View source for Naproxen

{{Short description|Nonsteroidal anti-inflammatory drug (NSAID) used to treat pain}}
{{Redirect-distinguish|Antalgin|Analgin}}
{{Use dmy dates|date=February 2024}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 464372587
| image = Naproxen2DACS.svg
| image_class = skin-invert-image
| width = 200
| alt = 
| image2 = (S)-naproxen-from-xtal-3D-bs-17.png
| image_class2 = bg-transparent
| width2 = 
| alt2 = 
| caption = <!-- Clinical data -->
| pronounce = {{IPAc-en|n|ə|ˈ|p|r|ɒ|k|s|ən}}
| tradename = Aleve, Naprosyn, others<ref name="drugs"/><ref name="Naproxen international" />
| Drugs.com = {{drugs.com|monograph|naproxen}}
| MedlinePlus = a681029
| DailyMedID = Naproxen
| pregnancy_AU = C
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web |title=Naproxen Use During Pregnancy |website=Drugs.com |date=13 August 2019 |url=https://www.drugs.com/pregnancy/naproxen.html |access-date=27 December 2019}}</ref>
| pregnancy_category = 
| routes_of_administration = [[Oral administration|By mouth]]
| class = 
| ATC_prefix = G02
| ATC_suffix = CC02
| ATC_supplemental = {{ATC|M01|AE02}}, {{ATC|M02|AA12}}, {{ATC|M01|AE56}}, {{ATC|M01|AE52}}

<!-- Legal status -->| legal_AU = S2
| legal_AU_comment = when in preparations that contain no more than 15 days' supply. Otherwise it is Schedule 4 (Prescription only).<ref>{{cite book |title=Standard for the Uniform Scheduling of Medicines and Poisons No. 4 |publisher=Therapeutic Goods Administration |date=July 2013 |url=http://www.comlaw.gov.au/Details/F2013L01607/229bdf2e-7014-4379-b751-0b584f55d699 |format=PDF |isbn=978-1-74241-895-7 |editor=Gill, A}}</ref>
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment = 
| legal_CA = OTC
| legal_CA_comment = 
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = POM
| legal_UK_comment = /&nbsp;P<ref>{{cite web |title=Boots Period Pain Relief 250 mg Gastro-Resistant Tablets - Summary of Product Characteristics (SmPC) |website=(emc) |date=4 February 2013 |url=https://www.medicines.org.uk/emc/product/3935/smpc |access-date=12 February 2023}}</ref>
| legal_US = OTC
| legal_US_comment = /&nbsp;Rx-only
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment = 
| legal_status = <!--For countries not listed above-->

<!-- Pharmacokinetic data -->| bioavailability = 95% (by mouth)
| protein_bound = 99%
| metabolism = [[Liver]] (to 6-desmethylnaproxen)
| metabolites = 
| onset = 1 hour
| elimination_half-life = 12–17 hours (adults)<ref name="CV Safety Review Article"/>
| duration_of_action = 12 hours
| excretion = [[Kidney]]

<!-- Identifiers -->| index2_label = as salt
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 22204-53-1
| CAS_supplemental = 
| PubChem = 156391
| IUPHAR_ligand = 
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00788
| ChemSpiderID_Ref = {{chemspidercite |correct|chemspider}}
| ChemSpiderID = 137720
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 57Y76R9ATQ
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00118
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = D00970
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 7476
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 154
| NIAID_ChemDB = 
| PDB_ligand = NPX
| synonyms = <!-- Chemical and physical data -->
| IUPAC_name = (+)-(''S'')-2-(6-Methoxynaphthalen-2-yl)propanoic acid
| C = 14
| H = 14
| O = 3
| SMILES = COc1cc2ccc(cc2cc1)[C@H](C)C(=O)O
| StdInChI_Ref = {{stdinchicite |correct |chemspider}}
| StdInChI = 1S/C14H14O3/c1-9(14(15)16)10-3-4-12-8-13(17-2)6-5-11(12)7-10/h3-9H,1-2H3,(H,15,16)/t9-/m0/s1
| StdInChI_comment = 
| StdInChIKey_Ref = {{stdinchicite |correct |chemspider}}
| StdInChIKey = CMWTZPSULFXXJA-VIFPVBQESA-N
| density = 
| density_notes = 
| melting_point = 152-154
| melting_high = 
| melting_notes = 
| boiling_point = 
| boiling_notes = 
| solubility = 
| sol_units = 
| specific_rotation = 
}}

<!-- Definition and medical uses -->
'''Naproxen''', sold under the brand name '''Aleve''' among others, is a [[nonsteroidal anti-inflammatory drug]] (NSAID) used to treat pain, [[menstrual cramp]]s, and [[inflammatory diseases]] such as [[rheumatoid arthritis]], [[gout]] and [[fever]].<ref name=AHFS2018/> It is [[Oral administration|taken orally]].<ref name=AHFS2018/> It is available in immediate and [[Delayed release (pharmacology)|delayed release]] formulations.<ref name=AHFS2018/> Onset of effects is within an hour and lasts for up to twelve hours.<ref name=AHFS2018/> Naproxen is also available in [[Salt (chemistry)|salt form]], '''naproxen sodium''', which has better [[solubility]] when taken orally.<ref name=":0">{{cite journal | vauthors = Derry C, Derry S, Moore RA, McQuay HJ | title = Single dose oral naproxen and naproxen sodium for acute postoperative pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 2009 | issue = 1 | pages = CD004234 | date = January 2009 | pmid = 19160232 | pmc = 6483469 | doi = 10.1002/14651858.CD004234.pub3 }}</ref>

