A Comprehensive Monograph on Naproxen (DrugBank ID: DB00788): Pharmacology, Clinical Efficacy, and Comparative Risk-Benefit Analysis

1.0 Executive Summary of Naproxen

Naproxen is a well-established small molecule drug belonging to the propionic acid class of nonsteroidal anti-inflammatory drugs (NSAIDs).[1] First approved for prescription use in 1976 and later for over-the-counter (OTC) access in 1994, it has become a cornerstone therapy for managing pain, inflammation, and fever across a wide spectrum of clinical scenarios.[3] Its therapeutic utility is derived from its core pharmacological mechanism: the non-selective and reversible inhibition of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes.[1] By blocking these enzymes, naproxen effectively reduces the synthesis of prostaglandins, which are critical mediators in the pathways of pain, inflammation, and pyresis.[1]

Clinically, naproxen is indicated for numerous conditions, including chronic inflammatory disorders like rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis, as well as acute conditions such as gout, tendinitis, bursitis, and primary dysmenorrhea.[1] Its efficacy in these areas is supported by decades of clinical use and numerous studies. The development of various formulations, including immediate-release, extended-release, and gastro-protective combination products, has further solidified its place in the therapeutic armamentarium.[1]

However, the clinical profile of naproxen is defined by a critical and nuanced risk-benefit trade-off, a characteristic it shares with all NSAIDs but with a distinct signature. Extensive meta-analyses of cardiovascular outcomes have positioned naproxen as having one of the most favorable cardiovascular safety profiles among traditional NSAIDs, a feature that distinguishes it from agents like diclofenac and high-dose ibuprofen.[5] Conversely, its potent and sustained inhibition of the homeostatic COX-1 enzyme imparts a significant risk of gastrointestinal toxicity, including peptic ulcers and bleeding, which is generally higher than that of shorter-acting NSAIDs like ibuprofen.[5] This duality—relative cardiovascular safety at the cost of increased gastrointestinal risk—is the central consideration in its clinical application. This report provides a comprehensive analysis of naproxen's physicochemical properties, pharmacology, clinical efficacy, and its comparative safety profile, offering an evidence-based framework for its rational use in clinical practice.

2.0 Physicochemical Properties and Formulations

A thorough understanding of naproxen's chemical nature and the variety of its pharmaceutical preparations is fundamental to appreciating its clinical pharmacology and appropriate application.

2.1 Chemical Identity and Structure

Naproxen is a chiral compound, with the therapeutically active form being the (S)-enantiomer.[9] Its identity is precisely defined by several internationally recognized nomenclature systems and identifiers.

• Systematic Naming: The International Union of Pure and Applied Chemistry (IUPAC) name for the active enantiomer is (2S)-2-(6-methoxynaphthalen-2-yl)propanoic acid.[9] It is also commonly referred to by its semi-systematic name, (S)-(+)-6-Methoxy-α-methyl-2-naphthaleneacetic acid.[1]
• Molecular Formula and Weight: The chemical formula for naproxen is C14​H14​O3​.[1] It has an average molecular weight of approximately 230.26 g/mol and a precise monoisotopic mass of 230.094294314 Da.[1]
• Stereochemistry: As a member of the profen class of NSAIDs, naproxen possesses a chiral center at the alpha-carbon of the propionic acid moiety. The biological activity resides almost exclusively in the (S)-enantiomer.[1] The (R)-enantiomer, or (-)-Naproxen, is considered an impurity in pharmaceutical preparations.[9]
• Identifiers: For unambiguous identification in scientific literature and databases, naproxen is assigned several unique codes. These include its Chemical Abstracts Service (CAS) Number: 22204-53-1 [1]; DrugBank Accession Number: DB00788 [1]; and PubChem Compound ID (CID): 156391.[13] It is also known by numerous synonyms and research codes, such as Naprosyn, Aleve, Anaprox, RS 3540, and Methoxypropiocin.[1]

2.2 Physical and Chemical Properties

Naproxen's physical properties directly influence its formulation and bioavailability. It presents as a white to creamy-white, odorless crystalline powder.[10] A key characteristic is its solubility profile; the free acid form is practically insoluble in water but is soluble in organic solvents like methanol and ethanol.[10] This low aqueous solubility is overcome in some formulations by using its sodium salt, naproxen sodium, which is more readily soluble in water and thus allows for faster dissolution and absorption.[5] The melting point of the crystalline solid is reported to be in the range of 152-154 °C.[12]

2.3 Pharmaceutical Formulations

The pharmaceutical industry has developed a diverse range of formulations to optimize naproxen's delivery, improve patient compliance, and mitigate its known adverse effects.

• Oral Dosage Forms: Naproxen is available in multiple oral forms to cater to different clinical needs and patient populations [16]:
• Immediate-Release Tablets: These are standard tablets (e.g., Naprosyn®) that provide relatively rapid drug release and are suitable for both acute and chronic conditions.[16]
• Delayed-Release (Enteric-Coated) Tablets: These tablets (e.g., EC-Naprosyn®) have a special coating designed to resist disintegration in the acidic environment of the stomach and dissolve in the more neutral pH of the small intestine. This is intended to reduce local gastric irritation, though it does not eliminate the risk of systemic GI toxicity.[4]
• Controlled/Extended-Release Tablets: These formulations (e.g., Naprelan®) are engineered for once-daily administration, providing sustained plasma concentrations over a 24-hour period. This enhances convenience and adherence, particularly for patients with chronic conditions like arthritis.[16] Some utilize proprietary technologies like the IPDAS® (Intestinal Protective Drug Absorption System), which combines immediate and sustained-release components.[15]
• Oral Suspension: A liquid formulation is available for pediatric patients and adults who have difficulty swallowing solid dosage forms.[16]
• Capsules and Liquid-Filled Capsules: These offer alternative solid oral dosage forms.[16]
• Combination Products: A key aspect of naproxen's lifecycle has been its incorporation into fixed-dose combination products that either enhance its therapeutic effect for a specific indication or mitigate its adverse effects.
• With a Proton Pump Inhibitor (PPI): The combination of naproxen with esomeprazole (Vimovo®) is a prime example of a gastro-protective strategy. Esomeprazole suppresses gastric acid production, reducing the risk of naproxen-induced gastric ulcers. This formulation is specifically indicated for patients with arthritis who are at high risk for developing NSAID-associated ulcers.[1]
• With a Triptan: For the treatment of acute migraine, naproxen is combined with sumatriptan (Treximet®). This product targets both the inflammatory and serotonergic pathways of migraine pathophysiology.[1]
• With Decongestants and Antihistamines: OTC products like Aleve-D® (with pseudoephedrine) and Aleve PM® (with diphenhydramine) combine naproxen's analgesic properties with other agents to treat symptoms of sinus congestion, colds, and nighttime pain.[1]
• With Muscle Relaxants: In some international markets, naproxen is available in combination with the muscle relaxant thiocolchicoside for musculoskeletal conditions involving muscle spasms.[1]

