Naproxen was initially approved in 1976 for prescription use and remained a prescription drug until it received approval as an over-the-counter (OTC) medication in 1994. Naproxen has been FDA-approved for the treatment of acute gout, ankylosing spondylitis, bursitis, polyarticular juvenile idiopathic arthritis, osteoarthritis, tendonitis, rheumatoid arthritis, pain, and primary dysmenorrhea. It is considered first-line treatment for acute gouty arthritis, osteoarthritis, musculoskeletal pain, inflammation, and dysmenorrhea. While Naproxen and other NSAIDs have FDA approval for the treatment of inflammatory arthropathies, such as rheumatoid arthritis and ankylosing spondylitis, they do not alter the course of the disease nor do they prevent joint and soft tissue destruction that are common sequelae of these diseases. In these cases, disease-modifying anti-rheumatic drugs (DMARDs) have become the first-line treatment for inflammatory arthropathies, and NSAIDs such as Naproxen are used as adjunctive therapy. ,
Off-label uses of Naproxen include the treatment of acute migraines and migraine prophylaxis, with Naproxen being considered a first-line abortive remedy for acute migraines. Further, it can be used for chronic migraine prevention as well, along with other medications such as beta-blockers, anti-depressants, and anticonvulsants. 
Naproxen blocks arachidonate binding to competitively inhibit both cyclooxygenase (COX) isoenzymes, COX-1 and COX-2, resulting in analgesic and anti-inflammatory effects. COX-1 and COX-2 are catalysts of arachidonic acid conversion to prostaglandin G (PGG), the first step of the synthesis of prostaglandins and thromboxanes that are involved in rapid physiological responses. COX-1 is constitutively expressed in most tissues, while COX-2 is only expressed in the brain, kidney, bones, reproductive organs, and select tumors such as in colon and prostate cancers. COX-1 is responsible for prostaglandin synthesis in response to stimulation by circulating hormones, as well as maintenance of healthy renal function, gastric mucosal integrity, and hemostasis. COX-2 is inducible in many cells in response to specific mediators of inflammation (e.g., interleukin-1, tumor necrosis factor, lipopolysaccharide).
The anti-inflammatory mechanism of Naproxen is due to decreased prostaglandin synthesis by inhibiting COX-1 and COX-2. The majority of anti-inflammation that Naproxen induces is mostly due to inhibition of the COX-2 isoenzyme; though, it should be noted that COX-1 is also expressed at distinct inflammatory sites. Further, COX-1 is also expressed in the joints of patients with rheumatoid arthritis or osteoarthritis, especially in the synovial lining. Therefore, although Naproxen targets both COX-1 and COX2, it is slightly more selective for the former. Additionally, Naproxen is most effective in the setting of pain receptor sensitivity. It appears prostaglandins, specifically prostaglandins E and F, are responsible for sensitizing these pain receptors; therefore, Naproxen has an additional, indirect analgesic effect by inhibiting further prostaglandin production. 
The liver extensively metabolizes Naproxen and about 95% of the drug is excreted in the urine. Naproxen also has half-life of 12 to 17 hours.
Naproxen can be administered orally, in both immediate and extended-release tablets or suspension forms, or topically. Naproxen may be taken orally with food, milk, antacids (preferably aluminum and magnesium hydroxide-containing antacids), proton pump inhibitors (PPI) or misoprostol to decrease the incidence of GI adverse effects. Naproxen sodium is the form that is most readily available, and it has demonstrated a faster absorption compared to naproxen.
As a rule, treatment with naproxen, as well as all NSAIDs, begins with the lowest effective dose for the shortest possible duration. Also consider starting with a lower dose in geriatric patients due to the likelihood that the patient has comorbidities such as cardiovascular disease, chronic kidney disease, or history of GI ulcer/bleeding that increase the risk of adverse effects from NSAID therapy.
Specific dosing recommendations and treatment durations:
Mild to moderate arthritis (osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis):
Acute gouty arthritis:
Acute severe headache or migraine:
Maximum recommended daily doses for children:
Patients with Hepatic Impairment Dosing
Patients with Renal Impairment Dosing
Primary adverse effects for naproxen include dyspepsia, nausea, dizziness, elevated liver enzymes, increased blood pressure, diminished renal function, rash, increased bleeding risk, and GI ulcers. Serious but rare adverse effects include blood dyscrasias, Stevens-Johnson syndrome, myocardial infarction, stroke, heart failure, and anaphylaxis. The following are several mechanisms of the above adverse effects:
GI Effects: COX-1 and COX-2 inhibition lead to decreased prostaglandin synthesis in the gastric mucosa. The prostaglandins maintain mucosal integrity, therefore decreased synthesis causes reduced protection to the tissue. However, studies indicate COX-1 has a more significant effect on the integrity of the mucosa; consequently, selective COX-2 inhibitors such as Celecoxib do not have as much of an effect on gastric tissue. ,
Renal Effects: Prostaglandins produced by both COX-1 and COX-2 are important regulators of renal function, hemodynamics, and sodium and water reabsorption in the kidneys. When renal blood flow is dependent upon prostaglandin synthesis, NSAID administration can result in significant decreases in renal blood flow, leading to acute kidney injury and renal failure. Also, alterations in sodium and water reabsorption may increase blood pressure, especially in patients with pre-existing hypertension.
