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Mefenamic acid

Mefenamic acid is a nonsteroidal anti-inflammatory drug (NSAID) belonging to the fenamate class, primarily prescribed for the short-term (up to 7 days) relief of mild to moderate pain and for the treatment of primary dysmenorrhea in patients aged 14 years and older.^[1] Chemically designated as 2-[(2,3-dimethylphenyl)amino]benzoic acid, it has the molecular formula C₁₅H₁₅NO₂ and a molecular weight of 241.29 g/mol, appearing as a white to off-white crystalline powder.^[2] First approved for use in the United States in 1967 under the brand name Ponstel, it is available in 250 mg oral capsules and is typically initiated with a 500 mg dose followed by 250 mg every 6 hours as needed.^[2]^[1] The drug exerts its therapeutic effects through inhibition of cyclooxygenase (COX) enzymes, which reduces the synthesis of prostaglandins—mediators responsible for pain, inflammation, and fever—though its exact mechanism is not fully elucidated.^[1] It provides analgesic, anti-inflammatory, and antipyretic actions, making it suitable for conditions such as menstrual cramps, headaches, dental pain, and postoperative discomfort, but it is not indicated for chronic use or conditions like osteoarthritis or rheumatoid arthritis in standard labeling.^[2]^[1] Despite its efficacy, mefenamic acid is associated with significant risks, including increased chances of serious cardiovascular thrombotic events (such as myocardial infarction and stroke), gastrointestinal bleeding, ulceration, and perforation, particularly in elderly patients or those with preexisting conditions.^[1] It is contraindicated in patients with a history of coronary artery bypass graft (CABG) surgery, active gastrointestinal bleeding, or severe renal impairment, and use after 20 weeks of pregnancy is not recommended due to potential fetal harm.^[3] Common side effects include diarrhea, nausea, headache, and dizziness, while monitoring for hypersensitivity reactions is essential given cross-reactivity with other NSAIDs.^[3]^[2]

Clinical use

Indications

Mefenamic acid is indicated for the short-term relief (not exceeding 7 days) of mild to moderate pain in adults and adolescents aged 14 years and older, encompassing conditions such as headache, dental pain, postoperative pain, and muscular aches.^[1]^[4] It is also approved for the treatment of primary dysmenorrhea, with treatment typically limited to 2-3 days starting at the onset of symptoms or bleeding.^[1] Clinical trials have established the efficacy of mefenamic acid in managing primary dysmenorrhea, demonstrating pain relief comparable to other nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen.^[5]^[6] Off-label applications include the management of pain and inflammation associated with rheumatoid arthritis, where studies have shown it to be effective, though it is not recommended as a first-line option due to heightened gastrointestinal risks compared to other therapies.^[7] Additionally, per 2025 consensus guidelines on its use in pediatric practice, mefenamic acid serves as an off-label antipyretic for fever reduction in children above six months of age, particularly when associated with infectious conditions.^[8] Due to potential cardiovascular and gastrointestinal risks that escalate with duration, mefenamic acid is not suitable for long-term use or chronic conditions like osteoarthritis without close specialist monitoring.^[1]

Dosage and administration

Mefenamic acid is typically administered orally for the relief of mild to moderate pain and primary dysmenorrhea. The standard adult dose is an initial 500 mg, followed by 250 mg every 6 hours as needed, usually for no more than 7 days and not exceeding 1 g per day.^[9]^[10]^[4] For pediatric patients, mefenamic acid is approved for those 14 years of age and older, using the same dosing regimen as adults; it is not recommended for children under 14 years in many regions due to limited safety data, though caution is advised even in approved groups. A 2025 consensus from Indian pediatricians supports off-label use in children over 6 months at 4-6.5 mg/kg every 8 hours (maximum three doses per day) for fever and pain, divided into oral suspension for younger children.^[9]^[11]^[12] Available formulations include oral capsules of 250 mg and 500 mg (varying by region; in the US, only 250 mg capsules are available), as well as oral suspensions at 50 mg/5 mL; no intravenous or topical formulations are commercially available.^[1]^[13]^[2] Administration should occur with food or milk to minimize gastrointestinal upset, and therapy must be discontinued if symptoms persist beyond 7 days or if no improvement is seen. In elderly patients or those with renal impairment, lower doses should be considered with close monitoring due to heightened risk of adverse effects, and the drug is contraindicated in severe renal dysfunction.^[9]^[11]^[10]

