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How does paracetamol interfere with immune system?

How does paracetamol interfere with immune system?


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Paracetamol is used to reduce body temperature when it is to high. The high body temperature (fever) is known to be an indication that immune system fights against an infection.

In this context I have two related questions:

  1. Is high body temperature one of the mechanisms of immune system to suppress an infection or it is just a side effect?
  2. If it is just a side effect, does paracetamol remove it by decreasing the intensity with which immune system fights with an infection or not?

First question: Yes. The immune system releases pyrogenic cytokines such as IL-1. Bacteria aren't typically used to 37C, they prefer working at under that temperature to function in the environment. Our body however can take a few degrees here or there however this severely compromises the bacterial enzyme activity. The same is true for other pathogen enzymes. The body also increases copper concentrations in the blood for similar reasons. Problem is of course if the body goes into overdrive and raises our temperature too much, this compromises our own ability to fight the infection so in that case antipyretics like paracetamol can reduce fever.

Second question. It isn't a side effect, however paracetamol works by blocking things like IL-1 that raise temperature. How IL-1 raises your temperature is quite interesting, it tells the hypothalamus (our thermostat) that it should be set higher. So we feel cold (so we try to keep ourselves warm) and the body thinks it's cold (so it increases the temperature by burning glucose mainly)


The factors that most affect our immune system

Why do we respond differently to infections or vaccines? Why are some people allergic to pollen? These are still unanswered questions in biological and medical science. The Milieu Intérieur Laboratory of Excellence coordinated at the Institut Pasteur by CNRS research director, Dr. Lluis Quintana-Murci, has recently described immune variation on a large scale within the French population. To achieve this, the consortium studied an expansive collection of biological specimens from 1,000 French volunteers aged 20 to 69. This article provides an account of their work.

For many years, immunology, the branch of biology that examines our immune system, focused on dissecting the molecular mechanisms that control our physiological response to infections based on the assumption that this response does not differ among individuals. However, this premise has been challenged by recent studies suggesting that we are not all equally equipped to deal with pathogens. Our age, sex, infection history, and genetics can affect our immune system and make us more prone to disease. The task of identifying these factors that regulate our immune system has become the main challenge facing precision medicine, a proposed medical model aimed at offering patient treatments tailored to individual needs.

Some thirty scientists from several research centers thus joined forces to form the Milieu intérieur Laboratory of Excellence (or LabEx) coordinated at the Institut Pasteur by CNRS research director, Dr. Lluis Quintana-Murci with funding from the Investissements d'Avenir [Investing in the Future] program, with a view to describing immune variation on a large scale within the French population. This consortium gathered an expansive collection of biological specimens from 1,000 healthy donors (500 French men and 500 French women aged 20 to 69) recruited in Rennes. "The subjects' blood, DNA, vaccination and medical history, and intestinal and nasal bacteria were collected, measured, and examined for this large-scale study," explains Lluis Quintana-Murci. The first results from analysis of the entire cohort were recently published in PNAS on December 27, 2017 and in Nature Immunology on February 23, 2018.

Immune variation and differences in terms of sex and age

Using an ex vivo system, the researchers measured changes in immune gene expression in blood samples from the 1,000 donors when exposed to various viruses, bacteria, and fungi. At the same time, "we determined the molecular characteristics of the white blood cells, or leukocytes, in the donors' blood with an unprecedented level of precision," the CNRS researcher and study author Etienne Patin tells us. The two studies confirm that immune variation among individuals is largely due to differences in sex and age. "However, smoking and asymptomatic cytomegalovirus infection, which affects 35% of the population, also have a major impact on our blood cell composition. This may explain why smokers and people infected by this virus can be more prone to infection."

Genetic variations and risk of disease

The researchers' next task was to determine whether our genetics contribute to immune response variation among individuals. Surprisingly, "we identified hundreds of genetic variations which change the expression of molecules that play a key role in immune responses," reports Lluis Quintana-Murci "some of which are associated with a higher risk of developing diseases such as pollen allergy, lupus erythematosus, and type 1 diabetes." These results shed new light on the potential causes of these illnesses, which remain unclear.

The Milieu Intérieur Laboratory of Excellence (or Milieu intérieur LabEx) will now seek to determine whether our intestinal and nasal flora and epigenetics (temporary changes in our DNA) also contribute to immune variation. On a more general level, the extensive biobank developed for the purpose of this consortium will help identify disease risk factors, paving the way to precision medicine for infectious and autoimmune diseases.


Wide range of drugs affect growth of gut microbes, study says

A wide range of drugs from cancer therapies to antipsychotics affect the growth of microbes that are found in our gut, researchers say, highlighting that it is not only antibiotics that can have an impact on our internal flora.

These microbes, whose genes taken together are known as the gut microbiome, play an important role in our health, including for our immune system and our digestion, and have been linked to a host of diseases such as autoimmune conditions, obesity and mood disorders.

While, perhaps unsurprisingly, antibiotics are already known to affect the biodiversity of our gut microbes, in recent years scientists have found that a number of drugs designed to act on human cells – rather than bacteria – also appear to interfere with them. For instance, scientists found that one of the ways the diabetes drug metformin works might be by encouraging the growth of certain bacteria.

But the latest research goes further, to explore whether many other drugs could be affecting our inner microbes.

“We wanted to see the [extent] of this effect . and whether the effect was direct,” said Athanasios Typas, a coauthor of the research from the European Molecular Biology Laboratory in Germany.

Published in the journal Nature, the latest study looked at the impact on human gut flora of almost 1,200 common drugs including antipsychotics, proton-pump inhibitors, hormones and anti-cancer drugs.

In total, 38 bacterial species found in healthy humans were exposed to the chemicals in the lab, and for some species multiple strains were tested. The collection of microbes included C. difficile, infections with which can cause life-threatening diarrhoea.

The team were surprised to find that of the 835 drugs they tested that were designed to interact with human cells rather than bacteria, almost a quarter hindered the growth of at least one bacterial species, a phenomenon found among all the different types of drugs tested.

“This 25% estimate is likely to be valid even if we include more drugs in the screen,” said Kiran Patil, another author of the study, noting the wide range of drugs tested.