The availability of both the free acid (naproxen) and its more soluble salt (naproxen sodium) is not merely a chemical variation but a deliberate pharmaceutical strategy. The lower aqueous solubility of the acid form is suitable for standard and extended-release formulations for chronic conditions. In contrast, the enhanced solubility of naproxen sodium facilitates faster dissolution and absorption, leading to a more rapid onset of action. This pharmacokinetic advantage is leveraged in products like Anaprox®, which are specifically recommended for acute painful conditions where a prompt analgesic effect is desired.[5] This duality allows a single active molecule to be tailored to distinct clinical niches, maximizing its therapeutic utility.

Table 1: Physicochemical and Identification Data for Naproxen

Property	Value	Source(s)
IUPAC Name	(2S)-2-(6-methoxynaphthalen-2-yl)propanoic acid	9
Chemical Formula	C14​H14​O3​	1
Average Molecular Weight	230.26 g/mol	1
Monoisotopic Mass	230.094294314 Da	1
CAS Number	22204-53-1	1
DrugBank ID	DB00788	1
PubChem CID	156391	13
Stereochemistry	(S)-enantiomer (active)	1
Appearance	White to creamy crystalline powder	11
Solubility	Practically insoluble in water; soluble in methanol, ethanol	10
Melting Point	152-154 °C	12

3.0 Core Pharmacology and Mechanism of Action

The clinical effects of naproxen are a direct result of its interactions with specific enzymatic pathways and its subsequent journey through the body, defined by its pharmacokinetic profile.

3.1 Pharmacodynamics (Mechanism of Action)

Naproxen exerts its therapeutic effects—analgesia, anti-inflammation, and antipyresis—through a well-characterized mechanism of action.[1]

• Primary Target and Mechanism: The primary molecular targets of naproxen are the cyclooxygenase (COX) enzymes, specifically prostaglandin G/H synthase 1 (COX-1) and prostaglandin G/H synthase 2 (COX-2).[1] Naproxen acts as a non-selective, competitive inhibitor of these enzymes, blocking the active site where the substrate, arachidonic acid, would normally bind.[3] This inhibition prevents the conversion of arachidonic acid into prostaglandins (PGs), such as PGE2​ and PGI2​ (prostacyclin), which are lipid compounds that act as key signaling molecules in the body.[1]
• Therapeutic Consequences: The reduction in prostaglandin synthesis leads to naproxen's main therapeutic actions:
• Anti-inflammatory Effect: Prostaglandins are potent mediators of inflammation, causing vasodilation, increased vascular permeability, and edema. By inhibiting their production at sites of injury or disease (e.g., in synovial fluid), naproxen reduces these signs of inflammation.[1]
• Analgesic Effect: Prostaglandins sensitize peripheral nociceptors (pain receptors) to other chemical mediators like bradykinin and histamine. By lowering prostaglandin levels, naproxen raises the pain threshold and provides analgesia.[17]
• Antipyretic Effect: Fever is often triggered by pyrogens that cause the release of prostaglandins in the hypothalamus, which resets the body's thermoregulatory set point. Naproxen reduces fever by inhibiting this central prostaglandin synthesis.[1]
• Effects on Platelets: The COX-1 isoenzyme is constitutively expressed in platelets and is responsible for producing thromboxane A2 (TXA2), a powerful promoter of platelet aggregation and vasoconstriction.[3] By inhibiting platelet COX-1, naproxen decreases TXA2 synthesis, thereby inhibiting platelet aggregation and prolonging bleeding time. This effect is reversible and platelet function returns to normal after the drug is cleared from the body.[3]

3.2 Pharmacokinetics

The pharmacokinetic profile of naproxen dictates its dosing frequency, potential for drug interactions, and aspects of its safety profile.

• Absorption: Following oral administration, naproxen is rapidly and completely absorbed from the gastrointestinal tract, with a bioavailability of approximately 95%.[5] Peak plasma concentrations are typically reached within 2 to 4 hours for immediate-release formulations, and the onset of analgesic effect can be observed within an hour.[5] The co-administration of food can delay the rate of absorption but does not significantly alter the total amount of drug absorbed (the area under the curve, or AUC).[15]
• Distribution: Naproxen has a relatively small volume of distribution of 0.16 L/kg.[15] A defining characteristic is its extensive plasma protein binding, which is greater than 99% at therapeutic concentrations, primarily to serum albumin.[15] This high degree of binding has significant implications for potential drug-drug interactions.
• Metabolism: The liver is the primary site of naproxen metabolism. It is extensively converted to its major metabolite, 6-O-desmethylnaproxen, which is inactive.[1] Both the parent compound and this desmethyl metabolite undergo further phase II metabolism, primarily conjugation with glucuronic acid, to form water-soluble compounds that can be readily excreted.[1] Studies indicate that naproxen is a minor substrate of the cytochrome P450 enzymes CYP1A2 and CYP2C9.[5]
• Excretion: Elimination of naproxen and its metabolites is almost entirely through the kidneys.[5] Approximately 95% of an administered dose is recovered in the urine, with less than 1% excreted as the unchanged parent drug. The majority is excreted as 6-O-desmethylnaproxen and its conjugates.[15] A small fraction, less than 5%, is eliminated in the feces.[15]
• Half-Life: Naproxen is distinguished by its long plasma elimination half-life, which ranges from 12 to 17 hours.[3] This is significantly longer than that of other common NSAIDs like ibuprofen (approx. 2 hours).

