Naproxen

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Naproxen
Naproxen2DACS.svg
Naproxen3d.png
Clinical data
Pronunciation /nəˈprɒksən/
Trade names Aleve, Anaprox, Naprium, Flanax, Naprelan, Naprosyn, other
AHFS/Drugs.com Monograph
MedlinePlus a681029
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Routes of
administration		 Oral
ATC code
Legal status
Legal status
  • AU: S2 (Pharmacy only) when in preparations that contain no more than 15 days' supply. Otherwise it is Schedule 4 (Prescription only).[1]
  • CA: OTC
  • UK: POM (Prescription only) Pharmacy medicine (P) only for treatment of primary dysmenorrhoea in women aged 15-50 years subject to a maximum single dose of 500mg, maximum daily dose of 750mg for a maximum of 3 days, and max pack size of 9x250mg tablets[2]
  • US: OTC
Pharmacokinetic data
Bioavailability 95% (oral)
Protein binding 99%
Metabolism Hepatic (to 6-desmethylnaproxen)
Biological half-life 12-17 hours (adults)[3]
Excretion Renal
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.040.747
Chemical and physical data
Formula C14H14O3
Molar mass 230.259 g/mol
3D model (JSmol)
Melting point 152–154 °C (306–309 °F)
  (verify)

Naproxen (brand names: Aleve, Naprosyn, and many others) is a nonsteroidal anti-inflammatory drug (NSAID) of the propionic acid class (the same class as ibuprofen) that relieves pain, fever, swelling, and stiffness.[5][6] It is a nonselective COX inhibitor, usually sold as the sodium salt.

Naproxen poses an intermediate risk of stomach ulcers compared with ibuprofen, which is low-risk, and indometacin, which is high-risk.[7] 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.[5][6]

Medical uses[edit]

250 mg tablet of naproxen
220 mg tablet of naproxen sodium. Imprint L490 (upside-down). Round, light blue tablet.[8]

Naproxen's medical uses are related to its mechanism of action as an anti-inflammatory compound. 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). Notably, not all medications that reduce fever are anti-inflammatory compounds (such as paracetamol). Inflammatory sources of pain that may respond to naproxen's anti-inflammatory activity are conditions such as migraine, osteoarthritis, kidney stones, rheumatoid arthritis, psoriatic arthritis, gout, ankylosing spondylitis, menstrual cramps, tendinitis and bursitis.[9] It is also used to treat primary dysmenorrhea.[10]

Because of its anti-inflammatory mechanism of action, one would not expect naproxen to be useful in treating non-inflammatory causes of pain (e.g.,, diabetic nerve pain).

Naproxen is used as a "bridge therapy" in medication-overuse headache to wean patients off other medications.[11]

Diagnostics[edit]

Naproxen has been used to differentiate between infectious fevers and neoplastic or connective tissue disease-related fevers.[12] Although the literature is inconclusive, it is thought that naproxen may help differentiate between infectious fevers and neoplastic fevers by its efficacy in reducing them; in some studies, naproxen reduced neoplastic fevers far better than it reduced infectious fevers. This information could potentially be used to identify the etiology of the patient's fever, which can be complex in cancer patients (whom are often at heightened risk for infection in the first place).[13]

Adverse effects[edit]

Naproxen should be taken orally with food to decrease the risk of gastrointestinal side effects. Common adverse effects include dizziness, drowsiness, headache, rash, bruising, and gastrointestinal upset.[9]

In the U.S., naproxen is sold with boxed warnings about the risk of gastrointestinal ulceration or bleeding.[9]

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.[14] Naproxen is, however, associated with the smallest overall cardiovascular risks.[15][16] 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.[15] As with other non-COX-2 selective NSAIDs, naproxen can cause gastrointestinal problems, such as heartburn, constipation, diarrhea, ulcers and stomach bleeding.[17] Persons with a history of ulcers or inflammatory bowel disease should consult a doctor before taking naproxen.

