Zileuton for long COVID
ZILEUTON
What is zileuton (Zyflo)?
Zileuton is part of a class of medications known as leukotriene receptor antagonists. Leukotrienes, specifically LTC4, LTD4, and LTE4, are pro-inflammatory mediators heavily involved in the mechanisms behind asthma. When provoked, leukotrienes constrict the airways, making breathing harder. Zileuton blocks leukotrienes from closing the airways, effectively making breathing easier.
What is the relationship between zileuton and long-COVID?
For patients suffering from inflammatory respiratory symptoms of long-COVID such as wheezing, cough, exercise intolerance, and trouble breathing, zileuton may play a role in mitigating these symptoms [1]. Patients with COVID-19 have been found to have high levels of LTE4, a member of the leukotriene family, in the lung space. Zileuton could help decrease these levels. Studies have only been conducted on montelukast, a medication in the same class as zileuton. One of these studies found that adding montelukast decreased cough severity, decreased cough paroxysms per day, and a shorter duration of cough [2]. Although no formal recommendations for zileuton to treat long-COVID have been made, there is some potential for zileuton to aid in pulmonary symptoms associated with long-COVID.
1https://www.frontiersin.org/articles/10.3389/fphar.2022.784214/full
2https://doi.org/10.1186/s43168-022-00154-6
Treatment Article
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Naltrexone for long COVID
NALTREXONE
What is naltrexone (Vivitrol)?
Naltrexone is an opioid antagonist, a medication that blocks opioid receptors in the brain. Opioids are a class of drugs that derive from or mimic natural substances found in the opium poppy plant [1]. When taken, they can decrease pain and provide a sense of euphoria. Opioids can be very addictive due to their euphoric effects. Naltrexone is prescribed to combat this problem by preventing a person from getting “high.” Naltrexone blocks where the opioids bind at the opioid receptors. In addition to opioid use disorder, naltrexone can also be used for alcohol use disorder.
How can naltrexone be used in long-COVID?
There has been some evidence that naltrexone may be helpful for patients dealing with symptoms of long-COVID. In long-COVID, the body is theorized to be under constant inflammation. Although a person is no longer actively infected with COVID-19, the body is still shedding the virus. Since the virus is a foreign material, the immune response is invoked and causes inflammation [2]. Using naltrexone at doses much lower than for alcohol or opioid disorder emphasizes its anti-inflammatory properties to help the body recover quicker [3].
Current published studies have looked at the use of low-dose naltrexone and symptom relief. One study of 52 patients showed improvement in activities of daily living, energy levels, pain levels, concentration levels, and sleep disturbance with the use of low-dose naltrexone [4]. A second study found that low-dose naltrexone increased sleep patterns, headache, brain fog, fatigue, fewer symptoms, and overall better functional status [5].
Current studies are being conducted to help solidify naltrexone’s use as a treatment option for long-COVID, however, it is still in the beginning phases [6]. However, with the limited research conducted, naltrexone does show promise in treating the long-COVID disease state to help restore patients to their pre-COVID baselines.
References:
1https://www.hopkinsmedicine.org/health/treatment-tests-and-therapies/opioids
2https://www.covidcaregroup.org/blog/low-dose-naltrexone-for-post-covid-inflammation
4https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250701/
5https://doi.org/10.1101/2023.06.08.23291102
6https://classic.clinicaltrials.gov/ct2/show/NCT05430152
Search for: Long COVID, naltrexone | Card Results | ClinicalTrials.gov
Acetaminophen for long COVID
ACETAMINOPHEN
What is acetaminophen?
Acetaminophen, or paracetamol or Tylenol, helps reduce fevers, headaches, and muscle or body aches. It is found in many over-the-counter products, and patients can take 325 to 650 mg every 4-6 hours or 1 g every six hours as needed. Unlike other pain relievers like NSAIDs (nonsteroidal anti-inflammatory drugs like ibuprofen), acetaminophen does not have anti-inflammatory properties and is, thus, not beneficial in treating inflammatory conditions.
How can acetaminophen help alleviate certain long COVID symptoms?
The prevalence of post-COVID pain is estimated to be up to 63.3%, and patients with chronic pain can have exacerbated symptoms after COVID.1 There are multiple possible mechanisms behind post-COVID pain. Post-COVID pain may be caused by the virus entering and attacking musculoskeletal and nervous systems, including the brain.
Acetaminophen can be used to relieve arthralgias, myalgias, and headaches that persist after COVID; however, it does not help with inflammation and should not be used to treat COVID or to reduce the duration of COVID symptoms. Acetaminophen is often preferred for pain relief in older adults due to the potential side effects of NSAIDs.
What evidence supports acetaminophen’s use for long COVID?