The pharmacokinetic properties of naproxen are directly responsible for both its clinical advantages and some of its most significant risks. The long half-life is a major clinical benefit, as it allows for convenient twice-daily (or even once-daily for extended-release forms) dosing regimens, which can improve patient adherence, especially in the management of chronic diseases like arthritis.[8] However, this same attribute becomes a liability from a safety perspective. The sustained presence of the drug in the body leads to prolonged inhibition of the gastroprotective COX-1 enzyme in the gastric mucosa, which is a key reason why naproxen carries a higher risk of gastrointestinal ulcers and bleeding compared to shorter-acting NSAIDs.[8] Furthermore, its high degree of protein binding (>99%) creates a high potential for displacement interactions. When co-administered with other highly protein-bound drugs, such as the anticoagulant warfarin, naproxen can displace them from albumin, increasing their free (active) concentration and potentiating their effects and toxicity.[24] This inherent trade-off—dosing convenience versus a heightened risk of specific, mechanism-based toxicities—is a central challenge in naproxen therapy and has directly driven the development of risk-mitigation strategies, such as enteric coatings and co-formulation with proton pump inhibitors.[15]

4.0 Approved Therapeutic Indications and Clinical Efficacy

Naproxen is a versatile medication with a broad range of approved uses, validated by decades of clinical experience and regulatory review by bodies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).

4.1 Regulatory Approved Indications (FDA & EMA)

The approved indications for naproxen are largely consistent across major international regulatory agencies, underscoring its established role in treating pain and inflammation.[3]

• Chronic Inflammatory and Degenerative Joint Diseases: Naproxen is a first-line symptomatic treatment for several forms of arthritis. It is indicated for the relief of signs and symptoms of:
• Rheumatoid Arthritis (RA): A chronic autoimmune inflammatory disease.[1]
• Osteoarthritis (OA): A degenerative joint disease, also known as osteoarthrosis.[1]
• Ankylosing Spondylitis (AS): An inflammatory arthritis affecting the spine and large joints.[1]
• Polyarticular Juvenile Idiopathic Arthritis (JIA): A form of arthritis in children, also referred to as Juvenile Rheumatoid Arthritis.[1]

It is critical to recognize that while naproxen effectively reduces pain, stiffness, and swelling in these conditions, it does not alter the underlying disease progression or prevent joint destruction. In inflammatory arthropathies like RA, it serves as an important adjunctive therapy to Disease-Modifying Antirheumatic Drugs (DMARDs), which are the primary agents for controlling the disease itself.3

• Acute Pain and Musculoskeletal Disorders: Naproxen is widely used for a variety of acute painful and inflammatory conditions:
• Acute Gout: For the treatment of painful attacks of gouty arthritis.[1]
• Tendinitis and Bursitis: Inflammation of tendons and bursae, respectively.[1]
• Acute Musculoskeletal Disorders: Including sprains, strains, and lumbosacral pain.[24]
• General Analgesia: For the relief of mild to moderate pain from various causes, including headaches, toothaches, and post-surgical pain.[1]
• Gynecological Pain: It is a standard treatment for Primary Dysmenorrhea (painful menstrual cramps).[1]
• Fever Reduction (Antipyresis): Over-the-counter (OTC) formulations of naproxen are approved for the reduction of fever.[2]

4.2 Off-Label and Investigational Uses

Beyond its approved indications, clinicians and researchers have explored naproxen's utility in other areas.

• Migraine Management: Naproxen is frequently used off-label as a first-line abortive therapy for acute migraine attacks and can also be used for migraine prophylaxis.[3] The rationale for its efficacy is based on the inflammatory component of migraine pathophysiology. This use is further supported by the on-label approval of a fixed-dose combination product containing naproxen sodium and the triptan sumatriptan (Treximet®).[1]
• Other Investigational Uses: Naproxen has been used off-label for less common conditions such as Paget's disease of bone and Bartter syndrome.[17] Preclinical research has also explored its potential neuroprotective properties, with one study noting an anti-aggregation effect on amyloid-beta fibrils, a pathological hallmark of Alzheimer's disease, though this has not translated to a clinical indication.[11]

4.3 Evidence from Clinical Trials

The clinical development and lifecycle of naproxen are well-documented through numerous clinical trials. While the foundational efficacy trials were conducted decades ago, recent research continues to refine its use and expand its applications. The clinical trial landscape reveals a clear evolution in research focus, shifting from establishing primary efficacy to optimizing the drug's delivery, safety, and comparative effectiveness.

Early-phase trials have been instrumental in establishing the pharmacokinetic profiles and bioequivalence of its many formulations. For example, studies like NCT00692055 and NCT02549469 were designed to compare different formulations, such as extended-release versus immediate-release tablets, ensuring that newer, more convenient dosing options provide comparable drug exposure.[22] Other trials, like NCT00749385, have been crucial for the approval of combination products by demonstrating the pharmacokinetic behavior of naproxen when co-formulated with agents like esomeprazole.[26]

Later-stage trials (Phase 3 and 4) have focused on real-world use and comparative effectiveness. For instance, trial NCT00751400 was an "actual use" study for an extended-release formulation, providing data on its performance outside of a strictly controlled environment.[27] A particularly relevant modern trial, NCT04307940, was designed to compare the efficacy of naproxen to a hydrocodone/acetaminophen combination for relieving moderate to severe pain after wisdom tooth removal.[28] This type of study is highly significant in the current medical landscape, which is heavily focused on finding effective opioid-sparing analgesic strategies. By providing evidence that a well-established NSAID can be a viable alternative to an opioid combination for significant post-operative pain, such research reinforces naproxen's value and supports its role as a key component of multimodal pain management protocols aimed at reducing opioid prescribing and consumption.

Table 2: Summary of Approved Indications for Naproxen (FDA & EMA)

Indication Category	Specific Indication	Regulatory Body	Key Supporting Source(s)
Chronic Arthritis	Rheumatoid Arthritis (RA)	FDA, EMA	1
	Osteoarthritis (OA)	FDA, EMA	1
	Ankylosing Spondylitis (AS)	FDA, EMA	1
	Polyarticular Juvenile Idiopathic Arthritis (JIA)	FDA, EMA	1
Acute Pain & Inflammation	Acute Gout	FDA, EMA	1
	Tendinitis	FDA, EMA	1
	Bursitis	FDA, EMA	1
	Acute Musculoskeletal Disorders (e.g., sprains)	EMA	24
	Mild to Moderate Pain	FDA	19
Gynecological Pain	Primary Dysmenorrhea	FDA, EMA	1
Fever Reduction	Pyresis (Fever)	FDA (OTC)	2

5.0 Dosing Regimens and Administration Guidelines

The dosing of naproxen is highly specific and must be tailored to the patient, the clinical indication, and the particular pharmaceutical formulation being used. A fundamental principle, emphasized by regulatory agencies, governs all NSAID therapy.