<!-- Side effects -->
Common side effects include [[dizziness]], [[headache]], [[bruising]], [[allergic reactions]], [[heartburn]], and stomach pain.<ref name="AHFS2018" /> Severe side effects include an increased risk of [[heart disease]], [[stroke]], [[gastrointestinal bleeding]], and [[stomach ulcers]].<ref name=AHFS2018/> The heart disease risk may be lower than with other NSAIDs.<ref name=AHFS2018/> It is not recommended in people with [[kidney problems]].<ref name=AHFS2018/> Use is not recommended in the [[third trimester of pregnancy]].<ref name=AHFS2018/>

<!-- Mechanism -->
Naproxen is a nonselective [[Cyclooxygenase|COX]] inhibitor.<ref name=AHFS2018/> As an NSAID, naproxen appears to exert its anti-inflammatory action by reducing the production of inflammatory mediators called [[prostaglandins]].<ref>{{cite book |vauthors = McEvoy GK |title=AHFS Drug Information, 2000 |date=2000 |publisher=American Society of Health-System Pharmacists |isbn=978-1-58528-004-9 |page=1854 |url=https://books.google.com/books?id=E3iynUKXWoYC }}</ref> It is metabolized by the liver to inactive metabolites.<ref name=AHFS2018/>

<!-- History and culture -->
Naproxen was patented in 1967 and approved for medical use in the United States in 1976.<ref name="Naprosyn label">{{cite web |title=Naprosyn- naproxen tablet EC-Naprosyn- naproxen tablet, delayed release Anaprox DS- naproxen sodium tablet |website=DailyMed |date=1 July 2019 |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8bff5df5-d856-4237-b6a8-ae445b454844 |access-date=27 December 2019}}</ref><ref name=AHFS2018/><ref name=Fis2006>{{cite book |vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=978-3-527-60749-5 |page=520 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA520 }}</ref> In the United States it is available [[over the counter|over-the-counter]] and as a [[generic medication]].<ref name=AHFS2018>{{cite web |title=Naproxen Monograph for Professionals |url=https://www.drugs.com/monograph/naproxen.html |website=Drugs.com |publisher=AHFS |access-date=19 December 2018 }}</ref><ref>{{cite web |title=Medicines A to Z - Naproxen |url=https://www.nhs.uk/medicines/naproxen/ |website=NHS |publisher=National Health Service |access-date=11 March 2020 |date=24 October 2018}}</ref> In 2022, it was the 88th most commonly prescribed medication in the United States, with more than 7{{nbsp}}million prescriptions.<ref>{{cite web |title=The Top 300 of 2022 |url=https://clincalc.com/DrugStats/Top300Drugs.aspx |website=ClinCalc |access-date=30 August 2024 |archive-date=30 August 2024 |archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx |url-status=live }}</ref><ref>{{cite web |title = Naproxen Drug Usage Statistics, United States, 2013 - 2022 |website = ClinCalc |url = https://clincalc.com/DrugStats/Drugs/Naproxen |access-date = 30 August 2024 }}</ref>

== Medical uses ==
Naproxen's medical uses are related to its mechanism of action as an anti-inflammatory compound.<ref name="Naprosyn label" /> Naproxen is used to treat a variety of inflammatory conditions and symptoms that are due to excessive [[inflammation]], such as [[pain]] and [[fever]] (naproxen has fever-reducing, or [[antipyretic]], properties in addition to its anti-inflammatory activity).<ref name="Naprosyn label" /> Naproxen's anti-inflammatory properties may relieve pain caused by inflammatory conditions such as [[migraine]], [[osteoarthritis]], [[kidney stones]], [[rheumatoid arthritis]], [[psoriatic arthritis]], [[gout]], [[ankylosing spondylitis]], [[menstrual cramp]]s, [[tendinitis]], and [[bursitis]].<ref name="drugs" >{{cite web|url=https://www.drugs.com/naproxen.html|title=Naproxen|publisher=Drugs.com|date=2017|access-date=7 February 2017}}</ref>  Naproxen has also proven effective for acute post-operative pain.<ref name=":0" />

Naproxen sodium is used as a "bridge therapy" in [[medication overuse headache|medication-overuse headache]] to slowly take patients off other medications.<ref name="Chronic HA">{{cite journal | vauthors = Garza I, Schwedt TJ | title = Diagnosis and management of chronic daily headache | journal = Seminars in Neurology | volume = 30 | issue = 2 | pages = 154–166 | date = April 2010 | pmid = 20352585 | doi = 10.1055/s-0030-1249224 | publisher = WebMD LLC | doi-access = free }}</ref>