There needs to be more studies that have looked at acetaminophen for long COVID symptoms. A survey of 696 COVID patients in Italy reported that acetaminophen was the most commonly used in the post-acute phase of COVID for pain and had a temporary reduction in pain severity.2 Because of its established use today, acetaminophen is a reasonable option to use for fevers, muscle pain, or body aches after COVID.3
What are some things to watch out for with acetaminophen?
Many OTC products contain acetaminophen, so it is important to follow dosage information and stay within recommended dosages when taking a combination of these products. The recommended maximum daily dose is 4,000 mg to prevent liver damage, but it is best not to exceed 3,000 mg daily, especially in older adults. Acetaminophen may cause nausea, vomiting, and stomach pain and is not recommended in people with liver disease. If you take Tylenol for headaches, you should not take it more than 10-15 days out of the month.
References:
3) Landon E. Which over-the-counter medications are best for COVID-19 symptoms? October 19, 2023. Accessed November 13, 2023. https://www.uchicagomedicine.org/forefront/coronavirus-disease-covid-19/which-otc-medications-are-best-for-coronavirus-symptoms#:~:text=Acetaminophen%2C%20also%20called%20paracetamol%20or,the%20duration%20of%20your%20illness.
Fexofenadine (Allegra)
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Hydroxyzine for long COVID
HYDROXYZINE
What is hydroxyzine?
Hydroxyzine is an antihistamine that helps block H1 receptors, which stops histamine from being released in the body. It’s commonly prescribed to relieve allergy symptoms like itching and can also help with anxiety or make it easier to fall asleep. There are some over-the-counter antihistamines, like fexofenadine and loratadine, that tend to be less sedating.
What does hydroxyzine do in the body?
Histamine is crucial in how our immune system reacts, especially during allergic responses. It causes blood vessels to become more permeable (“leaky”), leading to swelling and redness. Antihistamines block these effects at the H1 receptors, which helps reduce allergy symptoms.
First-generation antihistamines, including hydroxyzine, can easily cross into the brain and affect central nervous system receptors. This leads to different effects compared to second-generation antihistamines, which primarily target receptors outside the brain.
How can hydroxyzine help in long-COVID?
For people dealing with long COVID, hydroxyzine might be helpful. After COVID-19, some patients experience an overwhelming immune response, often called a cytokine storm. This can also involve alterations in histamine levels as well [1]. Hydroxyzine helps manage this immune reaction, potentially leading to improvements such as reduced wheezing and better exercise tolerance [2]. Some reports suggest that using hydroxyzine for an extended period could help improve long COVID symptoms like exercise intolerance, chest pain, fatigue, and brain fog. While we need more research, early findings are promising [3].
There’s alson encouraging but limited evidence that antihistamines might help with other long COVID symptoms. For instance, a study by Glynne et al. showed that 72% of long COVID patients who took a combination of H1 and H2 blockers for at least four weeks noticed some improvement in various symptoms, although not in dysautonomia [4]. It also mentioned ongoing T cell issues in these patients, suggesting that antihistamines may play a role in modulating the immune response. However, since this study was observational, we can’t assume a direct cause-and-effect relationship.
Another study by Samimi et al. looked at people with COVID-19 who were using antihistamines and found no significant difference in their symptoms compared to those who didn’t use them for four weeks[5]. While this didn’t specifically focus on long COVID, it gives some background on how antihistamines treat COVID.
Overall, early evidence is that antihistamines may help with long COVID, but more clinical trials are needed to confirm this and establish treatment recommendations.
References:
1Eldanasory OA, Eljaaly K, Memish ZA, Al-Tawfiq JA. Histamine release theory and roles of antihistamine in the treatment of cytokines storm of COVID-19. Travel Medicine and Infectious Disease. 2020;37:101874. doi:10.1016/j.tmaid.2020.101874
2Mashauri HL. Covid‐19 Histamine theory: Why antihistamines should be incorporated as the basic component in Covid‐19 management? Health Science Reports. 2023;6(2). doi:10.1002/hsr2.1109
3Pinto MD, Lambert N, Downs CA, et al. Antihistamines for postacute sequelae of SARS-COV-2 infection. The Journal for Nurse Practitioners. 2022;18(3):335-338. doi:10.1016/j.nurpra.2021.12.016
4Glynne P, Tahmasebi N, Gant V, Gupta R. Long COVID following Mild SARS-CoV-2 Infection: Characteristic T Cell Alterations and Response to Antihistamines. Journal of Investigative Medicine. 2021;70(1):61-67. doi:10.1136/jim-2021-002051
5Samimi S, Nimrouzi M, Sousani M, Vazani Y. EXPRESS: Antihistamine and COVID-19 outcomes in outpatients. Journal of Investigative Medicine. Published online August 1, 2024. doi:10.1177/10815589241270449
Clinical Trials
Search for: Long COVID, Other terms: Histamine H1 Antagonists | Card Results | ClinicalTrials.gov
Paxlovid (Nirmatrelvir/Ritonavir) for long COVID
PAXLOVID(NIRMATRELVIR/RITONAVIR)
What is Paxlovid?