5.1 General Principles

The core tenet of naproxen administration is to use the lowest effective dose for the shortest duration necessary to achieve the desired therapeutic outcome.[15] This approach is designed to maximize efficacy while minimizing the risk of dose- and duration-dependent adverse events. To reduce the incidence of gastrointestinal upset, it is generally recommended that naproxen be taken with food, a glass of milk, or an antacid.[3] Patients should be instructed not to split, chew, or crush enteric-coated or extended-release tablets, as this would disrupt their specialized release mechanisms.[4]

5.2 Adult Dosing by Indication and Formulation

Dosing regimens vary significantly based on whether the condition is chronic or acute, and which naproxen salt and release formulation is used. Naproxen sodium doses are slightly higher than naproxen base doses to account for the weight of the sodium ion (e.g., 275 mg naproxen sodium is equivalent to 250 mg naproxen).

• Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis:
• Naproxen (e.g., Naprosyn®): The typical dosage is 250 mg, 375 mg, or 500 mg administered twice daily. The daily dose may be adjusted as needed but should generally not exceed 1500 mg.[16]
• Naproxen Sodium (e.g., Anaprox®): The usual dosage is 275 mg or 550 mg twice daily. The maximum daily dose is 1650 mg of naproxen sodium for limited periods.[3]
• Controlled-Release (e.g., Naprelan®): The recommended dose is 750 mg or 1000 mg taken once daily. The dose can be adjusted up to a maximum of 1500 mg per day.[16]
• Acute Gout: The treatment strategy for an acute gout flare involves a high initial loading dose to rapidly control severe inflammation, followed by a tapering maintenance schedule.
• Naproxen: An initial dose of 750 mg, followed by 250 mg every 8 hours until the attack has resolved.[16]
• Naproxen Sodium: An initial dose of 825 mg, followed by 275 mg every 8 hours.[16]
• Controlled-Release: An initial dose of 1000 mg to 1500 mg once daily, followed by 1000 mg once daily until the attack subsides.[16]

The use of delayed-release (enteric-coated) formulations is explicitly not recommended for acute gout because the delay in absorption is counterproductive to the need for a rapid onset of action.18 This highlights a crucial clinical point: the choice of formulation is as important as the choice of drug for certain conditions. The loading dose strategy is a direct application of pharmacokinetic principles to match the pathophysiology of the disease, aiming to quickly achieve high plasma concentrations to interrupt the intense inflammatory cascade of an acute gout attack.

• Mild to Moderate Pain, Primary Dysmenorrhea, and Acute Tendinitis/Bursitis:
• Naproxen Sodium: A common regimen is an initial dose of 550 mg, followed by 550 mg every 12 hours or 275 mg every 6 to 8 hours as needed. The initial total daily dose should not exceed 1375 mg of naproxen sodium, and subsequent daily doses should not exceed 1100 mg.[16]
• Controlled-Release: The recommended dose is 1000 mg once daily. For patients requiring greater analgesia, the dose may be increased to 1500 mg daily for a limited period.[16]

5.3 Pediatric Dosing

The use of naproxen in children is more restricted and requires careful, weight-based dosing.

• Polyarticular Juvenile Idiopathic Arthritis (Age ≥2 years): The recommended total daily dose is approximately 10 mg/kg of body weight, given in two divided doses at 12-hour intervals.[16] Standard tablet formulations may not be appropriate for children weighing less than 50 kg, for whom the oral suspension is preferred.[18]
• General Use: For adolescents (age ≥12 years), the maximum recommended daily dose is 20 mg/kg/day, not to exceed 1000 mg/day.[3] Non-prescription (OTC) use is not recommended for children under 12 years of age.[3] The safety and efficacy of naproxen have not been established in children younger than 2 years old.[3]

Table 3: Recommended Dosing Regimens for Naproxen by Indication and Formulation

Indication	Formulation	Initial Dose	Maintenance Dose	Maximum Daily Dose	Key Considerations / Source(s)
RA, OA, AS	Naproxen (Immediate-Release)	250-500 mg BID	250-500 mg BID	1500 mg	16
	Naproxen Sodium (Immediate-Release)	275-550 mg BID	275-550 mg BID	1650 mg (naproxen sodium)	3
	Naproxen (Controlled-Release)	750-1000 mg QD	750-1000 mg QD	1500 mg	16
Acute Gout	Naproxen (Immediate-Release)	750 mg	250 mg q8h	-	Attack-driven duration 16
	Naproxen Sodium (Immediate-Release)	825 mg	275 mg q8h	-	Delayed-release not recommended 16
Pain, Dysmenorrhea, Tendinitis	Naproxen Sodium (Immediate-Release)	550 mg	550 mg q12h or 275 mg q6-8h	1375 mg (Day 1), then 1100 mg	16
	Naproxen (Controlled-Release)	1000 mg QD	1000 mg QD	1500 mg (limited period)	16

6.0 Comprehensive Safety and Tolerability Profile

While naproxen is an effective therapeutic agent, its use is associated with a well-defined profile of potential adverse effects, some of which are serious and life-threatening. This has led to stringent warnings and contraindications from regulatory bodies worldwide.

6.1 Regulatory Boxed Warnings (FDA)

In the United States, naproxen and other NSAIDs carry FDA-mandated "black box" warnings, the agency's most serious alert, highlighting two major areas of risk.[18]

• Cardiovascular Thrombotic Events: NSAIDs cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. This risk may manifest early in the course of treatment and can increase with the duration of use. The risk is present in patients with and without known cardiovascular disease or risk factors.[15]
• Gastrointestinal Bleeding, Ulceration, and Perforation: NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events, including bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine. These events can be fatal and may occur at any point during therapy without preceding warning symptoms. Elderly patients and individuals with a prior history of peptic ulcer disease or GI bleeding are at a substantially higher risk for these complications.[17]

These warnings represent a significant regulatory response to a large body of post-marketing evidence that revealed risks not fully appreciated during initial clinical development. They have fundamentally altered the clinical perception of NSAIDs, shifting them from being viewed as relatively benign analgesics to drugs requiring a careful and individualized risk-benefit assessment for every patient. This evolution serves as a powerful case study in pharmacovigilance, demonstrating that a drug's complete safety profile often emerges only after millions of patient-years of real-world exposure.

