Naproxen

"Antalgin" redirects here. Not to be confused with Analgin.

Naproxen, sold under the brand name Aleve among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, inflammatory diseases such as rheumatoid arthritis, gout and fever.^[8] It is taken orally.^[8] It is available in immediate and delayed release formulations.^[8] Onset of effects is within an hour and lasts for up to twelve hours.^[8]

Naproxen

Clinical data
Pronunciation	/nəˈprɒksən/
Trade names	Aleve, Naprosyn, others^[1]^[2]
AHFS/Drugs.com	Monograph
MedlinePlus	a681029
License data	EU EMA: by INN US DailyMed: Naproxen US FDA: Naproxen
Pregnancy category	AU: C^[3]
Routes of administration	By mouth
ATC code	G02CC02 (WHO) M01AE02 (WHO), M02AA12 (WHO), M01AE56 (WHO), M01AE52 (WHO)
Legal status
Legal status	AU: S2 (Pharmacy medicine) when in preparations that contain no more than 15 days' supply. Otherwise it is Schedule 4 (Prescription only).^[5] CA: OTC UK: POM (Prescription only) / P^[6] US: WARNING^[4]OTC / Rx-only
Pharmacokinetic data
Bioavailability	95% (by mouth)
Protein binding	99%
Metabolism	Liver (to 6-desmethylnaproxen)
Elimination half-life	12–17 hours (adults)^[7]
Excretion	Kidney
Identifiers
IUPAC name (+)-(S)-2-(6-Methoxynaphthalen-2-yl)propanoic acid
CAS Number	22204-53-1^Y
PubChem CID	156391
DrugBank	DB00788^Y
ChemSpider	137720^Y
UNII	57Y76R9ATQ
KEGG	D00118^Y as salt: D00970^Y
ChEBI	CHEBI:7476^Y
ChEMBL	ChEMBL154^Y
PDB ligand	NPX (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID4040686
ECHA InfoCard	100.040.747
Chemical and physical data
Formula	C14H14O3
Molar mass	230.263 g·mol^−1
3D model (JSmol)	Interactive image
Melting point	152–154 °C (306–309 °F)
SMILES COc1cc2ccc(cc2cc1)[C@H](C)C(=O)O
InChI InChI=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^Y Key:CMWTZPSULFXXJA-VIFPVBQESA-N^Y
(verify)

Common side effects include dizziness, headache, bruising, allergic reactions, heartburn, and stomach pain.^[8] Severe side effects include an increased risk of heart disease, stroke, gastrointestinal bleeding, and stomach ulcers.^[8] The heart disease risk may be lower than with other NSAIDs.^[8] It is not recommended in people with kidney problems.^[8] Use is not recommended in the third trimester of pregnancy.^[8]

Naproxen is a nonselective COX inhibitor.^[8] As an NSAID, naproxen appears to exert its anti-inflammatory action by reducing the production of inflammatory mediators called prostaglandins.^[9] It is metabolized by the liver to inactive metabolites.^[8]

Naproxen was patented in 1967, and approved for medical use in the United States in 1976.^[10][8][11] In the United States it is available over the counter and as a generic medication.^[8][12] In 2020, it was the 91st most commonly prescribed medication in the United States, with more than 8 million prescriptions.^[13][14]

Medical uses

Naproxen's medical uses are related to its mechanism of action as an anti-inflammatory compound.^[10] 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).^[10] 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.^[1]

Naproxen sodium is used as a "bridge therapy" in medication-overuse headache to slowly take patients off other medications.^[15]

Available formulations

Naproxen sodium is available as both an immediate release and as 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.^[16]

•  
  250 mg tablet of naproxen
•  
  220 mg tablet of naproxen sodium. Imprint L490 (upside-down). Round, light blue tablet.^[16]
•  
  Naproxen extended release 500 mg, 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.^[1] However, adverse effects are uncommon in infants breastfed from a mother taking naproxen.^[17]

Adverse effects

Common adverse effects include dizziness, drowsiness, headache, rash, bruising, and gastrointestinal upset.^[10][1] Heavy use is associated with increased risk of end-stage renal disease and kidney failure.^[10][18] Naproxen may cause muscle cramps in the legs in 3% of people.^[19]

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.^[20][21] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.^[20][21]