===Available formulations===
Naproxen sodium is available as both an immediate-release and an extended-release tablet. The extended-release formulations (sometimes called "sustained release", or "enteric coated") take longer to take effect than the immediate-release formulations and therefore are less useful when immediate pain relief is desired. Extended-release formulations are more useful for the treatment of chronic, or long-lasting, conditions, in which long-term pain relief is desirable.<ref name="L490 Pill Identification"/>

<gallery mode="nolines" widths="170" perrow="3">
File:Naproxen2016.jpg|250{{nbsp}}mg tablet of naproxen
File:Naproxen.JPG|220{{nbsp}}mg tablet of naproxen sodium. Imprint L490 (upside-down). Round, light blue tablet<ref name="L490 Pill Identification">{{cite web|title=L490 (Naproxen 220 mg)|url=https://www.drugs.com/imprints/l490-13081.html|website=drugs.com|access-date=17 May 2017}}</ref>
File:Teva-naproxen-ec-500.png|Naproxen extended release 500{{nbsp}}mg, back and front
</gallery>

===Pregnancy and lactation===
As with all non-steroidal anti-inflammatory medications (NSAIDs), naproxen use should be avoided in pregnancy due to the importance of prostaglandins in vascular and renal function in the fetus. NSAIDs should especially be avoided in the third trimester. Small amounts of naproxen are excreted in breast milk.<ref name=drugs/> However, adverse effects are uncommon in infants breastfed from a mother taking naproxen.<ref name="LactMed">{{cite web|title=LACTMED: NAPROXEN|url=https://toxnet.nlm.nih.gov/cgi-bin/sis/search2/f?./temp/~H9DD3g:1|website=TOXNET|publisher=NIH|access-date=21 July 2017}}</ref>

==Adverse effects==
Common adverse effects include dizziness, drowsiness, headache, rash, bruising, and gastrointestinal upset.<ref name="Naprosyn label" /><ref name=drugs/> Heavy use is associated with an increased risk of end-stage renal disease and kidney failure.<ref name="Naprosyn label" /><ref>{{cite journal | vauthors = Perneger TV, Whelton PK, Klag MJ | title = Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs | journal = The New England Journal of Medicine | volume = 331 | issue = 25 | pages = 1675–1679 | date = December 1994 | pmid = 7969358 | doi = 10.1056/nejm199412223312502 | doi-access = free }}</ref> Naproxen may cause [[leg cramps|muscle cramps]] in the legs in 3% of people.<ref>{{cite journal | vauthors = Allen RE, Kirby KA | title = Nocturnal leg cramps | journal = American Family Physician | volume = 86 | issue = 4 | pages = 350–355 | date = August 2012 | pmid = 22963024 }}</ref>

In October 2020, the U.S. [[Food and Drug Administration]] (FDA) required the [[Drug labelling|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.<ref name="FDA PR 20201015" /><ref name="FDA safety 20201015" /> They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.<ref name="FDA PR 20201015">{{cite press release | title=FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications | website=U.S. [[Food and Drug Administration]] (FDA) | date=15 October 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-warns-using-type-pain-and-fever-medication-second-half-pregnancy-could-lead-complications | access-date=15 October 2020}}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}} {{PD-notice}}</ref><ref name="FDA safety 20201015">{{cite web | title=NSAIDs may cause rare kidney problems in unborn babies | website=U.S. Food and Drug Administration | date=21 July 2017 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic | archive-url=https://web.archive.org/web/20201017014419/https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic | url-status=dead | archive-date=17 October 2020 | access-date=15 October 2020}} {{PD-notice}}</ref>

===Gastrointestinal===
As with other non-[[COX-2]] selective NSAIDs, naproxen can cause [[gastrointestinal problem]]s, such as heartburn, constipation, diarrhea, ulcers and stomach bleeding.<ref>{{cite web | url = https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000526 | archive-url = https://web.archive.org/web/20100722112536/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000526 | archive-date = 22 July 2010 | date = 1 September 2008 | title = Naproxen | website = PubMed Health }}</ref> Naproxen should be taken orally with, or just after food, to decrease the risk of [[Gastrointestinal tract|gastrointestinal]] side effects.<ref name="NHS_2022">{{cite web |url=https://www.nhs.uk/medicines/naproxen/how-and-when-to-take-naproxen/ |title= How to take it|author=<!--Not stated--> |date=20 January 2022 |website=NHS.Gov |publisher= |quote=}}</ref> Persons with a history of [[ulcers]] or [[inflammatory bowel disease]] should consult a doctor before taking naproxen.<ref name="NHS_2022"/> In U.S. markets, naproxen is sold with [[boxed warning]]s about the risk of gastrointestinal ulceration or bleeding.<ref name=drugs/> Naproxen poses an intermediate risk of stomach ulcers compared with [[ibuprofen]], which is low-risk, and [[indometacin]], which is high-risk.<ref>{{cite journal | vauthors = Richy F, Bruyere O, Ethgen O, Rabenda V, Bouvenot G, Audran M, Herrero-Beaumont G, Moore A, Eliakim R, Haim M, Reginster JY | title = Time dependent risk of gastrointestinal complications induced by non-steroidal anti-inflammatory drug use: a consensus statement using a meta-analytic approach | journal = Annals of the Rheumatic Diseases | volume = 63 | issue = 7 | pages = 759–766 | date = July 2004 | pmid = 15194568 | pmc = 1755051 | doi = 10.1136/ard.2003.015925 }}</ref> To reduce stomach ulceration risk, it is often combined with a [[proton-pump inhibitor]] (a medication that reduces [[stomach acid]] production) during long-term treatment of those with pre-existing stomach ulcers or a history of developing stomach ulcers while on NSAIDs.<ref name="AMH">{{cite book | veditors = Rossi S | isbn = 978-0-9805790-9-3 | title = Australian Medicines Handbook | place = Adelaide | publisher = The Australian Medicines Handbook Unit Trust | year = 2013 | edition = 2013 }}</ref><ref name="BNF">{{cite book | isbn = 978-0-85711-084-8 | title = British National Formulary (BNF) | last1 = Joint Formulary Committee | year = 2013 | publisher = Pharmaceutical Press | location = London, UK | edition = 65 | pages = [https://archive.org/details/bnf65britishnati0000unse/page/665 665, 673] | url = https://archive.org/details/bnf65britishnati0000unse/page/665 }}</ref>

