Understanding Inflammation's Role in Long COVID
Long COVID, or Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), is characterized by a wide array of persistent symptoms that can last for months or even years after the initial infection [1.5.6]. A growing body of research points to sustained, low-grade inflammation as a central pathophysiological mechanism behind the condition [1.5.1, 1.5.3]. The initial viral infection can trigger a dysregulated immune response, leading to a state of chronic inflammation that contributes to symptoms like fatigue, brain fog, joint pain, and respiratory issues [1.5.2]. This hyperinflammatory state can involve elevated levels of cytokines (proteins that signal the immune system), mast cell activation, and even the formation of microclots [1.5.2, 1.5.6]. Because of this, researchers and clinicians are investigating whether medications designed to reduce inflammation can effectively treat long COVID symptoms [1.2.2].
Over-the-Counter NSAIDs
Non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen (Advil, Motrin) and naproxen (Aleve) are common first-line treatments for pain and inflammation [1.3.1]. While they can help manage symptoms like muscle aches, headaches, and fever associated with both acute and long COVID, they do not treat the underlying cause of the viral-induced inflammation [1.3.5]. Early in the pandemic, there were concerns that NSAIDs could worsen COVID-19 outcomes, but subsequent scientific evidence has not supported this connection [1.3.2, 1.3.3]. However, one Korean study noted a potential, though not statistically significant, link between NSAID use during the acute infection and a higher risk of developing long COVID [1.3.4]. For post-COVID symptoms like persistent joint and muscle pain, acetaminophen and ibuprofen are the most commonly used analgesics [1.3.6].
Corticosteroids
Corticosteroids, such as dexamethasone and prednisone, are powerful anti-inflammatory drugs. They are recommended by the World Health Organization for treating severe or critical COVID-19 because they can reduce the overstimulation of the immune system (cytokine storm) [1.4.3]. For long COVID, their role is less clear and more complex. Some small observational studies have suggested that a short course of corticosteroids may improve symptoms like fatigue, breathlessness, and joint pain, and may even help revert some of the immune alterations seen in long COVID patients [1.4.2, 1.4.7]. However, prolonged use of steroids carries risks of significant side effects, including increased blood sugar, psychiatric effects, and a higher risk of thrombosis [1.4.1, 1.4.4]. A 2024 meta-analysis found no clear evidence that corticosteroid treatment during the acute phase had a protective effect against developing long COVID and suggested more research is needed to clarify potential harmful effects [1.4.5].
Emerging and Repurposed Anti-Inflammatory Therapies
Given the central role of inflammation, researchers are actively exploring a range of other anti-inflammatory medications.
Specialized Anti-Inflammatory Drugs
Several drugs approved for autoimmune diseases like rheumatoid arthritis are being investigated for long COVID. These drugs target specific inflammatory pathways.
- JAK Inhibitors (e.g., Baricitinib, Upadacitinib): These drugs have been shown to reduce the uncontrolled inflammation in severe COVID-19. Research from 2024 suggests they may be able to halt the chronic inflammation and lung scarring associated with respiratory long COVID symptoms by targeting the underlying immune cell dysfunction [1.2.1].
- Other Arthritis Drugs (e.g., Abatacept, Infliximab, Tocilizumab): These medications have also been studied. A 2025 study showed that abatacept and infliximab reduced deaths in hospitalized COVID-19 patients, though they didn't speed recovery [1.2.4]. Clinical trials are underway to test repurposed drugs like upadacitinib and pirfenidone for long COVID [1.2.5].
Low-Dose Naltrexone (LDN)
Naltrexone in very low doses (typically 1 to 4.5 mg) is thought to have anti-inflammatory and immunomodulating properties [1.8.3, 1.8.5]. It may work by suppressing pro-inflammatory factors acting on microglia (immune cells in the brain), which could help with the neuroinflammatory aspects of long COVID, such as brain fog [1.8.2]. A September 2025 systematic review of four observational studies found that LDN may lead to moderate-to-large improvements in fatigue, pain, brain fog, and sleep quality in long COVID patients [1.8.4]. Another study found LDN may restore the function of TRPM3 ion channels in immune cells, which are dysfunctional in long COVID patients [1.8.6]. While promising, researchers emphasize the need for rigorous randomized controlled trials to confirm these findings [1.8.4].
Mast Cell Stabilizers & Antihistamines
Mast Cell Activation Syndrome (MCAS), where immune cells release excessive inflammatory mediators, is theorized to be a factor in long COVID [1.7.2]. Treatments for MCAS, including H1 and H2 antihistamines (like cetirizine and famotidine), mast cell stabilizers (like cromolyn sodium and ketotifen), and supplements (like quercetin and Vitamin C), are being explored to alleviate long COVID symptoms [1.7.1, 1.7.5]. One study showed that treatment with a combination of fexofenadine and famotidine led to significant symptom improvement in patients with long COVID symptoms attributed to mast cell activation [1.7.6].
Comparison of Anti-Inflammatory Approaches
| Medication Type | Mechanism of Action | Potential for Long COVID | Key Considerations |
|---|---|---|---|
| NSAIDs | General anti-inflammatory, reduces fever and pain [1.3.1]. | Symptom management for pain and aches [1.3.6]. | Does not treat root cause; long-term use has gastrointestinal and kidney risks [1.3.1]. |
| Corticosteroids | Potent, broad immunosuppression [1.4.3]. | May reduce severe inflammation; some small studies show symptom improvement [1.4.7]. | Significant side effects with long-term use; not recommended for non-severe cases [1.4.1, 1.4.3]. |
| JAK Inhibitors | Target specific inflammatory pathways (Janus kinase) [1.2.1]. | Promising for respiratory long COVID; clinical trials ongoing [1.2.1, 1.2.5]. | Requires prescription and monitoring; these are potent immunosuppressants. |
| Low-Dose Naltrexone | Believed to modulate immune system and reduce neuroinflammation [1.8.2]. | Observational studies show improvement in fatigue, pain, and brain fog [1.8.4]. | Used off-label; more high-quality trial data is needed to confirm efficacy [1.8.4]. |
| Mast Cell Stabilizers / Antihistamines | Block histamine receptors or prevent mast cell degranulation [1.7.2, 1.7.6]. | May help patients whose symptoms are driven by mast cell activation [1.7.6]. | Many are available over-the-counter; effectiveness may depend on the individual's specific long COVID pathology [1.7.2]. |
Conclusion
The evidence strongly suggests that inflammation is a key pillar of long COVID, making anti-inflammatory medications a logical and promising area of treatment research. While common NSAIDs can help manage some symptoms, they don't address the core problem. More powerful and specific drugs, such as repurposed arthritis medications, corticosteroids, low-dose naltrexone, and mast cell-targeting agents, show potential but require more definitive evidence from large-scale clinical trials. Research from 2024 and 2025 continues to identify specific inflammatory patterns, which may soon allow for a more personalized, precision-medicine approach to treating this complex condition [1.2.3, 1.5.4]. Patients should always consult with a healthcare professional before starting any new treatment for long COVID.
For more information from a leading research initiative, visit the RECOVER COVID Initiative.