Typas said both pathogens and good bacteria were affected by the drugs, with a larger effect for the latter.

“Most non-antibiotics target one or a handful of species from the species [of bacteria] we tested. But there are 40 non-antibiotics that target 10 or more species,” said Typas. Of these, the team note, 14 of the drugs were not previously known to have an antibacterial effect.

The team say the findings are not necessarily bad news, noting that similar bacterial species are affected by different antipsychotics, suggesting it could be that the drugs work, at least in part, by affecting gut microbes – a possibility the team say is backed up by the fact that it can take weeks for antipsychotics to start working.

The researchers add that previous studies probing the gut microbes of patients taking some of the drugs explored largely reflected the effects they found.

They also say their findings chimed with side effects linked to a number of the drugs tested. “We can actually separate non-antibiotics that [affect] gut microbiomes in our screen from those that don’t, based on their side effects in humans,” said Typas, noting the former had more antibiotic-like side effects, such as gastrointestinal problems.

In addition, the team found a link between bacterial species resistant to antibiotics and those that were not affected by the drugs tested, revealing that the same mechanism might be behind both and raising the possibility that non-antibiotic drugs could help drive antibiotic resistance.

“Antibiotic resistance emergence is a quite a big health risk at the moment worldwide and I think aspects that could contribute to this emergence should be looked at very seriously,” said Patil.

However, the study had a number of limitations, including that the bacterial species were considered separately, and that generally only one strain was probed per species. In addition, while the team say the concentration of drugs used in the experiments was generally in line with what is expected in the gut, some drugs might be present in the gut in higher or lower concentrations.

The team say the research could help in the development of new drugs to tackle C. difficile or for changing the composition of the community of gut microbes, and could even help drug companies to anticipate possible side effects.

Prof John Cryan, a neuropharmacologist and microbiome expert from University College Cork, said the paper highlighted the extent to which medications can affect the microbiome and, as a result, potentially work on the human body indirectly. “We have shown that this is the case for antipsychotic drugs some years ago but this is a major step-up, confirming that almost one-quarter of drugs investigated impact the microbiome,” he said, adding that work is now needed to unpick how effects on the microbiome might be linked to the efficacy and side effects of drugs.

“Moving forward,” he said, “we cannot ignore the microbiome when we talk about drug action in the body.”


How do painkillers work?

NSAIDs work by blocking (inhibiting) the effect of chemicals (enzymes) called cyclo-oxygenase (COX) enzymes. COX enzymes help to make other chemicals called prostaglandins. Some prostaglandins are involved in the production of pain and inflammation at sites of injury or damage. A reduction in prostaglandin production reduces both pain and inflammation. Not all NSAIDs are exactly the same, and some work in slightly different ways from others. See the separate leaflet called Anti-inflammatory Painkillers for more details.

Paracetamol - no one really knows for sure exactly how paracetamol works. But it is also thought to work by blocking COX enzymes in the brain and spinal cord (central nervous system). Paracetamol is used to treat pain and to lower a high temperature. However, it does not help with inflammation.

Opioids work by binding to certain receptors (opioid receptors) in your central nervous system, your gut and other parts of your body. This leads to a decrease in the way you feel pain and your reaction to pain, and it increases your tolerance for pain. See the separate leaflet called Strong Painkillers (Opioids) for more details.


Anemia is a condition in which the body does not have enough healthy red blood cells. Red blood cells provide oxygen to body tissues.

Normally, red blood cells last for about 120 days in the body. In hemolytic anemia, red blood cells in the blood are destroyed earlier than normal.

In some cases, a drug can cause the immune system to mistake your own red blood cells for foreign substances. The body responds by making antibodies to attack the body's own red blood cells. The antibodies attach to red blood cells and cause them to break down too early.

Drugs that can cause this type of hemolytic anemia include:

  • Cephalosporins (a class of antibiotics), most common cause
  • Dapsone
  • Levodopa
  • Levofloxacin
  • Methyldopa
  • Nitrofurantoin
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Penicillin and its derivatives
  • Phenazopyridine (pyridium)
  • Quinidine

A rare form of the disorder is hemolytic anemia from a lack of glucose-6 phosphate dehydrogenase (G6PD). In this case, the breakdown of red blood cells is due to a certain type of stress in the cell.

Drug-induced hemolytic anemia is rare in children.


First study to reveal how paracetamol works could lead to less harmful pain relief medicines

Researchers at King's College London have discovered how one of the most common household painkillers works, which could pave the way for less harmful pain relief medications to be developed in the future

Researchers at King's College London have discovered how one of the most common household painkillers works, which could pave the way for less harmful pain relief medications to be developed in the future.

Paracetamol, often known in the US and Asia as acetaminophen, is a widely-used analgesic (painkiller) and the main ingredient in everyday medications such as cold and flu remedies. Although discovered in the 1890s and marketed as a painkiller since the 1950s, exactly how it relieves pain was unknown.

This study, funded by the UK Medical Research Council (MRC) and published online today in Nature Communications, shows for the first time the principal mechanism of action for one of the most-used drugs in the world.

The researchers from King's, with colleagues from Lund University in Sweden, have identified that a protein called TRPA1, found on the surface of nerve cells, is a key molecule needed for paracetamol to be an effective painkiller.

Dr David Andersson, from the Wolfson Centre for Age Related Diseases at King's, said: 'This is an extremely exciting finding, which unlocks the secrets of one of the most widely-used medicines, and one which could impact hugely on the development of new pain relief drugs.

'Paracetamol is the go-to medicine for treating common aches and pains, but if the recommended dose is significantly exceeded it can lead to fatal complications.

'So now we understand the underlying principal mechanism behind how this drug works, we can start to look for molecules that work in the same way to effectively relieve pain, but are less toxic and will not lead to serious complications following overdose.'

The team of researchers used a 'hot-plate' test to observe the effects of paracetamol in mice. This involved measuring the number of seconds it takes for a mouse to withdraw its paw from a slightly hot surface. They found that paracetamol increased the time it took for mice to withdraw their paw, showing that the drug reduced the heat-induced pain.