6.2 Contraindications

Based on its mechanism of action and known risks, naproxen is strictly contraindicated in several patient populations:

• Hypersensitivity: Patients with a known hypersensitivity to naproxen, naproxen sodium, or any of the excipients in the formulation.[3]
• NSAID-Induced Allergic Reactions: Patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, and sometimes fatal, anaphylactic reactions have been reported in this group.[3]
• Coronary Artery Bypass Graft (CABG) Surgery: Use is contraindicated for the treatment of peri-operative pain in the setting of CABG surgery due to the increased risk of MI and stroke.[3]
• Pregnancy: Use is contraindicated during the last trimester of pregnancy (from 30 weeks gestation onward).[3]
• Severe Organ Failure: Patients with severe heart failure, severe hepatic failure, or severe renal failure (creatinine clearance less than 30 ml/minute).[18]

6.3 Common and Serious Adverse Reactions

The adverse effect profile of naproxen spans a range of organ systems.

• Common Adverse Events (Incidence ≥1%): The most frequently reported side effects are gastrointestinal and central nervous system-related. These include dyspepsia (heartburn), nausea, abdominal pain, constipation, diarrhea, headache, dizziness, drowsiness, and vertigo. Other common effects include edema, pruritus (itching), skin rashes, and tinnitus (ringing in the ears).[3]
• Serious Adverse Reactions:
• Cardiovascular: In addition to the boxed warnings for MI and stroke, naproxen can cause or exacerbate hypertension and fluid retention, which can lead to new-onset or worsening heart failure.[1]
• Gastrointestinal: Beyond the boxed warnings, other serious GI effects include pancreatitis, esophagitis, and exacerbation of inflammatory bowel disease (Crohn's disease, ulcerative colitis).[18]
• Renal: NSAIDs can induce renal toxicity, including acute kidney injury, renal papillary necrosis, interstitial nephritis, and nephrotic syndrome. Renal function must be monitored in at-risk patients, such as the elderly or those with pre-existing kidney disease, heart failure, or dehydration.[3]
• Hepatic: Elevation of liver enzymes can occur. While rare, severe hepatotoxicity, including jaundice, fulminant hepatitis, and liver failure (some cases fatal), has been reported. Therapy should be discontinued if clinical signs of liver disease develop.[3]
• Dermatologic: Naproxen should be stopped at the first sign of a rash. Rare but life-threatening skin reactions, including Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been associated with its use.[3]
• Hematologic: Anemia can occur, sometimes due to occult GI blood loss. Other rare but serious effects include thrombocytopenia (low platelets), agranulocytosis (low white blood cells), and aplastic anemia. Naproxen also prolongs bleeding time due to its effect on platelet aggregation.[3]
• Anaphylactic Reactions: Severe, systemic allergic reactions can occur, even in patients with no prior exposure.[3]

6.4 Use in Pregnancy and Lactation

• Pregnancy: Use of NSAIDs, including naproxen, during the third trimester (starting at 30 weeks gestation) is contraindicated due to the risk of causing premature closure of the fetal ductus arteriosus.[3] Furthermore, use from 20 weeks gestation onward should be avoided as it can cause fetal renal dysfunction, leading to oligohydramnios (low amniotic fluid) and potential neonatal renal impairment.[5]
• Fertility: Naproxen use may be associated with a reversible delay in ovulation and a temporary decrease in female fertility.[17]
• Lactation: Naproxen is excreted into human breast milk. Due to the potential for serious adverse reactions in nursing infants, a decision on whether to discontinue nursing or discontinue the drug should be made in consultation with a healthcare provider, taking into account the importance of the drug to the mother.[20]

7.0 Clinically Significant Drug and Food Interactions

Naproxen's pharmacokinetic and pharmacodynamic properties create a potential for numerous clinically significant interactions with other drugs. These interactions can either enhance toxicity or reduce therapeutic efficacy.

7.1 Pharmacodynamic Interactions

These interactions occur when two drugs have additive or antagonistic effects at the site of action.

• Anticoagulants and Antiplatelet Agents: This is one of the most critical areas of interaction.
• Warfarin: Co-administration with naproxen significantly increases the risk of bleeding. This occurs through a dual mechanism: naproxen inhibits platelet function, impairing primary hemostasis, and it can also displace warfarin from its binding sites on plasma albumin, increasing the anticoagulant effect. This combination should be avoided or undertaken only with intensive monitoring.[8]
• Aspirin: The combination of naproxen with analgesic doses of aspirin is generally not recommended as it increases the risk of serious GI events without providing additional therapeutic benefit.[15] A more complex interaction exists with low-dose (cardioprotective) aspirin. Naproxen, being a reversible COX-1 inhibitor, can competitively block the active site of the platelet COX-1 enzyme. If taken before aspirin, it can prevent aspirin from gaining access to the enzyme to exert its irreversible, antithrombotic effect. This pharmacological antagonism can potentially negate the cardioprotective benefit of aspirin, a point of significant clinical concern, especially in patients with cardiovascular disease.[24]
• Selective Serotonin Reuptake Inhibitors (SSRIs): Drugs like fluoxetine and sertraline can also impair platelet function. When combined with naproxen, there is an increased risk of GI bleeding.[20]
• Antihypertensives: Naproxen can diminish the therapeutic effect of many classes of antihypertensive medications, including ACE inhibitors, angiotensin II receptor blockers (ARBs), beta-blockers, and diuretics. The mechanism involves the inhibition of renal prostaglandin synthesis, which leads to sodium and water retention and can counteract the blood pressure-lowering effects of these drugs. Patients on these medications should have their blood pressure monitored closely after initiating NSAID therapy.[1] Furthermore, in patients who are elderly, volume-depleted, or have compromised renal function, the combination of an NSAID with an ACE inhibitor or ARB can increase the risk of acute renal failure.[18]

7.2 Pharmacokinetic Interactions

These interactions involve one drug affecting the absorption, distribution, metabolism, or excretion of another.