===Cardiovascular===
[[COX-2]] selective and nonselective [[NSAIDs]] have been linked to increases in the number of serious and potentially fatal cardiovascular events, such as [[myocardial infarctions]] and [[stroke]]s.<ref name="NissenYeomans2016">{{cite journal | vauthors = Nissen SE, Yeomans ND, Solomon DH, Lüscher TF, Libby P, Husni ME, Graham DY, Borer JS, Wisniewski LM, Wolski KE, Wang Q, Menon V, Ruschitzka F, Gaffney M, Beckerman B, Berger MF, Bao W, Lincoff AM | title = Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis | journal = The New England Journal of Medicine | volume = 375 | issue = 26 | pages = 2519–2529 | date = December 2016 | pmid = 27959716 | doi = 10.1056/NEJMoa1611593 | doi-access = free }}</ref> Naproxen is, however, associated with the smallest overall cardiovascular risks.<ref name = Trelle>{{cite journal | vauthors = Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, Egger M, Jüni P | title = Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis | journal = BMJ | volume = 342 | pages = c7086 | date = January 2011 | pmid = 21224324 | pmc = 3019238 | doi = 10.1136/bmj.c7086 | id = c7086 }}</ref><ref name=j1>{{cite journal | vauthors = Bhala N, Emberson J, Merhi A, Abramson S, Arber N, Baron JA, Bombardier C, Cannon C, Farkouh ME, FitzGerald GA, Goss P, Halls H, Hawk E, Hawkey C, Hennekens C, Hochberg M, Holland LE, Kearney PM, Laine L, Lanas A, Lance P, Laupacis A, Oates J, Patrono C, Schnitzer TJ, Solomon S, Tugwell P, Wilson K, Wittes J, Baigent C | title = Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials | journal = Lancet | volume = 382 | issue = 9894 | pages = 769–779 | date = August 2013 | pmid = 23726390 | pmc = 3778977 | doi = 10.1016/S0140-6736(13)60900-9 }}</ref> Cardiovascular risk must be considered when prescribing any nonsteroidal anti-inflammatory drug. The drug had roughly 50% of the associated risk of stroke compared with [[ibuprofen]] and was also associated with a reduced number of myocardial infarctions compared with [[Treatment and control groups|control groups]].<ref name=Trelle/>

A study found that high-dose naproxen induced near-complete suppression of platelet [[thromboxane]] throughout the dosing interval and appeared not to increase [[cardiovascular disease]] (CVD) risk, whereas other non-aspirin high-dose NSAID regimens had only transient effects on platelet [[COX-1]] and were associated with a small but definite vascular hazard. Conversely, naproxen was associated with higher rates of upper gastrointestinal bleeding complications compared with other NSAIDs.<ref name=j1/>

== Interactions ==

===Drug–drug interactions===
Naproxen may [[drug interaction|interact]] with [[antidepressant]]s, [[lithium (medication)|lithium]], [[methotrexate]], [[probenecid]], [[warfarin]] and other [[blood thinners]], heart or blood pressure medications, including [[diuretic]]s, or steroid medicines such as [[prednisone]].<ref name=drugs/>