The scientists then carried out experiments to observe what happened when a protein called TRPA1 was not present at all in the mice. They found that when they removed the TRPA1 protein and repeated the hot-plate test, the paracetamol had no analgesic effect. This identifies the protein as a key molecule needed for paracetamol to be an effective painkiller.

However, paracetamol on its own does not activate the TRPA1 protein. The study showed that when paracetamol is administered, a break-down product called NAPQI is formed in the spinal cord (where 'painful' information is processed). This product is also formed in the liver and is responsible for the toxic side effects seen following overdoses.

Furthermore, they demonstrated that other compounds that, unlike NAPQI, are not toxic can activate TPRA1 in the spinal cord when injected into mice. Because these compounds are not reactive, they are less likely to be harmful.

Professor Stuart Bevan, co-author from King's, said: 'What we saw happening in the mice was that the break-down product formed from paracetamol in turn stimulates a protein found on the surface of nerve cells called TRPA1. When this protein was activated, it appeared to interfere with the transmission of information from that nerve cell to other nerve cells, which would normally send a signal up to the brain, signalling pain. So in this case the NAPQI product that was formed from paracetamol acted on the TRPA1 protein to reduce transmission of information from pain-sensing nerves to the brain.

'These results are surprising because previous studies have shown that TRPA1 can actually produce pain, coughs and hypersensitivities - it is the receptor for many common irritants like onion, mustard and tear gas. So our discovery shows for the first time that the opposite is in fact true - this protein is a novel mechanism of action for a painkiller.'

The researchers say that if they can identify other analgesic compounds similar to paracetamol that use the same TRPA1 pathway to prevent pain signals sent by nerve cells to the brain, it is possible that they can find a compound that does not have toxic effects and will reduce the risk of overdose.

Dr Andersson concludes: 'This study validates TRPA1 as a new target for pain relief drugs. Many targets have been identified in the past, but as paracetamol is a medicine that we know works well in humans, this gives us a head-start in looking for effective molecules that utilise the same pathways but are less harmful.'

CONTACT
Katherine Barnes
International Press Officer
King's College London
Tel: 44-207-848-3076
Email: [email protected]

About King's College London (http://www. kcl. ac. uk)

King's College London is one of the top 30 universities in the world (2011/12 QS World University Rankings), and the fourth oldest in England. A research-led university based in the heart of London, King's has nearly 23,500 students (of whom more than 9,000 are graduate students) from nearly 140 countries, and some 6,000 employees. King's is in the second phase of a £1 billion redevelopment programme which is transforming its estate.

King's has an outstanding reputation for providing world-class teaching and cutting-edge research. In the 2008 Research Assessment Exercise for British universities, 23 departments were ranked in the top quartile of British universities over half of our academic staff work in departments that are in the top 10 per cent in the UK in their field and can thus be classed as world leading. The College is in the top seven UK universities for research earnings and has an overall annual income of nearly £450 million.

King's has a particularly distinguished reputation in the humanities, law, the sciences (including a wide range of health areas such as psychiatry, medicine, nursing and dentistry) and social sciences including international affairs. It has played a major role in many of the advances that have shaped modern life, such as the discovery of the structure of DNA and research that led to the development of radio, television, mobile phones and radar. It is the largest centre for the education of healthcare professionals in Europe no university has more Medical Research Council Centres.

King's College London and Guy's and St Thomas', King's College Hospital and South London and Maudsley NHS Foundation Trusts are part of King's Health Partners. King's Health Partners Academic Health Sciences Centre (AHSC) is a pioneering global collaboration between one of the world's leading research-led universities and three of London's most successful NHS Foundation Trusts, including leading teaching hospitals and comprehensive mental health services. For more information, visit: http://www. kingshealthpartners. org.

King's College London is one of the top 30 universities in the world (2011/12 QS international world rankings), and was The Sunday Times 'University of the Year 2010/11', and the fourth oldest in England. A research-led university based in the heart of London, King's has nearly 23,500 students (of whom more than 9,000 are graduate students) from nearly 140 countries, and some 6,000 employees. King's is in the second phase of a £1 billion redevelopment programme which is transforming its estate.

King's has an outstanding reputation for providing world-class teaching and cutting-edge research. In the 2008 Research Assessment Exercise for British universities, 23 departments were ranked in the top quartile of British universities over half of our academic staff work in departments that are in the top 10 per cent in the UK in their field and can thus be classed as world leading. The College is in the top seven UK universities for research earnings and has an overall annual income of nearly £450 million.

King's has a particularly distinguished reputation in the humanities, law, the sciences (including a wide range of health areas such as psychiatry, medicine, nursing and dentistry) and social sciences including international affairs. It has played a major role in many of the advances that have shaped modern life, such as the discovery of the structure of DNA and research that led to the development of radio, television, mobile phones and radar. It is the largest centre for the education of healthcare professionals in Europe no university has more Medical Research Council Centres.

King's College London and Guy's and St Thomas', King's College Hospital and South London and Maudsley NHS Foundation Trusts are part of King's Health Partners. King's Health Partners Academic Health Sciences Centre (AHSC) is a pioneering global collaboration between one of the world's leading research-led universities and three of London's most successful NHS Foundation Trusts, including leading teaching hospitals and comprehensive mental health services. For more information, visit: http://www. kingshealthpartners. org.

The College is in the midst of a five-year, £500 million fundraising campaign - World questions|King's answers - created to address some of the most pressing challenges facing humanity as quickly as feasible. The campaign's three priority areas are neuroscience and mental health, leadership and society, and cancer. More information about the campaign is available at http://www. kcl. ac. uk/ kingsanswers.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.


Contents

NSAIDs are usually used for the treatment of acute or chronic conditions where pain and inflammation are present.

