The Science Behind Long COVID and Pain

Discover the science behind long COVID and its connection to pain. Learn how COVID-19 affects comorbidities and the challenges of pain management during the pandemic. Explore new studies on hamsters that provide insights into the triggers of pain in long COVID patients. Find out how researchers are developing new therapies and potential pain management strategies.

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Ever since the end of 2019 and the next two years after that, to the present moment, the world has been besieged at large by the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). It was first detected in the Hubei province of China from where it transmitted through the whole nation, thereafter crossing geographical boundaries to literally infect the rest of the world.


Epidemic Breaches Shores

A short time after the outbreak, COVID-19 was classified as an epidemic by the World Health Organization (WHO) and posed a threat of global magnitude. Millions were infected and a huge percentage of infected persons passed away either due to the severity of the infection or because of associated comorbidities.

Direct contact and droplets are the main source of infection for COVID-19 where the spread range is 2.2 to 3.58. The time the virus incubates in the human body is about 5 days. These are factors that impede the battle against the virus, with a lack of targeted treatment, and a lack of suitable vaccines that contribute to the virus’s spread.


COVID And Comorbidities

Symptoms of COVID-19 are not specific at all. It could be something as banal as a common cold, or as severe and lethal, as a respiratory tract infection. Again there were many studies conducted that said that the COVID-19 infection could be totally asymptomatic, which made detection and treatment harder for doctors. Comorbidity is the most serious threat for patients with COVID


Reported frequencies for the 25 phenotypic features identified in 12 or more cohorts. Box plots are shown for each item, displaying the minimum (1.5 times the interquartile range below the lower quartile), first quartile, median, third quartile, and maximum (1.5 times the interquartile range above the upper quartile). Outliers are shown as dots.

where a study conducted on Chinese patients found that 50% of them had 1 or more medical conditions that were pre-existing. These pre-existing conditions were mostly cerebrovascular or cardiovascular.

Pain Management With COVID

There are numerous problems associated with the management of pain with COVID. Firstly they may relate to the onset of new symptoms and secondly, they happen because access to chronic pain management services is quite limited. Pain treatment at the time of COVID has challenges associated with it that compel both patients and doctors to operate in highly different conditions. According to the evidence available as well as reports from WHO, pain happens to be quite a familiar symptom with those affected by SARS-CoV-2.  These pains are commonly muscle pain, joint pain, sore throat, and headaches. If the painful symptoms persist, they can lead to depression in as many as 50% of patients. Of these, Cancer patients are especially vulnerable, being exposed to pain as well as pain-related issues during the course of the COVID pandemic.


We have a lot to learn from the previous studies that had been done on critical care survivors, a neglected area till now. This is a complex challenge and has been called PICS (Post Intensive Care Syndrome).  It takes into account the physical, cognitive, as well as psychological dysfunction that patients report after they are discharged from the ICU. Chronic and long-term pain is a part of this, but how this affects critical care survivors is understood poorly. This blog offers some hope, as scientists have now uncovered why long COVID infection periods are causing pain in patients.

New Studies Give Clues For Pain Triggers


Cellular response to SARS-CoV-2 infection in the lung and its

relationship to nociceptors. The cleavage of viral S protein by surface proteins

such as TMPRSS2 and furin facilitates SARS-CoV-2 entry into lung epithelial

cells through the ACE2 receptor. Neuropilin 1 and 2 (NRP1/2) act as additional

viral entry factors. Viral RNA activates interferon regulatory factors (IRF3 and

IRF7) that promote type I interferon (IFNa/b) production. The binding of type I

IFNs to IFN receptors on pulmonary nociceptors is postulated to stimulate

MNK-mediated eIF4E phosphorylation, resulting in nociceptor sensitization.

When the viral load is high, viral proteins (NSP13, NSP6, and ORF6) suppress

IFN production, contributing to evasion of type I IFN production and increasing

the severity of COVID-19. ACE2, angiotensin-converting enzyme 2.

A new study conducted on animals has given valuable insights into how COVID-19 SARS-CoV-2 which is the virus that is responsible for COVID-19 can cause long-term pain in patients who went through a long COVID. Randal (Alex) Serafini who is an MD/Ph.D. student from the Icahn School of Medicine in Mount Sinai in the city of New York has delved deep into research into this issue. He says that a sizeable number of people who have suffered from long COVID may experience abnormalities connected to the senses. This includes various kinds of pain. RNA sequencing was used to get a shot of the biochemical alterations SARS-CoV-2 triggered in a structure for transmission of pain. This structure is called the dorsal root ganglia.   