Safety profile

Contraindications

Mefenamic acid is contraindicated in patients with known hypersensitivity to the drug or to any other nonsteroidal anti-inflammatory drugs (NSAIDs), as well as in those with a history of asthma, urticaria, or other allergic-type reactions following exposure to aspirin or other NSAIDs.^[14]^[10] It is also contraindicated in the perioperative setting of coronary artery bypass graft (CABG) surgery, where NSAIDs like mefenamic acid have been associated with increased cardiovascular thrombotic events.^[14]^[10] Additionally, a history of serious NSAID-induced skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis, warrants absolute avoidance.^[10] Use of mefenamic acid should be avoided in patients with active peptic ulcer disease, a history of gastrointestinal (GI) bleeding, or chronic inflammation of the upper or lower GI tract, due to the heightened risk of severe GI complications.^[14]^[4] Use should also be avoided in severe renal impairment (creatinine clearance less than 30 mL/min) or preexisting advanced renal disease, as mefenamic acid can exacerbate renal function decline through inhibition of prostaglandin synthesis.^[10]^[4] Similarly, use with caution or avoid in severe hepatic impairment or active liver disease, given the drug's extensive hepatic metabolism and potential for hepatotoxicity.^[10] Use of mefenamic acid is not recommended after 20 weeks of pregnancy; avoid after 30 weeks gestation due to the risk of premature closure of the fetal ductus arteriosus and other fetal toxicities mediated by prostaglandin inhibition. Between 20 and 30 weeks, if necessary, use only at the lowest effective dose and shortest duration, with fetal monitoring.^[14]^[10] Relative contraindications include a history of asthma that may be exacerbated by NSAIDs (without prior reaction), uncontrolled hypertension, concurrent administration with other NSAIDs, and conditions predisposing to renal compromise such as dehydration or heart failure, where careful monitoring or avoidance is advised to mitigate risks of bronchospasm, cardiovascular events, or worsening renal function.^[10]^[4] In special populations, mefenamic acid should be avoided in children under 14 years of age unless under specialist guidance, as safety and efficacy have not been established in this group.^[10]^[4] For breastfeeding individuals, its use is relatively contraindicated due to excretion in breast milk, which may cause gastrointestinal effects or other adverse outcomes in the infant; discontinuation of nursing or the drug is recommended based on a risk-benefit assessment.^[10]^[4]

Adverse effects

Mefenamic acid, a nonsteroidal anti-inflammatory drug (NSAID), is associated with a range of adverse effects, primarily affecting the gastrointestinal (GI), cardiovascular (CV), renal, and hepatic systems. Common adverse effects occurring in 1-10% of patients include GI disturbances such as dyspepsia, nausea, diarrhea, abdominal pain, heartburn, and flatulence, as well as dizziness, headache, rash, and elevated liver enzymes.^[14] These effects are generally mild and dose-related, with GI symptoms reported in up to 10-20% of users in clinical settings, often resolving upon discontinuation.^[15] Serious adverse effects, though less common (<1%), carry significant clinical importance and are highlighted in the drug's black box warning. GI ulceration, bleeding, or perforation can occur at any time during treatment, with an incidence of approximately 1% after 3-6 months of use and 2-4% after one year; these risks are elevated compared to non-use and necessitate caution in patients with prior GI disorders.^[14] CV events, including thrombosis, myocardial infarction, and stroke, are increased with long-term or high-dose use, particularly in individuals with preexisting CV disease.^[14] Renal toxicity, such as acute kidney injury or papillary necrosis, is more likely in dehydrated patients or those with impaired renal function.^[14] Hepatotoxicity is rare, with transient aminotransferase elevations (ALT/AST) occurring in less than 5% of patients and marked elevations (≥3x upper limit of normal) in <1%; idiosyncratic cases may present as cholestatic or hepatocellular injury, often linked to hypersensitivity.^[16] Rare but notable adverse effects include aseptic meningitis, reported in isolated cases and potentially reversible upon drug withdrawal, as well as anaphylaxis in sensitive individuals manifesting as severe allergic reactions. Mefenamic acid has been associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), a severe hypersensitivity reaction, as reported in pharmacovigilance alerts.^[15]^[17] In 2024, the Malaysian National Pharmaceutical Regulatory Agency (NPRA) issued an alert on generalised bullous fixed drug eruption (GBFDE), a hypersensitivity-mediated skin reaction involving blisters and rash, prompting updates to product labeling for immediate reporting of skin symptoms.^[18] Pediatric-specific risks include potential dehydration if used for fever reduction without adequate fluid intake, alongside hypothermia in some cases; administration with food and hydration is recommended to mitigate GI effects in children.^[8] Risk factors for adverse effects are dose-dependent and include advanced age, smoking, alcohol use, and comorbidities such as heart failure or dehydration, which amplify GI, CV, and renal risks; patients in contraindicated groups, like those with active peptic ulcers, face heightened vulnerability.^[14] Monitoring recommendations involve periodic complete blood count (CBC) for anemia or bleeding detection and renal function tests, especially in at-risk populations.^[14]