NSAIDs are generally used for the symptomatic relief of the following conditions: [11] [12] [13]

    [12][14][15][16]
  • Mild-to-moderate pain due to inflammation and tissue injury [12][12][17]
  • Inflammatory arthropathies (e.g., ankylosing spondylitis, psoriatic arthritis, reactive arthritis) [18][12][11]
  • Acute gout[11] (menstrual pain) [11] bone pain [11]
  • Postoperative pain [11]
  • Muscle stiffness and pain due to Parkinson's disease[11] (fever) [11][11][11][19]
  • Traumatic Injury [20]

Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for antithrombosis through inhibition of platelet aggregation. This is useful for the management of arterial thrombosis and prevention of adverse cardiovascular events like heart attacks. Aspirin inhibits platelet aggregation by inhibiting the action of thromboxane A2. [21]

In a more specific application, the reduction in prostaglandins is used to close a patent ductus arteriosus in neonates if it has not done so physiologically after 24 hours. [22]

NSAIDs are useful in the management of post-operative dental pain following invasive dental procedures such as dental extraction. When not contra-indicated they are favoured over the use of paracetamol alone due to the anti-inflammatory effect they provide. [23] When used in combination with paracetamol the analgesic effect has been proven to be improved. [24] There is weak evidence suggesting that taking pre-operative analgesia can reduce the length of post operative pain associated with placing orthodontic spacers under local anaesthetic. [25] Combination of NSAIDs with pregabalin as preemptive analgesia has shown promising results for decreasing post operative pain intensity. [26] [27]

The effectiveness of NSAIDs for treating non-cancer chronic pain and cancer-related pain in children and adolescents is not clear. [28] [29] There have not been sufficient numbers of high-quality randomized controlled trials conducted. [28] [29]

Inflammation Edit

Differences in anti-inflammatory activity between NSAIDs are small, but there is considerable variation in individual response and tolerance to these drugs. About 60% of patients will respond to any NSAID of the others, those who do not respond to one may well respond to another. Pain relief starts soon after taking the first dose and a full analgesic effect should normally be obtained within a week, whereas an anti-inflammatory effect may not be achieved (or may not be clinically assessable) for up to 3 weeks. If appropriate responses are not obtained within these times, another NSAID should be tried. [30]

NSAIDs may be used with caution by people with the following conditions: [12]

    [12]
  • Persons who are over age 50, and who have a family history of GI (gastrointestinal) problems [12]
  • Persons who have had past GI problems from NSAID use [12]

NSAIDs should usually be avoided by people with the following conditions: [12]

    or stomach bleeding [12]
  • Uncontrolled hypertension[12][12]
  • People that suffer with inflammatory bowel disease (Crohn's disease or ulcerative colitis) [12]
  • Past transient ischemic attack (excluding aspirin) [12]
  • Past stroke (excluding aspirin) [12]
  • Past myocardial infarction (excluding aspirin) [12] (excluding aspirin) [12]
  • Undergoing coronary artery bypass surgery[12] (excluding low-dose aspirin) [31]
  • In third trimester of pregnancy [12]
  • Persons who have undergone gastric bypass surgery[32][33]
  • Persons who have a history of allergic or allergic-type NSAID hypersensitivity reactions, e.g. aspirin-induced asthma[34]

The widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly common. Use of NSAIDs increases risk of a range of gastrointestinal (GI) problems, kidney disease and adverse cardiovascular events. [35] [36] As commonly used for post-operative pain, there is evidence of increased risk of kidney complications. [37] Their use following gastrointestinal surgery remains controversial, given mixed evidence of increased risk of leakage from any bowel anastomosis created. [38] [39] [40]

An estimated 10–20% of people taking NSAIDs experience indigestion. In the 1990s high doses of prescription NSAIDs were associated with serious upper gastrointestinal adverse events, including bleeding. [41] Over the past decade, [ when? ] deaths associated with gastric bleeding have declined. [ medical citation needed ]

NSAIDs, like all medications, may interact with other medications. For example, concurrent use of NSAIDs and quinolone antibiotics may increase the risk of quinolones' adverse central nervous system effects, including seizure. [42] [43]

There is an argument over the benefits and risks of NSAIDs for treating chronic musculoskeletal pain. Each drug has a benefit-risk profile and balancing the risk of no treatment with the competing potential risks of various therapies should be considered. [44] For people over the age of 65 years old, the balance between the benefits of pain-relief medications such as NSAIDS and the potential for adverse effects has not been well determined. [45]

In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. [46] [47] They are recommending avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. [46] [47]

Combinational risk Edit

If a COX-2 inhibitor is taken, a traditional NSAID (prescription or over-the-counter) should not be taken at the same time. [48] In addition, people on daily aspirin therapy (e.g., for reducing cardiovascular risk) must be careful if they also use other NSAIDs, as these may inhibit the cardioprotective effects of aspirin. [ citation needed ]

Rofecoxib (Vioxx) was shown to produce significantly fewer gastrointestinal adverse drug reactions (ADRs) compared with naproxen. [49] The study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs (COX-2 inhibitors). A statistically significant increase in the incidence of myocardial infarctions was observed in patients on rofecoxib. Further data, from the APPROVe trial, showed a statistically significant relative risk of cardiovascular events of 1.97 versus placebo [50] —which caused a worldwide withdrawal of rofecoxib in October 2004. [ citation needed ]

Use of methotrexate together with NSAIDs in rheumatoid arthritis is safe, if adequate monitoring is done. [51]

Cardiovascular Edit

NSAIDs, aside from aspirin, increase the risk of myocardial infarction and stroke. [52] [53] This occurs at least within a week of use. [2] They are not recommended in those who have had a previous heart attack as they increase the risk of death or recurrent MI. [54] Evidence indicates that naproxen may be the least harmful out of these. [53] [55]

NSAIDs aside from (low-dose) aspirin are associated with a doubled risk of heart failure in people without a history of cardiac disease. [55] In people with such a history, use of NSAIDs (aside from low-dose aspirin) was associated with a more than 10-fold increase in heart failure. [56] If this link is proven causal, researchers estimate that NSAIDs would be responsible for up to 20 percent of hospital admissions for congestive heart failure. In people with heart failure, NSAIDs increase mortality risk (hazard ratio) by approximately 1.2–1.3 for naproxen and ibuprofen, 1.7 for rofecoxib and celecoxib, and 2.1 for diclofenac. [57]

On 9 July 2015, the Food and Drug Administration (FDA) toughened warnings of increased heart attack and stroke risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin. [58]

Possible erectile dysfunction risk Edit

A 2005 Finnish survey study found an association between long term (over 3 months) use of NSAIDs and erectile dysfunction. [59]