NSAIDs such as naproxen may interfere with and reduce the efficacy of [[SSRI]] antidepressants,<ref name="pmid21518864">{{cite journal | vauthors = Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P | title = Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 22 | pages = 9262–9267 | date = May 2011 | pmid = 21518864 | pmc = 3107316 | doi = 10.1073/pnas.1104836108 | doi-access = free | bibcode = 2011PNAS..108.9262W }}</ref> as well as increase the risk of bleeding greater than the individual bleeding risk of either class of agent, when taken together.<ref name="SSRI Bleeding Review Article">{{cite journal | vauthors = Turner MS, May DB, Arthur RR, Xiong GL | title = Clinical impact of selective serotonin reuptake inhibitors therapy with bleeding risks | journal = Journal of Internal Medicine | volume = 261 | issue = 3 | pages = 205–213 | date = March 2007 | pmid = 17305643 | doi = 10.1111/j.1365-2796.2006.01720.x | s2cid = 41772614 | doi-access = free }}</ref> Naproxen is not contraindicated in the presence of SSRIs, though concomitant use of the medications should be done with caution.<ref name="SSRI Bleeding Review Article" /> [[Alcohol (drug)|Alcohol]] consumption increases the risk of [[gastrointestinal bleeding]] when combined with NSAIDs like naproxen in a [[Dose–response relationship|dose-dependent]] manner (that is, the higher the dose of naproxen, the higher the risk of bleeding).<ref name="Pfau and Lichtenstein">{{cite journal | vauthors = Pfau PR, Lichenstein GR | title = NSAIDs and alcohol: never the twain shall mix? | journal = The American Journal of Gastroenterology | volume = 94 | issue = 11 | pages = 3098–3101 | date = November 1999 | pmid = 10566697 | doi = 10.1111/j.1572-0241.1999.03098.x | s2cid = 41310743 | doi-access = free }}</ref> The risk is highest for people who are heavy drinkers.<ref name="Pfau and Lichtenstein" />

==Pharmacology==

===Mechanism of action===
Naproxen works by [[Reversible inhibitor|reversibly inhibiting]] both the [[PTGS1|COX-1]] and [[Prostaglandin-endoperoxide synthase 2|COX-2]] [[enzymes]] as a non-selective [[coxib]].<ref name="pmid20810665">{{cite journal | vauthors = Duggan KC, Walters MJ, Musee J, Harp JM, Kiefer JR, Oates JA, Marnett LJ | title = Molecular basis for cyclooxygenase inhibition by the non-steroidal anti-inflammatory drug naproxen | journal = The Journal of Biological Chemistry | volume = 285 | issue = 45 | pages = 34950–34959 | date = November 2010 | pmid = 20810665 | pmc = 2966109 | doi = 10.1074/jbc.M110.162982 | doi-access = free }}</ref><ref name="pmid18397691">{{cite journal | vauthors = Hinz B, Cheremina O, Besz D, Zlotnick S, Brune K | title = Impact of naproxen sodium at over-the-counter doses on cyclooxygenase isoforms in human volunteers | journal = International Journal of Clinical Pharmacology and Therapeutics | volume = 46 | issue = 4 | pages = 180–186 | date = April 2008 | pmid = 18397691 | doi = 10.5414/CPP46180 }}</ref><ref name="pmid11028250">{{cite journal | vauthors = Van Hecken A, Schwartz JI, Depré M, De Lepeleire I, Dallob A, Tanaka W, Wynants K, Buntinx A, Arnout J, Wong PH, Ebel DL, Gertz BJ, De Schepper PJ | title = Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers | journal = Journal of Clinical Pharmacology | volume = 40 | issue = 10 | pages = 1109–1120 | date = October 2000 | pmid = 11028250 | doi = 10.1177/009127000004001005 | url = https://accp1.onlinelibrary.wiley.com/doi/abs/10.1177/009127000004001005 | access-date = 23 February 2020 | s2cid = 24736336 | archive-url = https://web.archive.org/web/20200223155551/https://accp1.onlinelibrary.wiley.com/doi/abs/10.1177/009127000004001005 | archive-date = 23 February 2020 }}</ref><ref name="pmid15161995">{{cite journal | vauthors = Gross GJ, Moore J | title = Effect of COX-1/COX-2 inhibition versus selective COX-2 inhibition on coronary vasodilator responses to arachidonic acid and acetylcholine | journal = Pharmacology | volume = 71 | issue = 3 | pages = 135–142 | date = July 2004 | pmid = 15161995 | doi = 10.1159/000077447 | s2cid = 34018223 }}</ref><ref name="pmid11566042">{{cite journal | vauthors = Hawkey CJ | title = COX-1 and COX-2 inhibitors | journal = Best Practice & Research. Clinical Gastroenterology | volume = 15 | issue = 5 | pages = 801–820 | date = October 2001 | pmid = 11566042 | doi = 10.1053/bega.2001.0236 }}</ref>