Overdose

Overdose of mefenamic acid, particularly acute ingestion exceeding 2-3 grams, commonly presents with gastrointestinal symptoms such as nausea, vomiting, and epigastric pain, alongside central nervous system effects including drowsiness, confusion, and dizziness.^[3]^[14] More severe manifestations, observed in cases involving doses of 2.5 grams or higher, include seizures (reported in approximately 9% of overdoses), coma, slowed breathing, and muscle twitching; additional complications can encompass metabolic acidosis, acute renal failure with oliguria and elevated creatinine, and gastrointestinal hemorrhage evidenced by bloody or coffee-ground-like vomit and black, tarry stools.^[19]^[20]^[21] Management of mefenamic acid overdose is primarily supportive and symptomatic, with no specific antidote available. Initial decontamination may involve administration of activated charcoal (60-100 grams in adults or 1-2 grams per kg in children) if ingestion occurred within 1-4 hours and the airway is protected, or orogastric lavage for massive recent ingestions in intubated patients; ongoing monitoring of vital signs, electrolytes, renal function, and acid-base status is essential, with intravenous fluids and sodium bicarbonate used to address dehydration or severe acidosis.^[14]^[22] Seizures should be treated promptly with benzodiazepines, while symptomatic patients with altered consciousness, gastrointestinal bleeding, or renal impairment require admission to an intensive care setting; hemodialysis may be considered for life-threatening acidosis or acute kidney injury but has limited efficacy due to the drug's high protein binding (approximately 99%), removing only a small fraction of the ingested dose.^[22]^[23] Contacting a poison control center (e.g., 1-800-222-1222 in the US) is recommended for tailored guidance.^[3] Prognosis following mefenamic acid overdose is generally favorable with early intervention, as most patients experience self-limiting symptoms and full recovery without long-term sequelae, though fatalities have been reported in massive ingestions exceeding 10 grams, often due to refractory seizures, coma, or multi-organ failure.^[20]^[24] Case reports spanning the 1960s to the 2020s underscore the predominance of gastrointestinal and central nervous system effects, with convulsions posing risks of injury or hypoxia but rarely leading to sudden death when managed appropriately.^[19] Prevention of mefenamic acid overdose emphasizes its short-term use as indicated (typically no longer than 7 days) to minimize accumulation risks, alongside storage in child-resistant packaging to reduce accidental pediatric ingestions, as required under regulations like the Poison Prevention Packaging Act for prescription medications.^[14]^[22]^[25]

Drug interactions

Mefenamic acid, a nonsteroidal anti-inflammatory drug (NSAID), exhibits several significant drug interactions primarily through pharmacodynamic mechanisms such as inhibition of cyclooxygenase (COX) enzymes and effects on platelet function, with some pharmacokinetic influences via cytochrome P450 (CYP) pathways.^[26] These interactions can increase the risk of adverse effects like gastrointestinal bleeding, renal impairment, or altered drug efficacy, necessitating careful monitoring or avoidance in clinical practice.^[1] Major interactions include those with anticoagulants such as warfarin, where mefenamic acid heightens bleeding risk through synergistic inhibition of platelet aggregation and potential CYP2C9 inhibition that elevates warfarin levels.^[26]^[4] Concomitant use with antihypertensives like ACE inhibitors or diuretics can reduce their efficacy and exacerbate renal impairment due to NSAID-induced prostaglandin suppression affecting renal blood flow.^[1] Other NSAIDs or aspirin additively increase gastrointestinal and renal toxicity without enhancing therapeutic benefits.^[26] Lithium levels may rise due to decreased renal clearance, risking toxicity, while methotrexate toxicity is enhanced through reduced clearance.^[1]^[26] Moderate interactions encompass selective serotonin reuptake inhibitors (SSRIs), which amplify gastrointestinal bleeding risk via combined effects on serotonin-mediated platelet function.^[26] Corticosteroids potentiate ulcer formation, and alcohol exacerbates gastrointestinal irritation.^[27] Herbal supplements like ginkgo biloba may further elevate bleeding risk through antiplatelet activity.^[27] Most interactions are pharmacodynamic, stemming from COX inhibition synergy with other agents affecting hemostasis or renal function, though pharmacokinetic effects occur via minor CYP2C9 inhibition impacting substrates like warfarin.^[4]^[26] Management involves avoiding high-risk combinations where possible, such as with other NSAIDs or anticoagulants; dose adjustments and monitoring, including international normalized ratio (INR) for warfarin or renal function for antihypertensives and diuretics, are recommended.^[28]^[1] Patients should consult healthcare providers before combining mefenamic acid with these agents.^[26]