A 2011 publication [60] in The Journal of Urology received widespread publicity. [61] According to the study, men who used NSAIDs regularly were at significantly increased risk of erectile dysfunction. A link between NSAID use and erectile dysfunction still existed after controlling for several conditions. However, the study was observational and not controlled, with low original participation rate, potential participation bias, and other uncontrolled factors. The authors warned against drawing any conclusion regarding cause. [62]

Gastrointestinal Edit

The main adverse drug reactions (ADRs) associated with NSAID use relate to direct and indirect irritation of the gastrointestinal (GI) tract. NSAIDs cause a dual assault on the GI tract: the acidic molecules directly irritate the gastric mucosa, and inhibition of COX-1 and COX-2 reduces the levels of protective prostaglandins. [35] Inhibition of prostaglandin synthesis in the GI tract causes increased gastric acid secretion, diminished bicarbonate secretion, diminished mucus secretion and diminished trophic [ clarification needed ] effects on the epithelial mucosa. [ medical citation needed ]

Common gastrointestinal side effects include: [11]

Clinical NSAID ulcers are related to the systemic effects of NSAID administration. Such damage occurs irrespective of the route of administration of the NSAID (e.g., oral, rectal, or parenteral) and can occur even in people who have achlorhydria. [64]

Ulceration risk increases with therapy duration, and with higher doses. To minimize GI side effects, it is prudent to use the lowest effective dose for the shortest period of time—a practice that studies show is often not followed. Over 50% of patients who take NSAIDs have sustained some mucosal damage to their small intestine. [65]

The risk and rate of gastric adverse effects is different depending on the type of NSAID medication a person is taking. Indomethacin, ketoprofen, and piroxicam use appear to lead to the highest rate of gastric adverse effects, while ibuprofen (lower doses) and diclofenac appear to have lower rates. [11]

Certain NSAIDs, such as aspirin, have been marketed in enteric-coated formulations that manufacturers claim reduce the incidence of gastrointestinal ADRs. Similarly, some believe that rectal formulations may reduce gastrointestinal ADRs. However, consistent with the systemic mechanism of such ADRs, and in clinical practice, these formulations have not demonstrated a reduced risk of GI ulceration. [11]

Numerous "gastro-protective" drugs have been developed with the goal of preventing gastrointestinal toxicity in people who need to take NSAIDs on a regular basis. [35] Gastric adverse effects may be reduced by taking medications that suppress acid production such as proton pump inhibitors (e.g.: omeprazole and esomeprazole), or by treatment with a drug that mimics prostaglandin in order to restore the lining of the GI tract (e.g.: a prostaglandin analog misoprostol). [35] Diarrhea is a common side effect of misoprostol, however, higher doses of misoprostol have been shown to reduce the risk of a person having a complication related to a gastric ulcer while taking NSAIDs. [35] While these techniques may be effective, they are expensive for maintenance therapy. [ citation needed ]

Hydrogen sulfide NSAID hybrids prevent the gastric ulceration/bleeding associated with taking the NSAIDs alone. Hydrogen sulfide is known to have a protective effect on the cardiovascular and gastrointestinal system. [66]

Inflammatory bowel disease Edit

NSAIDs should be used with caution in individuals with inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) due to their tendency to cause gastric bleeding and form ulceration in the gastric lining. [67]

Renal Edit

NSAIDs are also associated with a fairly high incidence of adverse drug reactions (ADRs) on the kidney and over time can lead to chronic kidney disease. The mechanism of these kidney ADRs is due to changes in kidney blood flow. Prostaglandins normally dilate the afferent arterioles of the glomeruli. This helps maintain normal glomerular perfusion and glomerular filtration rate (GFR), an indicator of kidney function. This is particularly important in kidney failure where the kidney is trying to maintain renal perfusion pressure by elevated angiotensin II levels. At these elevated levels, angiotensin II also constricts the afferent arteriole into the glomerulus in addition to the efferent arteriole it normally constricts. Since NSAIDs block this prostaglandin-mediated effect of afferent arteriole dilation, particularly in kidney failure, NSAIDs cause unopposed constriction of the afferent arteriole and decreased RPF (renal perfusion flow) and GFR. [ medical citation needed ]

Common ADRs associated with altered kidney function include: [11]

These agents may also cause kidney impairment, especially in combination with other nephrotoxic agents. Kidney failure is especially a risk if the patient is also concomitantly taking an ACE inhibitor (which removes angiotensin II's vasoconstriction of the efferent arteriole) and a diuretic (which drops plasma volume, and thereby RPF)—the so-called "triple whammy" effect. [68]

In rarer instances NSAIDs may also cause more severe kidney conditions: [11]

NSAIDs in combination with excessive use of phenacetin or paracetamol (acetaminophen) may lead to analgesic nephropathy. [69]

Photosensitivity Edit

Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs. [70] The 2-arylpropionic acids are the most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including piroxicam, diclofenac, and benzydamine. [ medical citation needed ]

Benoxaprofen, since withdrawn due to its liver toxicity, was the most photoactive NSAID observed. The mechanism of photosensitivity, responsible for the high photoactivity of the 2-arylpropionic acids, is the ready decarboxylation of the carboxylic acid moiety. The specific absorbance characteristics of the different chromophoric 2-aryl substituents, affects the decarboxylation mechanism. [ citation needed ]

During pregnancy Edit

NSAIDs are not recommended during pregnancy, particularly during the third trimester. While NSAIDs as a class are not direct teratogens, they may cause premature closure of the fetal ductus arteriosus and kidney ADRs in the fetus. Additionally, they are linked with premature birth [71] and miscarriage. [72] Aspirin, however, is used together with heparin in pregnant women with antiphospholipid syndrome. [73] Additionally, indomethacin is used in pregnancy to treat polyhydramnios by reducing fetal urine production via inhibiting fetal kidney blood flow. [ citation needed ]

In contrast, paracetamol (acetaminophen) is regarded as being safe and well tolerated during pregnancy, but Leffers et al. released a study in 2010, indicating that there may be associated male infertility in the unborn. [74] [75] Doses should be taken as prescribed, due to risk of liver toxicity with overdoses. [76]