Platelet Effects: Platelet aggregation inhibition with naproxen is due to the dose-dependent inhibition of COX-1 in platelets. This action leads to decreased levels of platelet thromboxane A2 and an increase in bleeding time. This inhibition is reversible upon discontinuation of naproxen. Despite the known inhibition of platelet function, the results of studies examining an increase in clinical bleeding time have shown mixed results.
Relative Risk/Caution against use:
Patients taking naproxen should have monitoring for pain relief, significant changes in blood pressure, worsening kidney function, and GI symptoms such as gastroesophageal reflux disease (GERD), abdominal pain, or melena. For patients on chronic NSAID therapy, periodic monitoring with complete blood counts to assess for anemia and chemistry panels to evaluate kidney and liver function merit consideration. 
Naproxen overdose is common due to its OTC availability, but the overdose is usually mild in severity, and serious adverse effects from overdose are rare. There is no available antidote for naproxen overdose, however monitoring of vital signs and supportive care is recommended. The role of activated charcoal is uncertain due to time constraints and unclear benefits, and there is no role for hemodialysis due to naproxen's high degree of protein binding. However, ingestion of large amounts of Naproxen can lead to severe toxicity causing seizures and metabolic acidosis, which can potentially cause renal failure. Therefore, although hemodialysis is not generally recommended, in specific situations, it can correct acid-base disturbances and provide additional support to those with renal impairment. 
Naproxen is readily available OTC and widely used for pain relief for many different types of patients. Some of these patients are taking medications or have medical comorbidities that place them at a significantly higher risk of serious adverse events. Yet, they are unaware of the risk and may think that naproxen's availability OTC means its use is safe for everyone. It is essential for all health professionals who work in a primary care setting to routinely ask their patients whether they are taking OTC medications and educate them about the potential risks and benefits of NSAIDs, particularly as it relates to their specific medical histories and conditions. It is also crucial for specialist healthcare providers to communicate with primary care providers, nurse practitioners, and pharmacists when starting medication or to treat a patient for a condition in which NSAID therapy is not advised or contraindicated. Providers should also educate their patients about their medical condition and how it affects their ability to take a widely available OTC medication.
|||Ong CK,Lirk P,Tan CH,Seymour RA, An evidence-based update on nonsteroidal anti-inflammatory drugs. Clinical medicine & research. 2007 Mar [PubMed PMID: 17456832]|
|||Simon LS, Biologic effects of nonsteroidal anti-inflammatory drugs. Current opinion in rheumatology. 1997 May [PubMed PMID: 9204251]|
|||Armstrong C, AAN/AHS update recommendations for migraine prevention in adults. American family physician. 2013 Apr 15 [PubMed PMID: 23668450]|
|||Giménez M,Pujol J,Ali Z,López-Solà M,Contreras-Rodríguez O,Deus J,Ortiz H,Soriano-Mas C,Llorente-Onaindia J,Monfort J, Naproxen effects on brain response to painful pressure stimulation in patients with knee osteoarthritis: a double-blind, randomized, placebo-controlled, single-dose study. The Journal of rheumatology. 2014 Nov [PubMed PMID: 25274897]|
|||Gargallo CJ,Sostres C,Lanas A, Prevention and Treatment of NSAID Gastropathy. Current treatment options in gastroenterology. 2014 Dec [PubMed PMID: 25209136]|
|||Suthisisang CC,Poolsup N,Suksomboon N,Lertpipopmetha V,Tepwitukgid B, Meta-analysis of the efficacy and safety of naproxen sodium in the acute treatment of migraine. Headache. 2010 May [PubMed PMID: 20236345]|
|||Law S,Derry S,Moore RA, Naproxen with or without an antiemetic for acute migraine headaches in adults. The Cochrane database of systematic reviews. 2013 Oct 20 [PubMed PMID: 24142263]|
|||Pellicano R, Gastrointestinal damage by non-steroidal anti-inflammatory drugs: updated clinical considerations. Minerva gastroenterologica e dietologica. 2014 Dec [PubMed PMID: 25384803]|
|||[PubMed PMID: 16184416]|
|||Schafer AI, Effects of nonsteroidal anti-inflammatory therapy on platelets. The American journal of medicine. 1999 May 31 [PubMed PMID: 10390125]|
|||[PubMed PMID: 29392089]|
|||[PubMed PMID: 24756481]|