Pharmacology

Mechanism of action

Mefenamic acid exerts its primary therapeutic effects through non-selective inhibition of the cyclooxygenase enzymes COX-1 and COX-2, which are responsible for converting arachidonic acid into prostaglandin H2 (PGH2), a key precursor in the synthesis of proinflammatory prostaglandins. This inhibition disrupts the arachidonic acid cascade, reducing the production of prostaglandins that mediate pain, inflammation, and fever. The reaction inhibited by mefenamic acid can be represented as:

\text{Arachidonic acid} \xrightarrow{\text{COX-1/COX-2}} \text{PGH}_2

By competitively binding to the active sites of these enzymes, mefenamic acid prevents the oxygenation of arachidonic acid, thereby lowering overall prostaglandin levels in tissues.^[29]^[16] The analgesic effects of mefenamic acid arise from both peripheral and central mechanisms. Peripherally, it reduces the sensitization of nociceptors at sites of injury or inflammation by decreasing local prostaglandin concentrations, which otherwise potentiate pain signaling. Centrally, it may contribute to pain relief through actions in the hypothalamus, though this is less pronounced than its peripheral effects. Additionally, its antipyretic action involves inhibition of prostaglandin E2 (PGE2) synthesis in the hypothalamus, which normally elevates the thermoregulatory set point during fever. These combined effects make mefenamic acid effective for short-term relief of mild to moderate pain.^[29]^[16] As an anti-inflammatory agent, mefenamic acid decreases vascular permeability and inhibits leukocyte migration to inflamed sites by limiting prostaglandin-mediated responses, though its potency in this regard is weaker than that of indomethacin. Despite this relative weakness in broad anti-inflammatory activity, mefenamic acid remains particularly effective for managing dysmenorrhea, where uterine prostaglandin overproduction drives symptoms.^[16]^[6] Recent research has identified an additional off-target effect of mefenamic acid on the IKs potassium channel (encoded by KCNQ1 and modulated by KCNE1), where low doses (up to 100 μM) potentiate channel activity by accelerating activation kinetics and stabilizing open states. This potentiation suggests potential therapeutic applications in treating arrhythmias, such as long QT syndrome, by enhancing cardiac repolarization; however, at higher concentrations relevant to analgesic dosing (around 300 μM), it exhibits inhibitory effects, highlighting a dual role that is incidental to its primary anti-inflammatory uses.^[30]

Pharmacokinetics

Mefenamic acid is rapidly absorbed from the gastrointestinal tract following oral administration, with peak plasma concentrations (Cmax) of 10 to 20 mg/L achieved 2 to 4 hours (Tmax) after a 500 mg dose.^[14] The absolute bioavailability is high, approximately 90–100%, though exact values relative to intravenous administration have not been established due to lack of intravenous formulation studies.^[31] While the effect of food on absorption has not been formally evaluated in dedicated pharmacokinetic studies, available data from comparative formulation trials indicate that food may delay the rate of absorption (prolonging Tmax) but does not significantly alter the overall extent of bioavailability, with some evidence of slight increases in area under the curve (AUC) for certain capsule formulations.^[32] First-pass metabolism contributes to the drug's disposition, but it does not substantially limit overall absorption. Following absorption, mefenamic acid exhibits extensive distribution throughout the body, with an apparent volume of distribution (Vz/F) of 1.06 L/kg after a 500 mg dose.^[14] The drug is highly bound to plasma proteins, primarily albumin, at levels greater than 90%.^[14] Based on its physicochemical properties, mefenamic acid is expected to cross the placenta, and it is excreted into human breast milk in trace amounts that are unlikely to pose significant risk to nursing infants, though use during breastfeeding is generally discouraged in favor of alternative agents.^[14]^[33] Mefenamic acid undergoes hepatic metabolism primarily via the cytochrome P450 enzyme CYP2C9, forming 3-hydroxymethyl-mefenamic acid as a major metabolite, which retains some pharmacological activity, and subsequent oxidation to the inactive 3-carboxy-mefenamic acid.^[14] Additional Phase II metabolism involves glucuronidation of both the parent drug and metabolites, with the acyl glucuronide capable of irreversible binding to plasma proteins.^[14] Enterohepatic recirculation of mefenamic acid and its metabolites occurs to a notable extent, contributing to prolongation of its plasma presence beyond what would be expected from primary elimination pathways alone.^[14] Excretion of mefenamic acid occurs mainly through the kidneys, with approximately 52% of the dose recovered in urine primarily as glucuronide conjugates of the parent drug and metabolites, and about 20% eliminated in feces, likely via biliary secretion.^[14] The elimination half-life is approximately 2 hours in healthy adults, though metabolites may persist longer.^[14] Renal clearance is a significant route of elimination, and thus total body clearance may be reduced in patients with renal impairment; dedicated pharmacokinetic studies in this population are lacking, but closer monitoring is recommended.^[14] Similarly, clearance can be diminished in the elderly due to age-related declines in renal function, warranting cautious use in this group.^[34]