In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy. [77]

In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. [46] [47] They are recommending avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. [46] [47]

Allergy and allergy-like hypersensitivity reactions Edit

A variety of allergic or allergic-like NSAID hypersensitivity reactions follow the ingestion of NSAIDs. These hypersensitivity reactions differ from the other adverse reactions listed here which are toxicity reactions, i.e. unwanted reactions that result from the pharmacological action of a drug, are dose-related, and can occur in any treated individual hypersensitivity reactions are idiosyncratic reactions to a drug. [78] Some NSAID hypersensitivity reactions are truly allergic in origin: 1) repetitive IgE-mediated urticarial skin eruptions, angioedema, and anaphylaxis following immediately to hours after ingesting one structural type of NSAID but not after ingesting structurally unrelated NSAIDs and 2) Comparatively mild to moderately severe T cell-mediated delayed onset (usually more than 24 hour), skin reactions such as maculopapular rash, fixed drug eruptions, photosensitivity reactions, delayed urticaria, and contact dermatitis or 3) far more severe and potentially life-threatening t-cell-mediated delayed systemic reactions such as the DRESS syndrome, acute generalized exanthematous pustulosis, the Stevens–Johnson syndrome, and toxic epidermal necrolysis. Other NSAID hypersensitivity reactions are allergy-like symptoms but do not involve true allergic mechanisms rather, they appear due to the ability of NSAIDs to alter the metabolism of arachidonic acid in favor of forming metabolites that promote allergic symptoms. Afflicted individuals may be abnormally sensitive to these provocative metabolites or overproduce them and typically are susceptible to a wide range of structurally dissimilar NSAIDs, particularly those that inhibit COX1. Symptoms, which develop immediately to hours after ingesting any of various NSAIDs that inhibit COX-1, are: 1) exacerbations of asthmatic and rhinitis (see aspirin-induced asthma) symptoms in individuals with a history of asthma or rhinitis and 2) exacerbation or first-time development of wheals or angioedema in individuals with or without a history of chronic urticarial lesions or angioedema. [34]

Possible effects on bone and soft tissue healing Edit

It has been hypothesized that NSAIDs may delay healing from bone and soft-tissue injuries by inhibiting inflammation. [79] On the other hand, it has also been hypothesized that NSAIDs might speed recovery from soft tissue injuries by preventing inflammatory processes from damaging adjacent, non-injured muscles. [80]

There is moderate evidence that they delay bone healing. [81] Their overall effect on soft-tissue healing is unclear. [80] [79] [82]

Ototoxicity Edit

Long-term use of NSAID analgesics and paracetamol is associated with an increased risk of hearing loss. [83] [84] [85]

Other Edit

The use of NSAIDs for analgesia following gastrointestinal surgery remains controversial, given mixed evidence of an increased risk of leakage from any bowel anastomosis created. This risk may vary according to the class of NSAID prescribed. [38] [39] [40]

Common adverse drug reactions (ADR), other than listed above, include: raised liver enzymes, headache, dizziness. [11] Uncommon ADRs include an abnormally high level of potassium in the blood, confusion, spasm of the airways, and rash. [11] Ibuprofen may also rarely cause irritable bowel syndrome symptoms. NSAIDs are also implicated in some cases of Stevens–Johnson syndrome. [ medical citation needed ]

Most NSAIDs penetrate poorly into the central nervous system (CNS). However, the COX enzymes are expressed constitutively in some areas of the CNS, meaning that even limited penetration may cause adverse effects such as somnolence and dizziness. [ citation needed ]

NSAIDs may increase the risk of bleeding in patients with Dengue fever [86] For this reason, NSAIDs are only available with a prescription in India. [87]

In very rare cases, ibuprofen can cause aseptic meningitis. [88]

As with other drugs, allergies to NSAIDs might exist. While many allergies are specific to one NSAID, up to 1 in 5 people may have unpredictable cross-reactive allergic responses to other NSAIDs as well. [89]

Drug interactions Edit

NSAIDs reduce kidney blood flow and thereby decrease the efficacy of diuretics, and inhibit the elimination of lithium and methotrexate. [90]

NSAIDs cause decreased ability to form blood clots, which can increase the risk of bleeding when combined with other drugs that also decrease blood clotting, such as warfarin. [90]

NSAIDs may aggravate hypertension (high blood pressure) and thereby antagonize the effect of antihypertensives, [90] such as ACE inhibitors. [91]

NSAIDs may interfere and reduce efficiency of SSRI antidepressants. [92] [93] NSAIDs, when used in combination with SSRIs, increases the risk of adverse gastrointestinal effects. [94] NSAIDs, when used in combination with SSRIs, increases the risk of internal bleeding and brain hemorrhages. [95]

Various widely used nonsteroidal anti-inflammatory drugs (NSAIDs) enhance endocannabinoid signaling by blocking the anandamide-degrading membrane enzyme fatty acid amide hydrolase (FAAH). [96]

NSAIDs may reduce the effectiveness of antibiotics. Tests on cultured bacteria found that antibiotic effectiveness was reduced by 18-30% on average compared to tests which did not include NSAIDs. [97]

Immune response Edit

Although small doses generally have little to no effect on the immune system, large doses of NSAIDs significantly suppress the production of immune cells. [98] As NSAIDs affect prostaglandins, they affect the production of most fast growing cells. [98] This includes immune cells. [98] Unlike corticosteroids, they do not directly suppress the immune system and so their effect on the immune system is not immediately obvious. [98] They suppress the production of new immune cells, but leave existing immune cells functional. [98] Large doses slowly reduce the immune response as the immune cells are renewed at a much lower rate. [98] Causing a gradual reduction of the immune system, much slower and less noticeable than the immediate effect of Corticosteroids. [98] The effect significantly increases with dosage, in a nearly exponential rate. [98] Doubling of dose reduced cells by nearly four times. [98] Increasing dose by five times reduced cell counts to only a few percent of normal levels. [98] This is likely why the effect was not immediately obvious in low dose trials, as the effect is not apparent until much higher dosages are tested. [98]