The researchers used a hamster model of the SARS-CoV-2 virus, and initial findings led them to see that the infection had left a signature in the gene expression which remained there even after the virus had cleared. This signature was the same as other gene expressions that were seen in the pain that is caused by other conditions not related to COVID-19.

Hamster Models Offer Hope


Serafini said that the findings had the potential to develop new kinds of therapy for those patients who are suffering from acute as well as long COVID gestations, along with hope for pain management for other conditions. The study also showed that SARS-CoV-2 has the potential to cause long-term effects on the human body in many different ways, a drastic finding to say the least. This further underscores why people have to try their best to avoid any infection from COVID-19, following the dictates of social distancing and sterilization of hands and surfaces that have the potential to transmit the virus.

In the experiments, a hamster was infected with intranasal COVID-19 that had a close resemblance to the actual symptoms experienced by affected people. According to the findings by the researchers, the SARS-CoV-2 infected hamsters demonstrated a slender hypersensitivity to haptic touch in the early stage of infection, and this became much more severe over a time period of 30 days. The scientists then did similar experiments with Influenza A virus `to see and determine if the other RNA viruses evoked similar responses in the hamster model.

In Stark contrast to SARS-CoV-2, Influenza A caused a hypersensitivity that was more pronounced and severe but faded 4 days to post the infection. The gene expression pattern in the dorsal root ganglia also showed that SARS-CoV-2 had the potential to cause a more significant change in the level of expression of genes that were involved in neuron-specific processes of signaling as compared to influenza.


More Experiments Conducted


Potential mechanism(s) for nociceptor sensitization in severe COVID-19. SARS-CoV-2 enters lung epithelial cells and resident immune cells through

ACE2. In severe COVID-19 cases, IFN production is abrogated allowing the virus to replicate unrestricted. Subsequent increase in viral load further enhances the

production of inflammatory mediators and leads to the development of a hyperinflammatory state known as a “cytokine storm.” Cytokines produced in the lower

respiratory tract may interact with receptors on sensory nerve endings promoting neurogenic inflammation and nociceptor hypersensitivity. An exaggerated

immune response leads to systemic inflammation affecting multiple organs. As such, peripheral blood mononuclear cells (PBMCs) produce potent inflammatory

mediators that have known receptors in the sensory neurons and resident immune cells of the DRG, driving nociceptor sensitization. ACE2, angiotensinconverting enzyme 2; DRG, dorsal root ganglia

Additional experiments were conducted which showed that after a period of 4 weeks post-recovery from the viral infection, hamsters that were flu-infected showed no signs of long-term hypersensitiveness. However, the SARS-CoV-2 infected ones exhibited worsened hypersensitivity which was an expression of chronic pain.  The gene expression signatures of these hamsters who recovered from SARS-CoV-2 were of a similar kind as that seen in the dorsal root ganglia of a mouse when it is in pain induced by nerve injury or inflammation.

In order to delve deeper into the molecular structure and machinery of the SARS-Cov-2 infected hamsters, these researchers then applied bioinformatics analysis to the gene expression data obtained. This analysis predicted SARS-CoV-2  plays down the activity of previously identified regulators of pain as well as a protein called interleukin enhancer-binding factor 3 (ILF3). The down-regulation occurs at a time when the pain behaviors of the hamsters are very mild in spite of loaded systemic inflammation. In stark contrast, the Influenza A-induced hypersensitivity was severe at those time intervals. The ILF3 protein has not yet been studied in the context of pain but it is known that it is quite a potent cancer regulator.

Researchers Develop Working Hypothesis

Based on the findings, the researchers came to the hypothesis that if the acute effects of ILF3 were mimicked, it could be a new strategy to battle pain. In order to test this, researchers administered an anti-cancer drug, clinically approved, that inhibits ILF3 in the test hamsters. Resultantly, they discovered that it was a very effective way of preventing pain in the mouse model of localized inflammation.

Serafini ends by saying that the therapeutic candidates that were derived from the gene expression data like ILF3 inhibitors have the potential to target pain mechanisms specific to COVID patients battling long-term pain. Again, there were a few proteins associated with cancer that came up as pain targets, but they were predicted previously. This is quite exciting, in the sense that there are many drugs that have been developed to act against some of these proteins like ILF3 and have gone through clinical trials. If these drugs are repurposed, therapeutic development times can be drastically cut down.

Right now, these researchers are actively working to identify other kinds of compounds which can be repurposed while at the same time looking out for other compounds of a novel nature that can inhibit the activity of the ILF3 protein.

Gurbaksh Chahal
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