=== Pharmacokinetics ===
Naproxen is a minor substrate of [[CYP1A2]] and [[CYP2C9]]. It is extensively metabolized in the liver to 6-O-desmethylnaproxen, and both the parent drug and the desmethyl metabolite undergo further metabolism to their respective acylglucuronide conjugated metabolites.<ref>{{cite journal | vauthors = Vree TB, van den Biggelaar-Martea M, Verwey-van Wissen CP, Vree JB, Guelen PJ | title = Pharmacokinetics of naproxen, its metabolite O-desmethylnaproxen, and their acyl glucuronides in humans | journal = Biopharmaceutics & Drug Disposition | volume = 14 | issue = 6 | pages = 491–502 | date = August 1993 | pmid = 8218967 | doi = 10.1002/bdd.2510140605 | s2cid = 35920001 }}</ref> An analysis of two [[clinical trials]] shows that naproxen's time to [[Cmax (pharmacology)|peak plasma concentration]] occurs between 2 and 4 hours after oral administration, though naproxen sodium reaches peak plasma concentrations within 1–2 hours.<ref name="CV Safety Review Article" >{{cite journal | vauthors = Angiolillo DJ, Weisman SM | title = Clinical Pharmacology and Cardiovascular Safety of Naproxen | journal = American Journal of Cardiovascular Drugs | volume = 17 | issue = 2 | pages = 97–107 | date = April 2017 | pmid = 27826802 | pmc = 5340840 | doi = 10.1007/s40256-016-0200-5 | author-link1 = Dominick Angiolillo }}</ref>{{what|date=December 2021}}

=== Pharmacogenetics ===
The [[pharmacogenetics]] of naproxen has been studied to better understand its adverse effects.<ref name="2C9 PK COX-i Review">{{cite journal | vauthors = Rodrigues AD | title = Impact of CYP2C9 genotype on pharmacokinetics: are all cyclooxygenase inhibitors the same? | journal = Drug Metabolism and Disposition | volume = 33 | issue = 11 | pages = 1567–1575 | date = November 2005 | pmid = 16118328 | doi = 10.1124/dmd.105.006452 | s2cid = 5754183 }}</ref> In 1998, a small [[pharmacokinetic]] (PK) study failed to show that differences in a patient's ability to [[Clearance (pharmacology)|clear]] naproxen from the body could account for differences in a patient's risk of experiencing the adverse effect of a serious gastrointestinal bleed while taking naproxen.<ref name="2C9 PK COX-i Review" /> However, the study failed to account for differences in the activity of [[CYP2C9]], a drug-metabolizing enzyme that is necessary for clearing naproxen.<ref name="2C9 PK COX-i Review" /> Studies on the relationship between CYP2C9 [[genotype]] and NSAID-induced gastrointestinal bleeds have shown that genetic variants in CYP2C9 that reduce the clearance of major CYP2C9 substrates (like naproxen) increase the risk of NSAID-induced gastrointestinal bleeds, especially for [[homozygous]] defective variants.<ref name="2C9 PK COX-i Review" />

== Chemistry ==
Naproxen is a member of the [[profen (drug class)|2-arylpropionic acid]] (profen) family of NSAIDs.<ref name="pmid2893700">{{cite journal | vauthors = el Mouelhi M, Ruelius HW, Fenselau C, Dulik DM | title = Species-dependent enantioselective glucuronidation of three 2-arylpropionic acids. Naproxen, ibuprofen, and benoxaprofen | journal = Drug Metabolism and Disposition | volume = 15 | issue = 6 | pages = 767–772 | year = 1987 | doi = 10.1016/S0090-9556(25)06837-0 | pmid = 2893700 }}</ref> The free acid is an odorless, white to off-white crystalline substance.{{Citation needed|date=July 2019}} Naproxen free base is [[lipid]]-soluble and practically insoluble in water, while naproxen sodium and many other salts are freely soluble in water, often soluble in methanol, and sparingly soluble in alcohol; check the specific solubility of each salt before use. Naproxen has a [[melting point]] of 152–155 [[Celsius|°C]], while naproxen salts tend to have higher melting points.{{Citation needed|date=July 2019}}

===Synthesis===
Naproxen has been industrially produced by [[Syntex]] starting from [[2-naphthol]] as follows:<ref name = Harrington>{{cite journal | journal = [[Org. Process Res. Dev.]] | year = 1997 | volume = 1 | issue = 1 | pages = 72–76 | title = Twenty Years of Naproxen Technology |vauthors=Harrington PJ, Lodewijk E | doi = 10.1021/op960009e}}</ref>

:[[File:Scale Synthesis of S-naproxen.svg|center|thumb|500x500px|Synthesis of Naproxen]]

==Society and culture==
===Brand names ===
Naproxen and naproxen sodium are marketed under various [[brand name]]s, including Accord, Aleve,<ref>{{cite ssrn |ssrn=1420558 |title=The Aleve Launch (A) |vauthors=Parry ME, Katie F}}</ref> Anaprox, Antalgin, Apranax, Feminax Ultra, Flanax, Inza, Maxidol, Nalgesin, Naposin, Naprelan, Naprogesic, Naprosyn, Narocin, Pronaxen, Proxen, Soproxen, and Xenifar.<ref name="Naproxen international">{{cite web | title=Naproxen international | website=Drugs.com | date=7 December 2020 | url=https://www.drugs.com/international/naproxen.html | access-date=3 January 2021}}</ref> It is also available as the combination [[naproxen/esomeprazole magnesium]] in delayed-release tablets under the brand name Vimovo.<ref name="Naproxen international" /><ref name="Vimovo">{{cite web | title=Vimovo- naproxen and esomeprazole magnesium tablet, delayed release | website=DailyMed | date=2 August 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=baa47781-7151-4c75-a9a2-d2eac0a7d55e | access-date=27 December 2019}}</ref>

