Naproxen

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| _other_data=(+)-(S)-2-(6-Methoxynaphthalen-2-yl)propanoic acid

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Naproxen, sold under the brand name Aleve among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, and inflammatory diseases such as rheumatoid arthritis, gout and fever.<ref name=AHFS2018/> It is taken orally.<ref name=AHFS2018/> It is available in immediate and 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 form, naproxen sodium, which has better solubility when taken orally.<ref name=":0">Template:Cite journal</ref>

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/>

Naproxen is a nonselective 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>Template:Cite book</ref> It is metabolized by the liver to inactive metabolites.<ref name=AHFS2018/>

Naproxen was patented in 1967 and approved for medical use in the United States in 1976.<ref name="Naprosyn label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=AHFS2018/><ref name=Fis2006>Template:Cite book</ref> In the United States it is available over-the-counter and as a generic medication.<ref name=AHFS2018>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In 2022, it was the 88th most commonly prescribed medication in the United States, with more than 7Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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 cramps, tendinitis, and bursitis.<ref name="drugs" >{{#invoke:citation/CS1|citation |CitationClass=web }}</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 to slowly take patients off other medications.<ref name="Chronic HA">Template:Cite journal</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"/>

• Naproxen2016.jpg

  250Template:Nbspmg tablet of naproxen

• Naproxen.JPG

  CitationClass=web }}</ref>

• Teva-naproxen-ec-500.png

  Naproxen extended release 500Template:Nbspmg, back and front

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">{{#invoke:citation/CS1|citation |CitationClass=web }}</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>Template:Cite journal</ref> Naproxen may cause muscle cramps in the legs in 3% of people.<ref>Template:Cite journal</ref>

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.<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">Template:Cite press releaseTemplate:Dead linkTemplate:Cbignore Template:PD-notice</ref><ref name="FDA safety 20201015">{{#invoke:citation/CS1|citation |CitationClass=web }} Template:PD-notice</ref>

Gastrointestinal

As with other non-COX-2 selective NSAIDs, naproxen can cause gastrointestinal problems, such as heartburn, constipation, diarrhea, ulcers and stomach bleeding.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Naproxen should be taken orally with, or just after food, to decrease the risk of gastrointestinal side effects.<ref name="NHS_2022">{{#invoke:citation/CS1|citation |CitationClass=web }}</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 warnings 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>Template:Cite journal</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">Template:Cite book</ref><ref name="BNF">Template:Cite book</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 strokes.<ref name="NissenYeomans2016">Template:Cite journal</ref> Naproxen is, however, associated with the smallest overall cardiovascular risks.<ref name = Trelle>Template:Cite journal</ref><ref name=j1>Template:Cite journal</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 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 interact with antidepressants, lithium, methotrexate, probenecid, warfarin and other blood thinners, heart or blood pressure medications, including diuretics, 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">Template:Cite journal</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">Template:Cite journal</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 consumption increases the risk of gastrointestinal bleeding when combined with NSAIDs like naproxen in a dose-dependent manner (that is, the higher the dose of naproxen, the higher the risk of bleeding).<ref name="Pfau and Lichtenstein">Template:Cite journal</ref> The risk is highest for people who are heavy drinkers.<ref name="Pfau and Lichtenstein" />

Pharmacology

Mechanism of action

Naproxen works by reversibly inhibiting both the COX-1 and COX-2 enzymes as a non-selective coxib.<ref name="pmid20810665">Template:Cite journal</ref><ref name="pmid18397691">Template:Cite journal</ref><ref name="pmid11028250">Template:Cite journal</ref><ref name="pmid15161995">Template:Cite journal</ref><ref name="pmid11566042">Template:Cite journal</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>Template:Cite journal</ref> An analysis of two clinical trials shows that naproxen's time to 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" >Template:Cite journal</ref>Template:What

Pharmacogenetics

The pharmacogenetics of naproxen has been studied to better understand its adverse effects.<ref name="2C9 PK COX-i Review">Template:Cite journal</ref> In 1998, a small pharmacokinetic (PK) study failed to show that differences in a patient's ability to 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 2-arylpropionic acid (profen) family of NSAIDs.<ref name="pmid2893700">Template:Cite journal</ref> The free acid is an odorless, white to off-white crystalline substance.Template:Citation needed 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 °C, while naproxen salts tend to have higher melting points.Template:Citation needed