Most NSAIDs act as nonselective inhibitors of the cyclooxygenase (COX) enzymes, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. This inhibition is competitively reversible (albeit at varying degrees of reversibility), as opposed to the mechanism of aspirin, which is irreversible inhibition. [99] COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A2). Prostaglandins act (among other things) as messenger molecules in the process of inflammation. This mechanism of action was elucidated in 1970 by John Vane (1927–2004), who received a Nobel Prize for his work (see Mechanism of action of aspirin). [ citation needed ]

COX-1 is a constitutively expressed enzyme with a "house-keeping" role in regulating many normal physiological processes. One of these is in the stomach lining, where prostaglandins serve a protective role, preventing the stomach mucosa from being eroded by its own acid. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs. [100]

When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels, ulcers of the stomach or duodenum and internal bleeding can result. [ citation needed ]

NSAIDs have been studied in various assays to understand how they affect each of these enzymes. While the assays reveal differences, unfortunately, different assays provide differing ratios. [101]

The discovery of COX-2 led to research to the development of selective COX-2 inhibiting drugs that do not cause gastric problems characteristic of older NSAIDs. [ citation needed ]

Paracetamol (acetaminophen) is not considered an NSAID because it has little anti-inflammatory activity. It treats pain mainly by blocking COX-2 mostly in the central nervous system, but not much in the rest of the body. [9]

However, many aspects of the mechanism of action of NSAIDs remain unexplained, and for this reason, further COX pathways are hypothesized. The COX-3 pathway was believed to fill some of this gap but recent findings make it appear unlikely that it plays any significant role in humans and alternative explanation models are proposed. [9]

NSAIDs interact with the endocannabinoid system and its endocannabinoids, as COX2 have been shown to utilize endocannabinoids as substrates, and may have a key role in both the therapeutic effects and adverse effects of NSAIDs, as well as in NSAID-induced placebo responses. [102] [103] [104]

NSAIDs are also used in the acute pain caused by gout because they inhibit urate crystal phagocytosis besides inhibition of prostaglandin synthase. [105]

Antipyretic activity Edit

NSAIDs have antipyretic activity and can be used to treat fever. [106] [107] Fever is caused by elevated levels of prostaglandin E2, which alters the firing rate of neurons within the hypothalamus that control thermoregulation. [106] [108] Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus. [106] [107] PGE2 signals to the hypothalamus to increase the body's thermal setpoint. [107] [109] Ibuprofen has been shown more effective as an antipyretic than paracetamol (acetaminophen). [108] [110] Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D, and E. [ medical citation needed ]

NSAIDs can be classified based on their chemical structure or mechanism of action. Older NSAIDs were known long before their mechanism of action was elucidated and were for this reason classified by chemical structure or origin. Newer substances are more often classified by mechanism of action. [ medical citation needed ]

Salicylates Edit

Propionic acid derivatives Edit

Acetic acid derivatives Edit

Enolic acid (oxicam) derivatives Edit

Anthranilic acid derivatives (fenamates) Edit

The following NSAIDs are derived from fenamic acid. which is a derivative of anthranilic acid, [114] : 235 which in turn is a nitrogen isostere of salicylic acid, which is the active metabolite of aspirin. [114] : 235 [115] : 17

Selective COX-2 inhibitors (coxibs) Edit

    (FDA alert [116] ) (withdrawn from market [117] ) (withdrawn from market [118] ) FDA withdrawn, licensed in the EU TGA cancelled registration not FDA approved, licensed in the EU used in dogs and horses

Sulfonanilides Edit

Others Edit

Chirality Edit

Most NSAIDs are chiral molecules diclofenac is a notable exception. However, the majority are prepared as racemic mixtures. Typically, only a single enantiomer is pharmacologically active. For some drugs (typically profens), an isomerase enzyme in vivo converts the inactive enantiomer into the active form, although its activity varies widely in individuals. This phenomenon is likely responsible for the poor correlation between NSAID efficacy and plasma concentration observed in older studies when specific analysis of the active enantiomer was not performed. [ medical citation needed ]

Ibuprofen and ketoprofen are now available in single-enantiomer preparations (dexibuprofen and dexketoprofen), which purport to offer quicker onset and an improved side-effect profile. Naproxen has always been marketed as the single active enantiomer. [ medical citation needed ]

Main practical differences Edit

NSAIDs within a group tend to have similar characteristics and tolerability. There is little difference in clinical efficacy among the NSAIDs when used at equivalent doses. [122] Rather, differences among compounds usually relate to dosing regimens (related to the compound's elimination half-life), route of administration, and tolerability profile. [ medical citation needed ]

Regarding adverse effects, selective COX-2 inhibitors have lower risk of gastrointestinal bleeding. [122] With the exception of naproxen, nonselective NSAIDs increase the risk of having a heart attack. [122] Some data also supports that the partially selective nabumetone is less likely to cause gastrointestinal events. [122]

A consumer report noted that ibuprofen, naproxen, and salsalate are less expensive than other NSAIDs, and essentially as effective and safe when used appropriately to treat osteoarthritis and pain. [123]

Most nonsteroidal anti-inflammatory drugs are weak acids, with a pKa of 3–5. They are absorbed well from the stomach and intestinal mucosa. They are highly protein-bound in plasma (typically >95%), usually to albumin, so that their volume of distribution typically approximates to plasma volume. Most NSAIDs are metabolized in the liver by oxidation and conjugation to inactive metabolites that typically are excreted in the urine, though some drugs are partially excreted in bile. Metabolism may be abnormal in certain disease states, and accumulation may occur even with normal dosage. [ medical citation needed ]

Ibuprofen and diclofenac have short half-lives (2–3 hours). Some NSAIDs (typically oxicams) have very long half-lives (e.g. 20–60 hours). [ medical citation needed ]

From the era of Greek medicine to the mid-19th century, the discovery of medicinal agents was classed as an empirical art folklore and mythological guidance were combined in deploying the vegetable and mineral products that made up the expansive pharmacopeia of the time. Myrtle leaves were in use by 1500 BCE. Hippocrates (460–377 BCE) first reported using willow bark [124] and in 30 BCE Celsus described the signs of inflammation and also used willow bark to mitigate them. On 25 April 1763, Edward Stone wrote to the Royal Society describing his observations on the use of willow bark-based medicines in febrile patients. [125] The active ingredient of willow bark, a glycoside called salicin, was first isolated by Johann Andreas Buchner in 1827. By 1829, French chemist Henri Leroux had improved the extraction process to obtain about 30g of purified salicin from 1.5 kg of bark. [125]