• Lithium: NSAIDs, including naproxen, can reduce the renal clearance of lithium by inhibiting renal prostaglandin synthesis. This can lead to an accumulation of lithium in the plasma, increasing the risk of lithium toxicity. Lithium levels should be carefully monitored if naproxen is co-administered.[24]
• Methotrexate: Naproxen has been reported to reduce the tubular secretion of methotrexate in the kidneys. This can lead to elevated levels of methotrexate and a significant risk of methotrexate-related toxicity, particularly with high-dose regimens used in oncology. Caution is strongly advised when these drugs are used concurrently.[15]
• Probenecid: When given concurrently, probenecid, a uricosuric agent, inhibits the metabolism and clearance of naproxen. This results in significantly increased plasma concentrations and a prolonged half-life of naproxen, which may necessitate a dose reduction.[24]
• Highly Protein-Bound Drugs: Due to its own extensive binding to plasma albumin (>99%), naproxen has the theoretical potential to displace other highly protein-bound drugs, such as hydantoins (e.g., phenytoin) or sulfonamides. While clinically significant interactions are not frequently reported, patients receiving these combinations should be observed for signs of toxicity from the displaced drug.[24]

7.3 Drug-Food Interaction

The interaction with food is relatively minor but can be clinically relevant. The presence of food in the stomach can delay the rate of naproxen's absorption, meaning it may take longer to feel the analgesic effect. However, food does not significantly impact the total amount of drug absorbed.[15] For this reason, and to minimize direct gastric irritation, taking naproxen with food or milk is a common and recommended practice.[3]

8.0 Comparative Analysis with Other Non-Steroidal Anti-Inflammatory Drugs

The selection of an NSAID for a particular patient is a complex decision that requires a comparative assessment of efficacy, duration of action, and, most importantly, the relative risks of cardiovascular and gastrointestinal toxicity. The most common comparators for naproxen are ibuprofen and diclofenac.

8.1 Comparative Efficacy

In general, for most common pain and inflammatory conditions, the efficacy of traditional NSAIDs is considered broadly similar when used at equipotent doses. However, some nuances exist.

• Naproxen vs. Ibuprofen: For most indications, naproxen and ibuprofen are considered to have comparable efficacy. A dose of 440 mg of naproxen is considered roughly equivalent to 400 mg of ibuprofen.[8]
• Diclofenac: Several analyses suggest that diclofenac may be a more potent analgesic than other traditional NSAIDs. One network meta-analysis focusing on osteoarthritis pain found that diclofenac at 150 mg/day was likely more effective at alleviating pain than naproxen at 1000 mg/day and ibuprofen at 2400 mg/day.[29] Another study suggested diclofenac was more effective than naproxen for tension-type headaches.[31]

8.2 Comparative Duration of Action

The duration of action, dictated by the drug's elimination half-life, is a key differentiator that influences dosing frequency and suitability for acute versus chronic conditions.

• Naproxen: Is a long-acting NSAID with a half-life of 12-17 hours. This allows for convenient once or twice-daily dosing, making it well-suited for managing chronic conditions like arthritis where sustained relief is needed.[8]
• Ibuprofen: Is a short-acting NSAID with a half-life of approximately 2 hours. This necessitates more frequent dosing (every 4 to 6 hours) and makes it more suitable for acute pain. It is also the preferred NSAID for use in children.[8]
• Diclofenac: Is also relatively short-acting, typically requiring dosing two or three times per day.[31]

8.3 Comparative Cardiovascular (CV) Risk

The relative cardiovascular risk is arguably the most critical factor in modern NSAID selection, particularly for patients with or at risk for heart disease. The risk profiles are a direct and predictable consequence of the drugs' differential inhibition of the COX-1 and COX-2 enzymes and their pharmacokinetic properties. CV risk is thought to be driven primarily by the inhibition of vascular COX-2 (which produces cardioprotective prostacyclin) without a counterbalancing inhibition of platelet COX-1 (which produces pro-thrombotic thromboxane A2).[6]

• Naproxen: A large body of evidence from multiple meta-analyses and observational studies consistently shows that naproxen is associated with the lowest cardiovascular risk among the traditional NSAIDs. At standard doses (up to 1000 mg/day), it does not appear to be associated with a significant increase in the risk of major vascular events like MI or stroke.[5] This favorable profile is attributed to its potent and sustained inhibition of platelet COX-1, which confers an antiplatelet effect that may offset any pro-thrombotic risk from COX-2 inhibition.[6]
• Diclofenac: In stark contrast, diclofenac is consistently associated with the highest cardiovascular risk among traditional NSAIDs, with a risk profile similar to that of the selective COX-2 inhibitors (coxibs) that were withdrawn from the market. High-dose diclofenac increases the risk of a major vascular event by approximately one-third.[6] This is believed to be due to its relatively greater selectivity for COX-2 over COX-1.
• Ibuprofen: The cardiovascular risk of ibuprofen is dose-dependent. At low, OTC doses (≤1200 mg/day), the risk is considered low.[7] However, at high, prescription-level doses (e.g., 2400 mg/day), ibuprofen is associated with an increased risk of cardiovascular events, particularly stroke.[6]

8.4 Comparative Gastrointestinal (GI) Risk

The GI risk profile of these drugs is largely the inverse of their CV risk profile and is driven primarily by the degree and duration of COX-1 inhibition in the gastric mucosa.[8]

• Naproxen: Due to its potent, non-selective COX inhibition and its long half-life, naproxen is associated with a higher risk of GI complications (such as ulcers and bleeding) than ibuprofen.[5] One meta-analysis found naproxen had a very high relative risk (RR 4.22) for upper GI complications compared to placebo.[34]
• Ibuprofen: Generally considered to have a more favorable GI safety profile than naproxen, particularly at low doses. Its short half-life may allow for periods of recovery for the gastric mucosa between doses.[5] However, the risk is still substantial, especially at high doses (RR 3.97).[34]
• Diclofenac: Poses a significant GI risk (RR 1.89), which is clearly elevated over placebo but, in some analyses, appears to be lower than that of naproxen or high-dose ibuprofen.[30]

This comparative analysis reveals that there is no single "safest" or "best" NSAID for all patients. The choice must be individualized. For a patient with a high cardiovascular risk but a healthy GI tract, naproxen is the most logical choice. Conversely, for a young patient with no CV risk factors but a history of dyspepsia, low-dose ibuprofen may be preferred. For a patient with high risk in both domains, all NSAIDs should be used with extreme caution or avoided altogether. This evidence-based, risk-stratified approach is the cornerstone of modern, rational NSAID prescribing.