=== Access restrictions ===
[[Syntex]] first marketed naproxen in 1976, as the [[prescription drug]] Naprosyn. They first marketed naproxen sodium under the brand name Anaprox in 1980. It remains a prescription-only drug in much of the world.{{Citation needed|date=July 2019}} In the United States, the [[Food and Drug Administration]] (FDA) approved it as an [[Over-the-counter drug|over-the-counter (OTC) drug]] in 1994. OTC preparations of naproxen in the U.S. are mainly marketed by [[Bayer USA|Bayer HealthCare]] under the brand name Aleve and generic [[store brand]] formulations in 220{{nbsp}}mg tablets.<ref>{{cite web | title=Aleve- naproxen sodium tablet | website=DailyMed | date=4 November 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=00ef5b30-71d0-4cb4-84a3-48c67d1cea2a | access-date=27 December 2019}}</ref> In Australia, packets of 275{{nbsp}}mg tablets of naproxen sodium are [[Standard for the Uniform Scheduling of Drugs and Poisons#Schedule 2 Pharmacy Medicine|Schedule 2 pharmacy medicines]], with a maximum daily dose of five tablets or 1375{{nbsp}}mg. In the United Kingdom, 250{{nbsp}}mg tablets of naproxen were approved for OTC sale under the brand name Feminax Ultra in 2008, for the treatment of primary [[dysmenorrhoea]] in women aged 15 to 50.<ref>{{cite press release | date = 1 April 2008 | title=Medicines regulator approves availability of a new OTC medicine for period pain | url = http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=CON014482&RevisionSelectionMethod=LatestReleased | archive-url = https://web.archive.org/web/20130921061443/http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=CON014482&RevisionSelectionMethod=LatestReleased | archive-date = 21 September 2013 | format = PDF | publisher = Medicines and Healthcare products Regulatory Agency (MHRA) }}</ref> In the Netherlands, 220{{nbsp}}mg and 275{{nbsp}}mg tablets are available OTC in drugstores, 550{{nbsp}}mg is OTC only at pharmacies. Aleve became available over the counter in some provinces in Canada<ref>{{Cite web|title=Aleve products released in Canada|url=https://ctchealth.ca/?s=Aleve&post_type=product}}</ref> on 14 July 2009, but not [[British Columbia]], [[Quebec]] or [[Newfoundland and Labrador]];<ref>{{cite press release|url=http://www.bayer.ca/files/Aleve%20Release.July14.FINAL_.pdf|title=Aleve – Welcome to Canada, Eh!|date=14 July 2009|publisher=Bayer Health Care|access-date=24 March 2012}}</ref> it subsequently became available OTC in British Columbia in January 2010<ref name="Press Release, January 2010">{{cite web|title=Aleve – Helping British Columbians with Joint and Arthritis Pain Get Back to Doing the Activities They Love|url=http://www.newswire.ca/en/story/703499/aleve-r-helping-british-columbians-with-joint-and-arthritis-pain-get-back-to-doing-the-activities-they-love|website=newswire.ca|date=28 January 2010|access-date=27 September 2012|archive-date=21 September 2013|archive-url=https://web.archive.org/web/20130921060225/http://www.newswire.ca/en/story/703499/aleve-r-helping-british-columbians-with-joint-and-arthritis-pain-get-back-to-doing-the-activities-they-love}}</ref> and Quebec in 2023.<ref>{{Cite web |title=Modifications aux annexes de médicaments |url=https://www.opq.org/nouvelles/modifications-aux-annexes-de-medicaments/ |access-date=2025-05-16 |website=Ordre des pharmaciens du Québec |language=fr-CA}}</ref> 