The FDA approved Paxlovid in December 2021 for the acute treatment of COVID-19. According to current guidelines, it is most efficacious if used within the first five days of infection. Paxlovid is a combination of two antiviral medications, nirmatrelvir, and ritonavir, which inhibit the virus’s replication in cells.
What can Paxlovid do for those with long-COVID?
Recently, there has been evidence that Paxlovid may be beneficial in reducing the possibility of developing symptoms associated with long COVID [1] Researchers found it did not matter whether the patient had a recurrence of COVID-19 or whether they were vaccinated. By taking Paxlovid within the first five days of a COVID-19 diagnosis, the potential to develop long-COVID diminished [2].
Additionally, for those already diagnosed with long-COVID, it is possible that Paxlovid, taken for a duration longer than five days, may help to reduce long-COVID symptoms further. The notion behind this theory points to COVID-19 viral shedding. In long-COVID, although a person does not have an active infection, the virus may still be shedding in the body, leading to an upregulation by the immune system [3]. This upregulation leads to an immune response characterized by fatigue, lightheadedness, trouble breathing, and exercise intolerance. Although more research needs to be conducted regarding the extension of Paxlovid past its recommended duration of use, current results are mixed. A recent study showed that a 15-day course of Paxlovid did not improve long COVID symptoms it does show promise in alleviating the symptoms of long-COVID for patients.
References:
3https://www.ucsf.edu/news/2022/05/422771/covid-drug-may-also-ease-symptoms-long-covid
Active Clinical Trials: Long COVID, nirmatrelvir | Card Results | ClinicalTrials.gov
Aspirin for long COVID
ASPIRIN
What is aspirin?
Aspirin is an antiplatelet agent that is commonly used for the prevention of blood clots and secondary prevention of cardiovascular disease after patients have a stroke or heart attack. It is often taken indefinitely in these cases at a low dose of 81 mg, also known as baby aspirin. Aspirin has many strengths, and its drug properties vary depending on the dosage. At higher doses greater than 325 mg every 4-6 hours, it serves as a non-steroidal anti-inflammatory drug (NSAID) that can be used to relieve pain and reduce fever.
How can aspirin help alleviate certain long COVID symptoms?
An acute COVID infection can lead to hyperactivated platelets and damaged red blood cells, making it more likely for the body to form a clot. Patients from South Africa with long COVID have been found to have amyloid deposits in their blood samples called microclots.1 It is believed that these microclots can prevent oxygen from adequately reaching all of our tissues, which may cause long COVID symptoms. Aspirin works by irreversibly inhibiting enzymes called COX-1 and COX-2 that are needed for platelets (cells in our blood that form clots) to aggregate and activate. Thus, agents that prevent clots may play a role in helping people experiencing long COVID symptoms such as fatigue, brain fog, loss of concentration, shortness of breath, and joint and muscle pains.
What evidence supports aspirin’s use for long COVID?
The use of aspirin within the first day of hospitalization for moderate COVID was associated with lower odds of in-hospital mortality within 28 days. However, the absolute difference in mortality rates for the treatment vs placebo group was slight.2
A study done in South Africa treated 24 patients with a combination of clopidogrel 75 mg (an antiplatelet agent), aspirin 75 mg daily, and a direct oral anticoagulant apixaban (Eliquis) 5 mg twice a day. A proton pump inhibitor, pantoprazole, was also added to prevent gastrointestinal ulcers or bleeding. All patients reported that their main fatigue symptoms were resolved, as well as their other long-term COVID symptoms.3 It is important to note, however, that this study was not placebo-controlled and has not yet been peer-reviewed for publication. This treatment combination also puts patients at high risk of bleeding and is not recommended for certain patients and demographics.
While aspirin does have beneficial effects in preventing blood clots, aspirin alone may not be sufficient for the breakdown of microclots. Increased risks of bleeding with aspirin should also be taken into consideration when asking your doctor about treatments for long COVID.
What should you be aware of when taking aspirin?
Aspirin is associated with a 2- to 4-fold increase in upper gastrointestinal (GI) events ranging from indigestion to GI ulcers or bleeding. The use of enteric-coated aspirin does not necessarily decrease this risk. Some people can have immediate or delayed allergic reactions to aspirin, leading to anaphylaxis, which can be serious in some rare cases. Because of its antiplatelet effects, it can cause you to bleed more easily, especially if you are taking other blood thinners or medications/supplements that can increase your risk of bleeding.
Large doses of aspirin (greater than 325 mg daily) should be avoided for long-term use, especially in people with chronic kidney disease, heart failure, cirrhosis, older adults, or those taking diuretics (also known as water pills). Even if you are taking baby aspirin, it is important to let your doctor know you are on this medication.
References:
Naproxen
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