Table 4: Comparative Risk Profile of Naproxen, Ibuprofen, and Diclofenac

NSAID	Duration of Action	Cardiovascular (CV) Risk	Gastrointestinal (GI) Risk	Key Clinical Considerations	Supporting Source(s)
Naproxen	Long (12-17h)	Lowest among tNSAIDs; generally neutral risk at ≤1000 mg/day.	High; greater than ibuprofen due to long half-life and potent COX-1 inhibition.	Preferred choice for patients with high CV risk but low GI risk. Dosing convenience for chronic conditions.	6
Ibuprofen (Low-Dose)	Short (2-4h)	Low; considered a safer alternative from a CV perspective.	Lower than naproxen; considered one of the safer tNSAIDs for GI tract.	Suitable for acute pain and patients with GI risk but low CV risk. Preferred in pediatrics.	7
Ibuprofen (High-Dose)	Short (2-4h)	Increased; risk of MI and stroke increases at doses approaching 2400 mg/day.	Increased; risk approaches that of other tNSAIDs.	High doses negate some of the safety advantages seen at lower doses.	6
Diclofenac	Short (1-2h)	High; risk is comparable to selective COX-2 inhibitors (coxibs).	Intermediate to High; significant risk, though some analyses place it below naproxen.	Use should be avoided in patients with established CV disease or significant CV risk factors.	6

9.0 Use in Specific Patient Populations

The standard dosing and safety considerations for naproxen must be modified for certain vulnerable patient populations due to age-related physiological changes or underlying organ dysfunction.

9.1 Geriatric Patients

The elderly represent a high-risk population for NSAID-related adverse events. They are more susceptible to serious GI complications like bleeding and perforation, as well as cardiovascular and renal toxicity.[20] Pharmacokinetic changes also play a role; studies indicate that while the total plasma concentration of naproxen remains unchanged in the elderly, the unbound (active) plasma fraction is increased.[23] This occurs because of age-related decreases in serum albumin, to which naproxen is highly bound. A standard dose in an elderly patient may therefore produce a greater pharmacological effect—and a greater risk of toxicity—than the same dose in a younger adult. Consequently, the guiding principle is to use the lowest effective dose for the shortest possible duration. Prolonged use in this population is not recommended, and regular monitoring for adverse effects is essential.[24]

9.2 Pediatric Patients

Naproxen's use in children is limited to specific indications and requires careful dosing. It is FDA-approved for the treatment of polyarticular juvenile idiopathic arthritis in children aged 2 years and older.[1] The standard pediatric dose is calculated based on body weight, typically 10 mg/kg per day, administered in two divided doses.[16] In some jurisdictions, naproxen is not recommended for any other indication in children under 16.[23] Over-the-counter use is generally not advised for children under the age of 12.[3] For general pediatric pain and fever, ibuprofen is more widely studied and is often the preferred NSAID.[25]

9.3 Pregnancy and Lactation

The use of naproxen during pregnancy is subject to significant restrictions due to potential harm to the fetus.

• Pregnancy: While caution is advised throughout pregnancy, use becomes increasingly risky as the pregnancy progresses. From 20 weeks of gestation, NSAID use can cause fetal renal dysfunction, which may lead to oligohydramnios (a deficiency of amniotic fluid).[5] From 30 weeks of gestation, naproxen is absolutely contraindicated. At this stage, inhibition of prostaglandin synthesis can lead to the premature closure of the fetal ductus arteriosus, a blood vessel essential for fetal circulation, which can result in persistent pulmonary hypertension in the newborn.[3]
• Lactation: Naproxen is excreted in breast milk. Because of the potential for serious adverse effects in the nursing infant, clinicians must weigh the benefits of the drug for the mother against the potential risks to the child. A decision to breastfeed while taking naproxen should be made in close consultation with a physician.[20]

9.4 Patients with Renal Impairment

The kidneys are the primary route of elimination for naproxen and its metabolites, and they are also a site of potential toxicity. Prostaglandins play a crucial role in maintaining renal blood flow and function. In patients with conditions that compromise renal perfusion (e.g., heart failure, dehydration, pre-existing kidney disease), the administration of an NSAID can precipitate acute renal failure.[24] Because the metabolites of naproxen can accumulate in patients with poor kidney function, its use is not recommended in individuals with moderate to severe renal impairment (defined as a creatinine clearance <30 mL/min).[18] In all patients with risk factors, renal function should be carefully monitored during therapy.[18]

9.5 Patients with Hepatic Impairment

The liver is the site of naproxen metabolism. In patients with severe liver disease, such as chronic alcoholic liver disease or other forms of cirrhosis, the pharmacokinetics of naproxen are altered. While the total plasma concentration may be reduced, the concentration of the unbound, pharmacologically active drug is increased.[23] This increases the potential for adverse effects. Therefore, while not absolutely contraindicated, it is prudent to use the lowest effective dose in patients with hepatic impairment and to monitor them closely for signs of toxicity.[19]

10.0 Global Regulatory Status and Commercial Landscape

Naproxen's journey from a novel patented compound to a global pharmaceutical staple provides a compelling case study in drug development, regulatory evolution, and commercial lifecycle management.

10.1 Approval History and Regulatory Status

Naproxen was first patented in 1967 and received its initial approval for prescription use in the United States from the FDA in 1976.[3] A pivotal moment in its history was the 1994 approval for over-the-counter (OTC) sale in the U.S., which dramatically expanded its accessibility to consumers for self-management of mild pain and fever.[1]

The regulatory status of naproxen varies by country, reflecting different national healthcare policies:

• United States: Available both by prescription (Rx-only) and OTC.[5]
• United Kingdom: Marketed as a Prescription Only Medicine (POM) for higher strengths and as a Pharmacy (P) medicine, available without a prescription but under the supervision of a pharmacist, for lower strengths.[5]
• Canada: Available OTC.[5]
• Australia: Lower-dose, limited-quantity packs are classified as Schedule 2 (Pharmacy Medicine), while larger packs and higher strengths are Schedule 4 (Prescription Only).[5]
• European Union: Naproxen is an established active substance described in the European Pharmacopoeia. Its innovator product, Naprosyn®, was first registered in Europe (Portugal) in 1973, and it is widely available across the EU as both branded and generic products.[10]

10.2 Global Brand Names and Generic Availability

As a mature drug with decades of use, naproxen is marketed under a vast portfolio of brand names worldwide and is widely available as a low-cost generic medication.[5] In 2022, it was the 88th most commonly prescribed medication in the United States, attesting to its enduring clinical importance.[5]

• Major Brand Names: Some of the most recognized brand names include Aleve®, Naprosyn®, Anaprox® (naproxen sodium), Naprelan® (controlled-release), and Synflex®.[1]
• International Names and Brands: It is known as Naproxène in French and Naproxeno in Spanish.[1] A multitude of other brand names exist in various countries, such as Flanax®, Apranax®, and Adco-Naproxen.[20]

10.3 Combination Products and Lifecycle Management

The commercial history of naproxen exemplifies a classic pharmaceutical lifecycle. After its period of market exclusivity as a novel prescription drug, it faced price erosion from generic competition. In response, pharmaceutical companies have employed two key strategies to manage its lifecycle and create new value: OTC switching and the development of innovative combination products.