Gastrointestinal

As with other non-COX-2 selective NSAIDs, naproxen can cause gastrointestinal problems, such as heartburn, constipation, diarrhea, ulcers and stomach bleeding.^[22] Naproxen should be taken orally with, or just after food, to decrease the risk of gastrointestinal side effects.^[23] Persons with a history of ulcers or inflammatory bowel disease should consult a doctor before taking naproxen.^[23] In U.S. markets, naproxen is sold with boxed warnings about the risk of gastrointestinal ulceration or bleeding.^[1] Naproxen poses an intermediate risk of stomach ulcers compared with ibuprofen, which is low-risk, and indometacin, which is high-risk.^[24] 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.^[25][26]

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.^[27] Naproxen is, however, associated with the smallest overall cardiovascular risks.^[28][29] 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.^[28]

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.^[29]

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.^[1]

NSAIDs such as naproxen may interfere with and reduce the efficacy of SSRI antidepressants,^[30] as well as increase the risk of bleeding greater than the individual bleeding risk of either class of agent, when taken together.^[31] Naproxen is not contraindicated in the presence of SSRIs, though concomitant use of the medications should be done with caution.^[31] 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).^[32] The risk is highest for people who are heavy drinkers.^[32]

Pharmacology

Mechanism of action

Naproxen works by reversibly inhibiting both the COX-1 and COX-2 enzymes as a non-selective coxib.^{[33][34][35][36][37]}

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.^[38] 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.^{[7][clarification needed]}

Pharmacogenetics

The pharmacogenetics of naproxen has been studied in an effort to better understand its adverse effects.^[39] 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.^[39] However, the study failed to account for differences in the activity of CYP2C9, a drug-metabolizing enzyme that is necessary for clearing naproxen.^[39] 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.^[39]

Chemistry

Naproxen is a member of the 2-arylpropionic acid (profen) family of NSAIDs.^[40] The free acid is an odorless, white to off-white crystalline substance.^{[citation needed]} It is lipid-soluble and practically insoluble in water. It has a melting point of 152–155 °C.^{[citation needed]}

Synthesis

Naproxen has been industrially produced by Syntex starting from 2-naphthol as follows:^[41]

 

"Pope-Peach" should read "Pope-Peachey"

Society and culture

Brand names

Naproxen and naproxen sodium are marketed under various brand names, including Accord, Aleve, Anaprox, Antalgin, Apranax, Feminax Ultra, Flanax, Inza, Maxidol, Nalgesin, Naposin, Naprelan, Naprogesic, Naprosyn, Narocin, Pronaxen, Proxen, and Soproxen.^[2] It is also available as the combination naproxen/esomeprazole magnesium in delayed release tablets under the brand name Vimovo.^[2][42]

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]} 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 220 mg tablets.^[43] In Australia, packets of 275 mg tablets of naproxen sodium are Schedule 2 pharmacy medicines, with a maximum daily dose of five tablets or 1375 mg. In the United Kingdom, 250 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.^[44] In the Netherlands, 220 mg and 275 mg tablets are available OTC in drugstores, 550 mg is OTC only at pharmacies. Aleve became available over the counter in some provinces in Canada^[45] on 14 July 2009, but not British Columbia, Quebec or Newfoundland and Labrador;^[46] it subsequently became available OTC in British Columbia in January 2010.^[47]

Toxicology scandal

Naproxen was one of the four substances named in the prosecution of Industrial Bio-Test Laboratories (IBT) for fraudulent toxicology testing ^[48] Naproxen passed subsequent legitimate toxicology testing.

Research

Naproxen may have antiviral activity against influenza. In laboratory research, it blocks the RNA-binding groove of the nucleoprotein of the virus, preventing formation of the ribonucleoprotein complex—thus taking the viral nucleoproteins out of circulation.^[49]

Veterinary use

Horses

Naproxen is given by mouth to horses at a dose of 10 mg/kg, and has shown to have a wide safety margin (no toxicity when given at three times the recommended dose for 42 days).^[50] It is more effective for myositis than the commonly used NSAID phenylbutazone, and has shown especially good results for treatment of equine exertional rhabdomyolysis,^[51] a disease of muscle breakdown; it is less commonly used for musculoskeletal disease.^{[medical citation needed]}

References

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    Lay summary at: "Pain reliever shows anti-viral activity against flu". EurekAlert!.
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External links

 

Look up naproxen in Wiktionary, the free dictionary.

• "Naproxen". Drug Information Portal. U.S. National Library of Medicine.
• "Naproxen sodium". Drug Information Portal. U.S. National Library of Medicine.