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. Notably, not all medications that reduce fever are anti-inflammatory compounds. 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. Naproxen sodium is used as a "bridge therapy" in medication-overuse headache to slowly take patients off other medications.
Available formulations
Naproxen sodium is available as both an immediate release and as an extended release tablet. The extended release formulations 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.
Pregnancy and lactation
Small amounts of naproxen are excreted in breast milk. However, adverse effects are uncommon in infants breastfed from mother taking naproxen.
Adverse effects
Common adverse effects include dizziness, drowsiness, headache, rash, bruising, and gastrointestinal upset. Heavy use is associated with increased risk of end-stage renal disease and kidney failure. Naproxen may cause muscle cramps in the legs in 3% of people.
Gastrointestinal
As with other non-COX-2 selective NSAIDs, naproxen can cause gastrointestinal problems, such as heartburn, constipation, diarrhea, ulcers and stomach bleeding. Naproxen should be taken orally with food to decrease the risk of gastrointestinal side effects. Persons with a history of ulcers or inflammatory bowel disease should consult a doctor before taking naproxen. In U.S. markets, naproxen is sold with boxed warnings about the risk of gastrointestinal ulceration or bleeding. Naproxen poses an intermediate risk of stomach ulcers compared with ibuprofen, which is low-risk, and indometacin, which is high-risk. To reduce stomach ulceration risk, it is often combined with a proton-pump inhibitor during long-term treatment of those with pre-existing stomach ulcers or a history of developing stomach ulcers while on NSAIDs.
Cardiovascular
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. Naproxen is, however, associated with the smallest overall cardiovascular risks. 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. 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 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.
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. NSAIDs such as naproxen may interfere with and reduce the efficacy of SSRI antidepressants, as well as increase the risk of bleeding greater than the individual bleeding risk of either class of agent when taken together. Naproxen is not contraindicated in the presence of SSRIs, though concomitant use of the medications should be done with caution.
Drug–food interactions
consumption increases the risk of gastrointestinal bleeding when combined with NSAIDs like naproxen in a dose-dependent manner. The risk is highest for people who are heavy drinkers.
Pharmacology
Mechanism of action
Naproxen works by reversibly inhibiting both the COX-1 and COX-2enzymes as a non-selective coxib. 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
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. 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.
Pharmacogenetics
The pharmacogenetics of naproxen has been studied in an effort to better understand its adverse effects. In 1998, a small pharmacokinetic 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. However, the study failed to account for differences in the activity of CYP2C9, a drug metabolizing enzyme responsible for clearing naproxen. 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 increase the risk of NSAID-induced gastrointestinal bleeds, especially for homozygous defective variants. , there are no recommendations for routine CYP2C9 testing for naproxen.
Chemistry
Naproxen is a member of the 2-arylpropionic acid family of NSAIDs. 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.
Synthesis
Naproxen has been industrially produced by Syntex starting from 2-naphthol as follows:
Society and culture
Brand names
Naproxen and naproxen sodium are marketed under various brand names, including: Synflex, Aleve, Accord, Anaprox, Antalgin, Apranax, Feminax Ultra, Flanax, Inza, Maxidol, Midol Extended Relief, Nalgesin, Naposin, Naprelan, Naprogesic, Naprosyn, Narocin, Pronaxen, Proxen, Soproxen, MotriMax, and Xenobid. It is also available as the combination naproxen/esomeprazole magnesium in delayed release tablets under the brand name Vimovo.
Access restrictions
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 approved it as an over-the-counter 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 220mg tablets. In Australia, packets of 275mg tablets of naproxen sodium are Schedule 2 pharmacy medicines, with a maximum daily dose of five tablets or 1375mg. In the United Kingdom, 250mg 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. In the Netherlands, 220mg and 275mg tablets are available OTC in drugstores, 550mg 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; it subsequently became available OTC in British Columbia in January 2010.
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.
Diagnostics
Naproxen has been used to differentiate between infectious fevers and neoplastic or connective tissue disease-related fevers. 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 better than it reduced infectious fevers.