The switch of Aleve® to OTC status in 1994 created a massive new consumer market and a durable brand identity separate from its prescription counterparts.[3] More recently, the focus has shifted to creating value-added, branded combination products that address specific clinical needs or solve known problems with the parent drug.

• Vimovo® (naproxen/esomeprazole): This product is a prime example of a problem-solving formulation. It was explicitly developed to mitigate the well-known gastrointestinal toxicity of naproxen by co-formulating it with a proton pump inhibitor, esomeprazole, in a single, sequential-delivery tablet.[21] This strategy simplifies therapy for high-risk patients and created a new, premium-priced product from two established, off-patent molecules. The selection of the 500 mg naproxen dose was a strategic decision based on market data showing it was the most commonly prescribed dose for chronic arthritis in major European markets.[21]
• Treximet® (naproxen/sumatriptan): This product combines naproxen with a triptan to create a synergistic effect for migraine treatment, targeting multiple pathological pathways and offering a differentiated product in a competitive market.[1]
• OTC Cold & Flu Products: Combinations like Aleve-D® add a decongestant to naproxen's analgesic effects, creating a tailored product for a specific consumer need.[1]

This evolution from a single-molecule prescription drug to a generic commodity, and its subsequent revitalization through OTC access and innovative combinations, demonstrates how the clinical and commercial value of a drug can be redefined and extended long after its initial discovery.

Table 5: Major International Brand Names and Combination Products

Brand Name	Active Ingredient(s)	Indication / Purpose	Key Markets / Notes	Supporting Source(s)
Aleve®	Naproxen Sodium	OTC pain and fever relief	Global (US, Canada, etc.)	1
Naprosyn®	Naproxen	Prescription for arthritis and pain	Global (innovator brand)	1
Anaprox® / Anaprox® DS	Naproxen Sodium	Prescription for arthritis and pain	US (sodium salt for faster absorption)	1
Naprelan®	Naproxen Sodium	Controlled-release for chronic arthritis	US (once-daily dosing)	1
Vimovo®	Naproxen / Esomeprazole	Arthritis in patients at risk for GI ulcers	US, EU (Gastro-protective combo)	1
Treximet®	Naproxen Sodium / Sumatriptan	Acute migraine treatment	US (Synergistic combination)	1
Aleve-D®	Naproxen Sodium / Pseudoephedrine	OTC sinus and cold symptom relief	US (Analgesic + Decongestant)	1
Synflex®	Naproxen Sodium	Pain and inflammation	UK, other international markets	2

11.0 Concluding Analysis and Expert Recommendations

Naproxen remains an effective and indispensable agent in the management of a wide array of painful and inflammatory conditions. Its long history of use, broad range of indications, and convenient dosing profile secure its place in the clinical armamentarium. However, its optimal and safe use demands a sophisticated clinical approach that moves beyond simple prescribing and embraces a nuanced, evidence-based understanding of its distinct risk-benefit profile.

The central conclusion of this comprehensive analysis is that the selection of an NSAID—particularly the choice between naproxen, ibuprofen, and diclofenac—should never be arbitrary. It must be a deliberate clinical decision guided by a hierarchical assessment of the individual patient's risk factors, with cardiovascular and gastrointestinal history being of paramount importance. The wealth of data from large-scale meta-analyses has clearly delineated the trade-offs inherent to this class of drugs: naproxen offers a superior cardiovascular safety profile at the cost of increased gastrointestinal toxicity, a risk profile that is largely inverted for a drug like low-dose ibuprofen. Diclofenac, with its high risk in both domains relative to other options, occupies a less favorable position for many patients.

Based on the synthesized evidence, the following expert recommendations are provided for the rational use of naproxen:

1. For Patients with High Cardiovascular Risk: In patients with established cardiovascular disease or multiple significant risk factors who require NSAID therapy, naproxen (at doses not exceeding 1000 mg/day) represents the most prudent choice among the non-selective NSAIDs due to its comparatively neutral effect on major vascular events. However, its use still requires caution and should be for the shortest duration possible.
2. For Patients with High Gastrointestinal Risk: In patients with a history of peptic ulcer disease, GI bleeding, or multiple risk factors for GI toxicity, all non-selective NSAIDs, including naproxen, should be avoided if possible. If NSAID therapy is deemed essential, a strategy to mitigate GI risk is mandatory. This should include one of the following: co-prescription of a proton pump inhibitor (PPI), use of a fixed-dose combination product (e.g., naproxen/esomeprazole), or consideration of a COX-2 selective inhibitor if the patient's cardiovascular risk is low.
3. Management of the Aspirin Interaction: Clinicians and patients must be made aware of the potential for naproxen to interfere with the cardioprotective effects of low-dose aspirin. For patients on this combination, counseling on the timing of administration (i.e., taking aspirin at least 30 minutes before or many hours after naproxen) may help mitigate this interaction, although its ultimate clinical significance continues to be debated.
4. Need for Continued Research and Education: While the comparative risks are well-documented, further research is warranted to better define the long-term safety of naproxen in specific high-risk subgroups and to clarify the real-world impact of the aspirin-naproxen interaction on clinical outcomes. Furthermore, a significant gap may exist between the evidence from meta-analyses and global prescribing patterns. Public health and continuing medical education initiatives are crucial to disseminate this nuanced comparative risk data to prescribers and the public to ensure that NSAID selection aligns with the best available evidence, promoting safer use of this vital class of medications.

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