By hydrolysis, salicin releases glucose and salicyl alcohol which can be converted into salicylic acid, both in vivo and through chemical methods. [124] The acid is more effective than salicin and, in addition to its fever-reducing properties, is anti-inflammatory and analgesic. In 1869, Hermann Kolbe synthesised salicylate, although it was too acidic for the gastric mucosa. [124] The reaction used to synthesise aromatic acid from a phenol in the presence of CO2 is known as the Kolbe-Schmitt reaction. [126] [127] [128]

By 1897 the German chemist Felix Hoffmann and the Bayer company prompted a new age of pharmacology by converting salicylic acid into acetylsalicylic acid—named aspirin by Heinrich Dreser. Other NSAIDs like ibuprofen were developed from the 1950s forward. [125] In 2001, NSAIDs accounted for 70,000,000 prescriptions and 30 billion over-the-counter doses sold annually in the United States. [41]

While studies have been conducted to see if various NSAIDs can improve behavior in transgenic mouse models of Alzheimer's disease and observational studies in humans have shown promise, there is no good evidence from randomized clinical trials that NSAIDs can treat or prevent Alzheimer's in humans clinical trials of NSAIDs for treatment of Alzheimer's have found more harm than benefit. [129] [130] [131] NSAIDs coordinate with metal ions affecting cellular function. [132]

Research supports the use of NSAIDs for the control of pain associated with veterinary procedures such as dehorning and castration of calves. [ citation needed ] The best effect is obtained by combining a short-term local anesthetic such as lidocaine with an NSAID acting as a longer term analgesic. [ citation needed ] However, as different species have varying reactions to different medications in the NSAID family, little of the existing research data can be extrapolated to animal species other than those specifically studied, and the relevant government agency in one area sometimes prohibits uses approved in other jurisdictions. [ citation needed ]

For example, ketoprofen's effects have been studied in horses more than in ruminants but, due to controversy over its use in racehorses, veterinarians who treat livestock in the United States more commonly prescribe flunixin meglumine, which, while labeled for use in such animals, is not indicated for post-operative pain. [ citation needed ]

In the United States, meloxicam is approved for use only in canines, whereas (due to concerns about liver damage) it carries warnings against its use in cats [133] [134] except for one-time use during surgery. [135] In spite of these warnings, meloxicam is frequently prescribed "off-label" for non-canine animals including cats and livestock species. [136] In other countries, for example The European Union (EU), there is a label claim for use in cats. [137]


When Doctors Use Interferon Betas

Doctors typically suggest interferon betas when you have “active relapsing MS,” which means two or more relapses in the last 2 years. In addition, some doctors prescribe them if you have one relapse and/or signs of active disease on an MRI scan (new brain or spine lesions).

Other reasons your doctor might suggest beta interferons:

  • You have secondary progressive MS, but with significant relapses.
  • You have a “clinically isolated syndrome” (first instance of possible MS symptoms) and an MRI shows you're likely to have MS.

Should you take a pain reliever before getting coronavirus vaccine?

Medical experts say pain relievers may prevent parts of the immune system from working and slow down the immune response, reducing the coronavirus vaccine's effectiveness. (Staten Island Advance/Paul Liotta)

STATEN ISLAND, N.Y. — Medical experts warn against taking over-the-counter pain medication in the hours before receiving a coronavirus (COVID-19) vaccine -- as doing so may affect the body’s immune response, according to a recent report.

Though both the Moderna and Pfizer-BioNTech vaccine recipients typically experience minor side effects, including temporary pain and swelling at the injection site, muscle aches, fever, fatigue and chills, recipients should not attempt to prevent them by taking pain relievers like acetaminophen (Tylenol), ibuprofen (Motrin, Advil) or naproxen (Aleve) beforehand, experts say.

“We do not recommend premedication with ibuprofen or Tylenol before COVID-19 vaccines due to the lack of data on how it impacts the vaccine-induced antibody responses,” Dr. Simone Wildes, an infectious disease specialist at South Shore Medical Center and a member of Massachusetts’ COVID-19 Vaccine Advisory Group, told ABC News.


How Should You Prepare for Your Second Shot?

You can expect to receive the second dose three to four weeks after the first. The Centers for Disease Control and Prevention (CDC) recommends spacing Pfizer-BioNTech doses 21 days apart and Moderna doses 28 days apart in accordance with company directives.  

If you’re concerned about side effects, you can take preliminary steps to reduce their potential severity, such as resting and ensuring that any existing medical conditions are well controlled. While you should make sure that you have ibuprofen, aspirin, acetaminophen, or antihistamines on hand as well, Wen strongly recommends against medicating beforehand.  

“There is some mixed data about this, but some people believe that if you blunt your response by taking Tylenol or ibuprofen, it may reduce the effectiveness of the vaccine," she says. "Now, I'd say that that is quite controversial, and there isn't definitive evidence about this."

However, it’s probably better to play it safe. Some studies have found that over-the-counter pain relievers can interfere with the immune response provoked by vaccines, including the COVID-19 vaccine.

One such study linked the use of nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, to a decrease in cytokine activity and antibody production. These findings, the authors wrote, raise “the possibility that NSAIDs may alter the immune response to SARS-CoV-2 vaccination.”  

If you do begin to fall ill after receiving the second dose, Suo recommends taking a sick day as well as asking a friend or family member to monitor you until your symptoms have abated entirely. Further measures depend on the nature of your symptoms.

For localized soreness, the CDC recommends exercising your arm and applying "a clean, cool, wet washcloth" to the affected area for a fever, the CDC recommends dressing lightly and drinking plenty of fluids. You should be aware that immunity may take up to two weeks to kick in.

The information in this article is current as of the date listed, which means newer information may be available when you read this. For the most recent updates on COVID-19, visit our coronavirus news page.