Chemistry

Structure and properties

Mefenamic acid has the chemical formula C₁₅H₁₅NO₂ and a molecular weight of 241.29 g/mol.^[2]^[35] Its IUPAC name is 2-[(2,3-dimethylphenyl)amino]benzoic acid.^[2] The molecule is an anthranilic acid derivative, featuring a benzoic acid core with an amino group at the ortho position substituted by a 2,3-dimethylphenyl ring, which introduces two ortho-methyl groups relative to the amine linkage.^[2] This structure includes both a carboxylic acid and an amine functionality, conferring potential zwitterionic character.^[2] Mefenamic acid appears as a white to off-white or greyish-white, odorless, microcrystalline powder.^[2]^[35] Its melting point is 230–231 °C.^[2]^[35] The carboxylic acid group has a pKa of 4.2, indicating moderate acidity.^[2] The compound exhibits high lipophilicity with a logP value of 5.12.^[2]^[36] It is sparingly soluble in water (approximately 0.02–0.04 mg/mL at neutral pH), slightly soluble in ethanol, and soluble in acetone.^[2]^[35]^[36] Mefenamic acid is sensitive to light, darkening upon prolonged exposure, and to moisture, particularly under high humidity conditions that can influence polymorphic transformations.^[2] It exists in multiple polymorphic forms, with Form I being the most stable under ambient conditions and Form II being metastable with higher solubility but prone to conversion to Form I.^[37] Degradation occurs primarily through hydrolysis under acidic or basic conditions and oxidation, leading to breakdown products that can be separated via chromatographic methods.^[38]

Synthesis

Mefenamic acid, chemically known as 2-[(2,3-dimethylphenyl)amino]benzoic acid, is classically synthesized through a copper-catalyzed coupling reaction between 2,3-dimethylaniline and a 2-halobenzoic acid derivative, typically employing the Ullmann-Goldberg condensation for N-arylation.^[39] In this method, the potassium salt of 2-bromobenzoic acid is reacted with 2,3-dimethylaniline in the presence of copper(II) acetate as a catalyst, facilitating nucleophilic aromatic substitution to form the key C-N bond. This approach, developed in the mid-20th century, yields the product after acidification and purification, with the reaction scheme simplified as 2,3-(CH₃)₂C₆H₃NH₂ + 2-BrC₆H₄COOK → mefenamic acid + KBr (catalyzed by Cu(OAc)₂).^[39] Industrial production of mefenamic acid follows a multi-step process starting from o-xylene, which is oxidized to o-toluic acid and further converted to 2,3-dimethylaniline via nitration and reduction, followed by coupling with 2-chlorobenzoic acid using a copper catalyst such as copper 8-quinolinolate in the presence of sodium acetate and a strong-acid cation-exchange resin.^[40] The condensation occurs at 104–110°C under controlled pH (6.5–7.5) with incremental addition of reagents to minimize by-products, achieving overall yields of 85–95% after filtration, decolorization with activated carbon, and recrystallization from dimethylformamide (DMF) or ethanol.^[41] This process emphasizes catalyst recycling and reduced waste, with purification ensuring high product purity (>99%) through crystallization.^[42] Modern variants incorporate greener methodologies to enhance efficiency and sustainability, such as microwave-assisted Ullmann reactions or palladium-catalyzed Buchwald-Hartwig couplings for the N-arylation step, which allow milder conditions and shorter reaction times while maintaining yields around 80–90%.^[43] Additionally, reductive C-N cross-coupling of nitroarenes and boronic acids using P(III)/P(V) catalysis has been applied to synthesize mefenamic acid analogs in one-pot processes, reducing solvent use and enabling scalability.^[44] Prodrug synthesis, particularly ester derivatives like the N-hydroxymethylsuccinimide ester, involves condensing mefenamic acid with alcohols or activated esters using dicyclohexylcarbodiimide (DCC) coupling from the 1960s onward, improving solubility and bioavailability with hydrolysis rates tailored for targeted release.^[45] These developments, spanning 1960s–2020s, prioritize enzymatic catalysis or solvent-free conditions to minimize environmental impact.^[46]