Synthesis

Naproxen has been industrially produced by Syntex starting from 2-naphthol as follows:<ref name = Harrington>Template:Cite journal</ref>

File:Scale Synthesis of S-naproxen.svg

Synthesis of Naproxen

Society and culture

Brand names

Naproxen and naproxen sodium are marketed under various brand names, including Accord, Aleve,<ref>Template:Cite ssrn</ref> Anaprox, Antalgin, Apranax, Feminax Ultra, Flanax, Inza, Maxidol, Nalgesin, Naposin, Naprelan, Naprogesic, Naprosyn, Narocin, Pronaxen, Proxen, Soproxen, and Xenifar.<ref name="Naproxen international">{{#invoke:citation/CS1|citation |CitationClass=web }}</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">{{#invoke:citation/CS1|citation |CitationClass=web }}</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.Template:Citation needed In the United States, the Food and Drug Administration (FDA) approved it as an over-the-counter (OTC) drug in 1994. OTC preparations of naproxen in the U.S. are mainly marketed by Bayer HealthCare under the brand name Aleve and generic store brand formulations in 220Template:Nbspmg tablets.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In Australia, packets of 275Template:Nbspmg tablets of naproxen sodium are Schedule 2 pharmacy medicines, with a maximum daily dose of five tablets or 1375Template:Nbspmg. In the United Kingdom, 250Template:Nbspmg 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>Template:Cite press release</ref> In the Netherlands, 220Template:Nbspmg and 275Template:Nbspmg tablets are available OTC in drugstores, 550Template:Nbspmg is OTC only at pharmacies. Aleve became available over the counter in some provinces in Canada<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> on 14 July 2009, but not British Columbia, Quebec or Newfoundland and Labrador;<ref>Template:Cite press release</ref> it subsequently became available OTC in British Columbia in January 2010<ref name="Press Release, January 2010">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and Quebec in 2023.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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 Template:Not a typo.<ref name="PMID31925484">Template:Cite journal</ref> Naproxen is not thoroughly removed by conventional water treatment methods,<ref name="PMID36293682">Template:Cite journal</ref> and its degradation pathways in the environment are limited.<ref name="PMID34767851">Template:Cite journal</ref><ref name="PMID34139498">Template:Cite journal</ref> Some methods more successfully remove naproxen from wastewater, including metal-organic complexes and porous carbon.<ref name="PMID37419350">Template:Cite journal</ref> Although the levels are generally low enough to not be acutely toxic, sub-lethal effects may still occur,<ref name="PMID32559537">Template:Cite journal</ref> such as reduced photosynthetic ability.<ref name="PMID34687686">Template:Cite journal</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">Template:Cite journal
Lay summary at: {{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Veterinary use

Horses

Naproxen is given by mouth to horses at a dose of 10Template:Nbspmg/kg and has shown to have a wide safety margin (no toxicity when given at three times the recommended dose for 42 days).<ref>Template:Cite journal</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>Template:Cite book</ref> a disease of muscle breakdown; it is less commonly used for musculoskeletal disease.Template:Medcn

External links

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• Mexiletine
• Nefopam
• Tricyclic antidepressants (e.g., amitriptyline^#)

• Na_v1.7/1.8-selective: DSP-2230^§
• Funapide^§
• PF-05089771^§
• Suzetrigine

  | group3 = Potassium openers
  | list3 =

• Flupirtine^‡

}}

| group6 = Myorelaxants
| list6 =

• Carisoprodol
• Chlorzoxazone
• Cyclobenzaprine
• Mephenoxalone
• Methocarbamol
• Orphenadrine

| group7 = Others
| list7 =

• Analgecine
• Analgesic adjuvant
• Bedinvetmab
• Camphor
• Capsaicin
• Clonidine
• Frunevetmab
• Ketamine
• Menthol
• Methoxyflurane
• Phenazopyridine
• Proglumide
• Rimazolium
• Tanezumab

| list8 =

}} Template:Prolactin inhibitors and anti-inflammatory products for vaginal administration Template:Prostanoidergics Template:Portal bar Template:Authority control