Antipyretic Explained

An antipyretic (from anti- 'against' and 'feverish') is a substance that reduces fever.^[1] Antipyretics cause the hypothalamus to override a prostaglandin-induced increase in temperature. The body then works to lower the temperature, which results in a reduction in fever.

Most antipyretic medications have other purposes. The most common antipyretics in the US are usually ibuprofen and aspirin, which are nonsteroidal anti-inflammatory drugs (NSAIDs) used primarily as anti-inflammatories and analgesics (pain relievers), but which also have antipyretic properties; and paracetamol (acetaminophen), an analgesic without anti-inflammatory properties.^[2]

There is some debate over the appropriate use of such medications, since fever is part of the body's immune response to infection.^{[3] [4]} A study published by the Royal Society claims that fever suppression causes at least 1% more influenza deaths in the United States, or 700 extra deaths per year.^[5]

Non-pharmacological treatment

Bathing or sponging with lukewarm or cool water can effectively reduce body temperature in those with heat illness, but not usually in those with fever.^[6] The use of alcohol baths is not an appropriate cooling method, because there have been reported adverse events associated with systemic absorption of alcohol.^[7]

Medications

The list of medications with antipyretic effects includes many common drugs that also have analgesic and anti-inflammatory activity, several of which are commonly sold over-the-counter (OTC).

• NSAIDs (non-steroidal anti-inflammatory drugs), a broad class of medications that in addition to their defining effect of reducing inflammation, also tend to be potent analgesics and antipyretics. The majority work by inhibiting the activity of the cyclooxygenase (COX) family of enzymes in the body.
  • Nonselective COX enzyme inhibitors like ibuprofen and naproxen.^[8]
  • Salicylates, including aspirin (acetylsalicylic acid), magnesium salicylate, and sodium salicylate. These are also primarily nonselective COX inhibitors, but also work through other mechanisms including activating AMP-activated protein kinase.^[9]
  • COX inhibitors that are relatively selective for the COX-1 enzyme, such as ketoprofen and flurbiprofen.
  • Conversely, COX inhibitors that are relatively selective for COX-2, including nimesulide, diclofenac and celecoxib.
  • Phenazone-like drugs (pyrazolones), many of which have been largely phased out of used owing to safety concerns in most countries (including metamizole, banned in over 30 countries for causing agranulocytosis), but remain available in some locations or for specific purposes such as for treating otitis media in the form of ear drops.
• Paracetamol (acetaminophen) class antipyretics, which have negligible anti-inflammatory activity. Apart from paracetamol itself, the medications in this class are mainly previously marketed drugs which were withdrawn owing to safety concerns, one example of this being phenacetin.
• A few other medications have antipyretic effects of varying strength. While these medications tend to have too weak fever reducing effects or too many adverse effects to use primarily as antipyretics, their antipyretic effect may occasionally be useful. For example, there are theoretical reasons to believe,^[10] as well as slight evidence from one human trial,^[11] that α₂-adrenergic agonists, and particularly clonidine (a common drug used to treat high blood pressure, ADHD, spasticity and several other conditions), may have antipyretic effects, which if verified could potentially be useful in patients with septic shock or acute respiratory distress syndrome.^[12]

Use in children

The U.S. Food and Drug Administration (FDA) notes that improper dosing is one of the biggest problems in giving acetaminophen (paracetamol) to children.^[13] The effectiveness of acetaminophen alone as an antipyretic in children is uncertain, with some evidence showing it is no better than physical methods.^[14] Therapies involving alternating doses of acetaminophen and ibuprofen have shown greater antipyretic effect than either drug alone.^[15] One meta-analysis indicated that ibuprofen is more effective than acetaminophen in children at similar doses when both are given alone.^[16]

Due to concerns about Reye syndrome, it is recommended that aspirin and combination products that contain aspirin not be given to children or teenagers during episodes of fever-causing illnesses.^{[17] [18]}

Traditional medicine

Traditional use of vascular plants with antipyretic properties is a common worldwide feature of many ethnobotanical cultures. In ethnobotany, a plant with naturally occurring antipyretic properties is commonly referred to as a febrifuge.^[19]