Conformational flexibility

Mefenamic acid displays significant conformational flexibility arising from rotation around the N-phenyl bond (N1–C8) and torsion within the carboxylic acid group, enabling the existence of multiple conformers such as cis and trans amide-like configurations.^[47]^[48]^[49] Density functional theory (DFT) calculations reveal energy barriers for these rotations in the range of 4.9 to 8.5 kcal/mol for the N-phenyl bond and up to approximately 12 kcal/mol for related torsions, facilitating interconversion between conformers under physiological conditions.^[47]^[50] This flexibility contributes to the polymorphism of mefenamic acid, with three known forms (I, II, and III) exhibiting distinct crystal structures and properties. Form I, the most stable under ambient conditions, adopts a triclinic crystal system (space group P-1), while Forms II and III are also triclinic but less stable, with Form II becoming thermodynamically favored at elevated temperatures above 160 °C.^[37]^[47] Conformational differences, particularly in the orientation of the phenyl ring and carboxylic group, drive variations in packing efficiency and intermolecular interactions, leading to higher solubility for Form II compared to Form I in solvent mixtures such as ethanol-water and ethyl acetate-ethanol.^[47]^[51] Specifically, Form II demonstrates larger dissolution rates and saturation concentrations, enhancing its potential for pharmaceutical formulations despite its metastability at room temperature.^[51] Recent studies have elucidated these dynamics through advanced spectroscopic and computational techniques. A 2023 investigation using 2D NOESY NMR in supercritical CO₂ (scCO₂) with 2 mol.% DMSO-d₆ at 45 °C and 9 MPa revealed conformer ratios of approximately 75:25 for mefenamic acid, with minimal equilibrium shifts upon DMSO addition, confirming the robustness of conformational analysis in mixed solvents.^[52] Quantum chemical modeling employing B3LYP/6-311+G(2d,p) has predicted conformer populations, identifying four primary conformers (A–D) and two hidden ones (AA, BB) involving hydroxyl group mobility, with fractions such as 6–7% for minor forms in DMSO-d₆ at 25 °C.^[53] These findings underscore implications for dissolution enhancement in formulations, as solvent-induced shifts can optimize polymorphic transitions for improved drug release.^[53]^[52] The conformational flexibility of mefenamic acid influences its biological interactions, particularly binding to cyclooxygenase (COX) enzymes, where adaptable conformers enable effective inhibition of prostaglandin synthesis.^[54] Hidden conformers further impact bioavailability by altering dissolution kinetics and absorption profiles, as evidenced by studies linking polymorphic forms to enhanced micronization outcomes that reduce variability in therapeutic delivery.^[53]

History and development

Discovery and approval

Mefenamic acid was discovered in 1961 by a team led by Claude Winder at Parke-Davis, as part of efforts to develop anthranilic acid derivatives in the era following aspirin's success as a salicylate-based analgesic and anti-inflammatory agent.^[55] This compound, chemically N-(2,3-dimethylphenyl)anthranilic acid, represented an early exploration beyond traditional salicylates, aiming to identify agents with enhanced potency and reduced side effects.^[56] Preclinical evaluation quickly highlighted its anti-inflammatory effects in animal models, notably through the carrageenan-induced paw edema assay, where it demonstrated significant inhibition of edema formation comparable to or exceeding that of aspirin.^[57] These studies, published in 1962, also confirmed its antipyretic and antinociceptive properties, establishing mefenamic acid's potential as a nonsteroidal anti-inflammatory drug (NSAID) with a focus on analgesic efficacy.^[57] Building on this, the compound received U.S. Patent 3,138,636 in 1964, enabling its commercialization under the brand name Ponstel. Initial human trials in the mid-1960s targeted primary dysmenorrhea, with early clinical data from 1963 supporting its use in conditions like rheumatoid arthritis by showing relief of pain and inflammation without the gastric irritation common to salicylates.^[58] The U.S. Food and Drug Administration (FDA) granted approval for mefenamic acid on February 20, 1967, specifically for the short-term treatment of mild to moderate pain and primary dysmenorrhea, marking it as one of the first fenamates approved for clinical use.^[59] In Europe, national approvals followed closely, with the United Kingdom licensing it as Ponstan in 1963 for similar indications.^[60] Early adoption positioned mefenamic acid as the prototype of the fenamate subclass of NSAIDs, distinguished from salicylates by its anthranilic acid backbone and preferential inhibition of prostaglandin synthesis; it played a key role in early research on NSAID pharmacokinetics and classification.^[16]^[55] Though concerns over gastrointestinal risks emerged soon after, leading to withdrawals in select markets like Sweden in 1982 due to fatal adverse events—with the drug remaining unavailable there—and similar actions in other Nordic countries, availability continued and expanded elsewhere.^[61]^[62]