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.[16]

Interactions[edit]

Naproxen should not be taken with antidepressants, lithium, methotrexate, probenecid, a blood thinner, heart or blood pressure medications, including diuretics or steroid medicine (such as prednisone).[9]

NSAIDs such as naproxen may interfere with and reduce the efficacy of SSRI antidepressants,[18] as well as increase the risk of bleeding greater than the individual bleeding risk of either class of agent when taken together.[19] Naproxen is not contraindicated in the presence of SSRIs, though concomitant use of the medications should be done with caution.[19]

Alcohol consumption increases the risk of gastrointestinal bleeding when combined with naproxen in a dose-dependent manner (that is, the higher the dose of naproxen, the higher the risk of bleeding).[20]

Pharmacology[edit]

Mechanism of action[edit]

Naproxen works by reversibly inhibiting both the COX-1 and COX-2 enzymes as a non-selective coxib.[21][22][23][24][25] This results in the inhibition of prostaglandin synthesis. Prostaglandins act as signaling molecules in the body, inducing inflammation. Thus, by inhibiting COX-1/2, naproxen induces an anti-inflammatory effect.

Pharmacokinetics[edit]

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.[citation needed] An analysis of two clinical trials shows that naproxen's time to peak plasma concentration occurs between 2–4 hours after oral administration, though naproxen sodium reaches peak plasma concentrations within 1–2 hours.[3]

Pharmacogenetics[edit]

The pharmacogenetics of naproxen has been studied in an effort to better understand its adverse effects.[26] 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.[26] However, the study failed to account for differences in the activity of CYP2C9, an drug metabolizing enzyme responsible for clearing naproxen.[26] 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.[26]

As of April 2017, there are no recommendations for routine CYP2C9 testing for naproxen.[27]

Pregnancy and lactation[edit]

Small amounts of naproxen are excreted in breast milk.[9]

Chemistry[edit]

Naproxen is a member of the 2-arylpropionic acid (profen) family of NSAIDs.[28] The free acid is an odorless, white to off-white crystalline substance. It is lipid-soluble and practically insoluble in water. It has a melting point of 152–155 °C.

Marketing and brand names[edit]

Naproxen and naproxen sodium are marketed under various brand names, including: Aleve, Accord, Anaprox, Antalgin, Apranax, Feminax Ultra, Flanax, Inza, Maxidol, Midol Extended Relief, Nalgesin, Naposin, Naprelan, Naprogesic, Naprosyn, Narocin, Pronaxen, Proxen, Soproxen, Synflex, MotriMax, and Xenobid. It is also available bundled with esomeprazole magnesium in delayed release tablets under the brand name Vimovo.[29]

Access restrictions[edit]

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. In the United States, the Food and Drug Administration (FDA) approved it as an over-the-counter (OTC) drug in 1994. OTC preparations in the U.S. are mainly marketed by Bayer HealthCare under the brand name Aleve and generic store brand formulations in 220 mg tablets. 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.[30] 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 most provinces in Canada on 14 July 2009, but not British Columbia, Quebec or Newfoundland and Labrador;[31] it subsequently became available OTC in British Columbia in January 2010.[32]

Research[edit]

Naproxen may have antiviral activity against influenza. Specifically, 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.[33]

Use in horses[edit]

Naproxen is given orally to horses at a dose of 10 mg/kg, and has shown to have a wide safety margin (no toxicity when given at 3-times the recommended dose of 42 days).[34] It is more effective for myositis than the commonly used NSAID phenylbutazone, and has shown especially good results for treatment of equine exertional rhabdomyolysis,[35] a disease of muscle breakdown, but is less commonly used for musculoskeletal disease.

Synthesis[edit]

Naproxen has been industrially produced by Syntex starting from 2-naphthol as follows:[36]

Large-Scale Synthesis of S-naproxen.svg

References[edit]

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External links[edit]

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