==Ecological effects==
Naproxen has been found in groundwater and drinking water in concentrations high enough to have adverse effects on invertebrates including fungi, algae, bacteria and {{not a typo|fishes}}.<ref name="PMID31925484">{{cite journal | vauthors = Wojcieszyńska D, Guzik U | title = Naproxen in the environment: its occurrence, toxicity to nontarget organisms and biodegradation | journal = Applied Microbiology and Biotechnology | volume = 104 | issue = 5 | pages = 1849–1857 | date = March 2020 | pmid = 31925484 | doi = 10.1007/s00253-019-10343-x | pmc = 7007908 }}</ref> Naproxen is not thoroughly removed by conventional water treatment methods,<ref name="PMID36293682">{{cite journal | vauthors = Rodríguez-Serin H, Gamez-Jara A, De La Cruz-Noriega M, Rojas-Flores S, Rodriguez-Yupanqui M, Gallozzo Cardenas M, Cruz-Monzon J | title = Literature Review: Evaluation of Drug Removal Techniques in Municipal and Hospital Wastewater | journal = International Journal of Environmental Research and Public Health | volume = 19 | issue = 20 | date = October 2022 | page = 13105 | pmid = 36293682 | doi = 10.3390/ijerph192013105 | doi-access = free | pmc = 9602914 }}</ref> and its degradation pathways in the environment are limited.<ref name="PMID34767851">{{cite journal | vauthors = Moreno Ríos AL, Gutierrez-Suarez K, Carmona Z, Ramos CG, Silva Oliveira LF | title = Pharmaceuticals as emerging pollutants: Case naproxen an overview | journal = Chemosphere | volume = 291 | issue = Pt 1 | page = 132822 | date = March 2022 | pmid = 34767851 | doi = 10.1016/j.chemosphere.2021.132822 | bibcode = 2022Chmsp.29132822M | hdl = 11323/9007 | hdl-access = free }}</ref><ref name="PMID34139498">{{cite journal | vauthors = Mulkiewicz E, Wolecki D, Świacka K, Kumirska J, Stepnowski P, Caban M | title = Metabolism of non-steroidal anti-inflammatory drugs by non-target wild-living organisms | journal = The Science of the Total Environment | volume = 791 | page = 148251 | date = October 2021 | pmid = 34139498 | doi = 10.1016/j.scitotenv.2021.148251 | bibcode = 2021ScTEn.79148251M }}</ref> Some methods more successfully remove naproxen from wastewater, including [[Metal–organic framework|metal-organic complex]]es and [[Carbon filtering|porous carbon]].<ref name="PMID37419350">{{cite journal | vauthors = Huynh NC, Nguyen TT, Nguyen DT, Tran TV | title = Occurrence, toxicity, impact and removal of selected non-steroidal anti-inflammatory drugs (NSAIDs): A review | journal = The Science of the Total Environment | volume = 898 | page = 165317 | date = November 2023 | pmid = 37419350 | doi = 10.1016/j.scitotenv.2023.165317 | bibcode = 2023ScTEn.89865317H }}</ref> Although the levels are generally low enough to not be acutely toxic, sub-lethal effects may still occur,<ref name="PMID32559537">{{cite journal | vauthors = Parolini M | title = Toxicity of the Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) acetylsalicylic acid, paracetamol, diclofenac, ibuprofen and naproxen towards freshwater invertebrates: A review | journal = The Science of the Total Environment | volume = 740 | page = 140043 | date = October 2020 | pmid = 32559537 | doi = 10.1016/j.scitotenv.2020.140043 | bibcode = 2020ScTEn.74040043P | hdl = 2434/747078 | hdl-access = free }}</ref> such as reduced photosynthetic ability.<ref name="PMID34687686">{{cite journal | vauthors = Mojiri A, Zhou JL, Ratnaweera H, Rezania S, Nazari VM | title = Pharmaceuticals and personal care products in aquatic environments and their removal by algae-based systems | journal = Chemosphere | volume = 288 | issue = Pt 2 | page = 132580 | date = February 2022 | pmid = 34687686 | doi = 10.1016/j.chemosphere.2021.132580 | bibcode = 2022Chmsp.28832580M }}</ref>

==Research==
Naproxen may have antiviral activity against [[influenza]]. In laboratory research, it blocks the RNA-binding groove of the nucleoprotein of the virus, preventing the formation of the ribonucleoprotein complex—thus taking the viral nucleoproteins out of circulation.<ref name="pmid23459490">{{cite journal | vauthors = Lejal N, Tarus B, Bouguyon E, Chenavas S, Bertho N, Delmas B, Ruigrok RW, Di Primo C, Slama-Schwok A | title = Structure-based discovery of the novel antiviral properties of naproxen against the nucleoprotein of influenza A virus | journal = Antimicrobial Agents and Chemotherapy | volume = 57 | issue = 5 | pages = 2231–2242 | date = May 2013 | pmid = 23459490 | pmc = 3632891 | doi = 10.1128/AAC.02335-12 }}<br />Lay summary at: {{cite web|url=https://www.eurekalert.org/news-releases/561119|title=Pain reliever shows anti-viral activity against flu|website=EurekAlert!}}</ref>

==Veterinary use==
===Horses===
Naproxen is given by mouth to horses at a dose of 10{{nbsp}}mg/kg and has shown to have a wide safety margin (no toxicity when given at three times the recommended dose for 42 days).<ref>{{cite journal | vauthors = McIlwraith CW, Frisbie DD, Kawcak CE |title=Nonsteroidal Anti-Inflammatory Drugs |journal=Proceedings of the Annual Convention of the American Association of Equine Practitioners |volume=47 |year=2001 |pages=182–187 |issn=0065-7182 }}</ref> It is more effective for [[myositis]] than the commonly used NSAID [[phenylbutazone]], and has shown especially good results for treatment of [[equine exertional rhabdomyolysis]],<ref>{{cite book | vauthors = May SA, Lees P |chapter=Nonsteroidal anti-inflammatory drugs | veditors = McIlwraith CW, Trotter GW |title=Joint disease in the horse |location=Philadelphia |publisher=WB Saunders |year=1996 |pages=223–237 |isbn=0-7216-5135-6 }}</ref> a disease of muscle breakdown; it is less commonly used for [[musculoskeletal disease]].{{medcn|date=December 2019}}

== References ==
{{Reflist}}

== External links ==
{{Wiktionary|naproxen}}

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[[Category:Antipyretics]]
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