Regulatory milestones

In the 1980s, mefenamic acid became available in generic form following the expiration of its original patent in 1984, broadening access while maintaining prescription status in major markets. The U.S. Food and Drug Administration (FDA) required all nonsteroidal anti-inflammatory drugs (NSAIDs), including mefenamic acid, to carry a boxed warning for increased risk of serious gastrointestinal adverse events such as bleeding, ulceration, and perforation in 2005, alongside a new boxed warning for cardiovascular risks including myocardial infarction and stroke.^[63]^[64] In 2015, the FDA further strengthened the cardiovascular boxed warning for all NSAIDs to emphasize the potential for fatal heart attack or stroke at any time during use, prompting label updates for mefenamic acid.^[63] Regulatory restrictions have included a 2024 safety signal alert from the Malaysian National Pharmaceutical Regulatory Agency (NPRA) highlighting cases of generalised bullous fixed drug eruption associated with mefenamic acid use, urging healthcare providers to monitor for severe cutaneous reactions.^[65] The National Institute of Diabetes and Digestive and Kidney Diseases' LiverTox database classifies mefenamic acid as a rare cause of clinically apparent liver injury, typically presenting as hepatocellular or mixed patterns with jaundice, based on case reports of acute hepatitis (entry last revised 2020).^[16] As of 2025, mefenamic acid is classified as a Schedule H drug in India, requiring a prescription from a registered medical practitioner for dispensing.^[66]^[67] It appears on several national essential medicines lists for pain management, such as India's National List of Essential Medicines (2022), though it is not included on the World Health Organization's core model list (23rd edition, 2023).^[68] In the United States, the branded product Ponstel was discontinued in 2020, with availability limited to generic formulations thereafter.^[69] Globally, regulatory approaches vary: mefenamic acid is available over-the-counter in several Asian markets, including parts of Southeast Asia, for short-term relief of dysmenorrhea, while in the European Union, product summaries recommend strict short-term use not exceeding seven days to minimize risks.^[70]^[4]

Society and culture

Availability and brand names

Mefenamic acid has been available as a generic medication since the 1980s, following the expiration of its original patents, and is now produced by multiple manufacturers worldwide. It is marketed under over 100 brand names across various countries, reflecting its broad distribution. Notable examples include Ponstel (formerly in the United States), Ponstan (in the United Kingdom and Australia), and Meftal (in India), with additional international brands such as Coslan, Ponalar, and Parkemed used in regions like Europe and Asia.^[29]^[71]^[72] The primary formulations are oral capsules and tablets in 250 mg and 500 mg strengths, which dominate global use for adults. Pediatric suspensions, typically at concentrations of 50 mg/5 mL or 100 mg/5 mL, are commonly available in developing regions such as India and the Middle East to facilitate dosing in children. Suppositories in 125 mg or 500 mg doses are offered in select markets, but no injectable formulations exist. It is available by prescription in the United States and many developed countries, but over-the-counter in select markets such as India.^[29]^[73]^[1]^[71] Mefenamic acid is accessible in over 100 countries, including much of Europe, Asia, Australia, and the Americas, with widespread availability supporting its role in primary care. Although not listed on the WHO Model List of Essential Medicines (24th edition, 2025), it remains a staple in many national formularies, particularly in low- and middle-income countries. Shortages are infrequent globally, though occasional supply chain disruptions have been reported in the European Union.^[74]^[75]^[76] In developing regions, mefenamic acid is often preferred for managing dysmenorrhea due to its cost-effectiveness and ease of access. Veterinary applications are limited, primarily due to risks of toxicity in animals such as dogs and cats.^[77]^[78]

