Hentsch, Patrick Stancu, Gilles Allali, Karl Olof Lövblad, Johannes A Lobrinus, et al. (2022): Decrease in pain perception during acute SARS-CoV-2 infection: a case series. Pain. 163(6): 1019-1022.
• Aubin Moutal, Laurent F Martin, Lisa Boinon, Kimberly Gomez, Dongzhi Ran, et al. (2021): SARS-CoV-2 spike protein co-opts VEGF-A/neuropilin-1 receptor signaling to induce analgesia. Pain 162(1): 243-252.
• Oaklander AL (2020) Clinical significance of angiotensin-converting enzyme 2 receptors for severe acute respiratory syndrome coronavirus 2 (COVID-19) on peripheral small-fiber sensory neurons is unknown today. Pain 161(11): 2431-33.
• (2020) What we know so far about how COVID affects the nervous system.
• Coen M, Kaiser C, Naimi R, Uginet M, Hentsch L, et al. (2021) Beyond silent hypoxemia: Does COVID-19 can blunt pain perception? Comment on "The neuroinvasive potential of SARS CoV2 may play a role in the respiratory failure of COVID 19 patients". J Med Virol 93: 1915-1916.
• Becker J, Papagianni A, Herrmann E, Nöller F, Sommer C, et al. (2022) Transient hypoalgesia after COVID-19 infection. Pain Rep 7(2): 990.
• Soker S, Gollamudi Payne S, Fidder H, Charmahelli H, Klagsbrun M (1997) Inhibition of vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation by a peptide corresponding to the exon 7-encoded domain of VEGF165. J Biol Chem. 272(50): 31582-31588.
• Abebe EC, Ayele TM, Muche ZT, Dejenie TA (2021) Neuropilin 1: A Novel Entry Factor for SARS-CoV-2 Infection and a Potential Therapeutic Target. Biologics 15: 143-152.
• Jinsung Yang, Simon J L Petitjean, Melanie Koehler, Qingrong Zhang, Andra C Dumitru, et al. (2022) Molecular interaction and inhibition of SARS-CoV-2 binding to the ACE2 receptor. Nat Commun 11(1): 4541.
• Ludovico Cantuti Castelvetri, Ravi Ojha, Liliana D Pedro, Minou Djannatian, Jonas Franz, et al. (2020) Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science 370(6518): 856-860.
• James L Daly, Boris Simonetti, Katja Klein, Kai En Chen, Maia Kavanagh Williamson, et al. (2020) Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science 370: 861-865.
• McWilliam M, Samuel M, Alkufri FH (2021) Neuropathic pain post-COVID-19: a case report. BMJ Case Rep 14(7): 243459.
• Stephanie Shiers, Pradipta R Ray, Andi Wangzhou, Ishwarya Sankaranarayanan, Claudio Esteves Tatsui, et al. (2020) ACE2 and SCARF expression in human dorsal root ganglion nociceptors: implications for SARS-CoV-2 virus neurological effects. Pain 161(11): 2494-2501.