Notes and References

1. Web site: Definition of antipyretic . Merriam-Webster Online Dictionary . 2007-12-19.
2. "Acetaminophen", PubChem, National Center for Biotechnology Information, U.S. National Library of Medicine. Modified 2016-08-07, accessed 2016-08-16.
3. Web site: Fever treatment: Quick guide to treating a fever . Mayo Clinic . live . https://web.archive.org/web/20131115193926/http://www.mayoclinic.com/health/fever/ID00052 . 2013-11-15 .
4. Web site: Fever . MedlinePlus Medical Encyclopedia .
5. News: Fight the Flu, Hurt Society? . Kupferschmidt . Kai . 2014-01-21 . Science . live . https://web.archive.org/web/20230212114036/https://www.science.org/content/article/fight-flu-hurt-society . 2023-02-12 .
6. Web site: Fever in infants and children: Pathophysiology and management.
7. Sullivan . J. E. . Committee On . H. C. . Sullivan . J. E. . Farrar . H. C. . 2011 . Fever and Antipyretic Use in Children . Pediatrics . 127 . 3 . 580–587 . 10.1542/peds.2010-3852 . 21357332. free .
8. Cryer B, Feldman M . Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs . Am J Med . 104 . 5 . 413–21 . May 1998 . 9626023 . 10.1016/s0002-9343(98)00091-6 .
9. Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, Kemp BE, Sakamoto K, Steinberg GR, Hardie DG . 6 . The ancient drug salicylate directly activates AMP-activated protein kinase . Science . 336 . 6083 . 918–22 . May 2012 . 22517326 . 3399766 . 10.1126/science.1215327 . 2012Sci...336..918H .
10. Madden CJ, Tupone D, Cano G, Morrison SF . α2 Adrenergic receptor-mediated inhibition of thermogenesis . J Neurosci . 33 . 5 . 2017–28 . January 2013 . 23365239 . 3711400 . 10.1523/JNEUROSCI.4701-12.2013 .
11. Mokhtari M, Sistanizad M, Farasatinasab M . Antipyretic Effect of Clonidine in Intensive Care Unit Patients: A Nested Observational Study . J Clin Pharmacol . 57 . 1 . 48–51 . January 2017 . 27264198 . 10.1002/jcph.776 . 3741978 .
12. Petitjeans F, Leroy S, Pichot C, Geloen A, Ghignone M, Quintin L . Hypothesis: Fever control, a niche for alpha-2 agonists in the setting of septic shock and severe acute respiratory distress syndrome? . Temperature (Austin) . 5 . 3 . 224–256 . 2018 . 30393754 . 6209424 . 10.1080/23328940.2018.1453771 .
13. https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm263989.htm Reducing Fever in Children: Safe Use of Acetaminophen
14. Meremikwu M, Oyo-Ita A . 2002 . Meremikwu . Martin M . Paracetamol for treating fever in children . The Cochrane Database of Systematic Reviews . 2002 . 2 . CD003676 . 10.1002/14651858.CD003676 . 6532671 . 12076499 . Trial evidence that paracetamol has a superior antipyretic effect than placebo is inconclusive..
15. E. Michael Sarrell, MD . Eliahu Wielunsky, MD . Herman Avner Cohen, MD . 2006 . Antipyretic treatment in young children with fever: acetaminophen, ibuprofen, or both alternating in a randomized, double-blind study . Archives of Pediatrics & Adolescent Medicine . 160 . 2 . 197–202 . 10.1001/archpedi.160.2.197 . 16461878. free .
16. Kauffman . Ralph . Sawyer, L.A. . Scheinbaum, M.L. . 1992 . Antipyretic Efficacy of Ibuprofen vs Acetaminophen . American Journal of Diseases of Children . 146 . 5 . 622–625 . 10.1001/archpedi.1992.02160170102024 . 1621668.
17. https://www.cdc.gov/ncidod/diseases/reye.htm CDC Study Shows Sharp Decline in Reye's Syndrome among U.S. Children
18. http://www.nhs.uk/Conditions/Reyes-syndrome/Pages/Prevention.aspx Reye's syndrome - Prevention
19. Schultes . Richard Evans . Raffauf . Robert F. . 1994 . De Plantis Toxicariis e Mundo Novo Tropicale Commentationes XXXIX Febrifuges of northwest Amazonia . Harvard Papers in Botany . 1 . 5 . 52–68 . 1043-4534. 41761491 .