Pricing and access

Mefenamic acid, available primarily as a generic medication, exhibits significant price variations globally due to differences in manufacturing, distribution, and regulatory environments. In the United States, the wholesale acquisition cost for generic 250 mg capsules is approximately $1.40 per unit, though patient out-of-pocket expenses can be reduced to around $34 (as of November 2025) for a 30-capsule supply (sufficient for a typical short-term course) using discount coupons from platforms like GoodRx.^[79] In contrast, prices in India are substantially lower, with generic 250 mg or 500 mg tablets available for as little as ₹1-2 per dose (about $0.012-0.024 USD), reflecting robust local generic production and competition.^[80] These low costs in developing markets contribute to broader affordability, while a 30-day supply of generics in the US rarely exceeds $50 with assistance programs. Several factors influence pricing, including widespread generic availability since the patent expiration, which has driven down costs through competition from multiple manufacturers. Patented reformulations, such as orodispersible tablets designed for faster dissolution, command higher prices—up to 20-50% more than standard generics in markets where they are available—due to additional development and regulatory expenses.^[81] Insurance coverage further modulates access: in the European Union, public health systems often provide full reimbursement for prescribed mefenamic acid as an essential analgesic, whereas in the US, Medicare Part D plans typically do not cover it, and private insurers may require prior authorization with partial copays averaging 20-30% of the cost.^[82]^[83] Access remains equitable in many low- and middle-income countries, where mefenamic acid is included in national essential medicines lists (e.g., India's NLEM 2022), promoting affordability at under $0.05 per dose through government procurement.^[68] However, barriers persist, including intermittent shortages reported in 2025 across regions like Australia and Canada due to supply chain disruptions, and logistical challenges in remote areas where transportation costs can inflate effective prices by 20-50%. The global market, valued at approximately USD 250 million in 2024, is projected to grow at a 5% CAGR, reaching around USD 320 million by 2030, driven by demand in emerging economies.^[84] To address equity gaps, mefenamic acid is subsidized in national formularies such as Saudi Arabia's Ministry of Health list, where it is procured at bulk rates for public distribution, often at no cost to patients.^[85] In the US, uninsured individuals can access discounts through programs like SingleCare or GoodRx, reducing a 30-day supply to under $36, though no manufacturer-specific patient assistance exists for this generic drug.^[86]

Research

Clinical investigations

Pivotal clinical trials in the 1960s and 1970s established mefenamic acid's efficacy for primary dysmenorrhea through randomized controlled trials (RCTs). In a double-blind, crossover study involving women with moderate to severe symptoms, mefenamic acid (500 mg initial dose followed by 250 mg every 6 hours) significantly reduced pain intensity and frequency compared to placebo over multiple menstrual cycles, with patients requiring less concurrent analgesia.^[1] Another RCT from the late 1970s reported an 84% response rate for pain relief with mefenamic acid versus 16% for placebo, highlighting its superiority in alleviating spasmodic symptoms.^[87] These early investigations, often involving 50-100 participants per arm, demonstrated pain reductions of up to 70-88% in treated groups relative to baseline or placebo, supporting its approval for short-term use in dysmenorrhea.^[88] Recent pediatric studies have expanded mefenamic acid's role as an antipyretic. A 2025 Indian consensus from pediatricians, informed by multiple RCTs totaling over 700 children, recommends mefenamic acid (4-6.5 mg/kg every 8 hours) for fever in children over 6 months, citing faster onset than paracetamol. For instance, in a randomized study of 180 children, mefenamic acid (8 mg/kg) achieved greater temperature reduction at 2 and 6 hours compared to paracetamol (15 mg/kg) or ibuprofen (10 mg/kg), with effects sustained up to 24 hours (p<0.05).^[8] Similarly, a 2013 prospective trial (n=124) showed mefenamic acid reducing fever more rapidly at 1, 4, and 6 hours versus paracetamol (p<0.05).^[8] Safety profiles from meta-analyses in the 2020s indicate elevated gastrointestinal (GI) risks with mefenamic acid, consistent with other NSAIDs. A network meta-analysis of RCTs for dysmenorrhea ranked mefenamic acid among the safest NSAIDs for adverse events, including low risk of gastrointestinal issues compared to alternatives like indomethacin.^[6] Hepatotoxicity remains rare, with LiverTox reporting isolated cases of acute liver injury, often idiosyncratic and resolving upon discontinuation; typically mild and linked to hypersensitivity.^[16] In special populations, pregnancy data indicate animal studies showing fetal risks but limited human evidence; it is contraindicated in the third trimester due to potential premature closure of the ductus arteriosus, similar to other NSAIDs.^[14] Elderly patients may experience prolonged half-life due to reduced renal clearance, necessitating dose adjustments to avoid accumulation and heightened adverse events.^[89] Off-label exploration includes a 2019 phenotypic screening trial in mice with Schistosoma mansoni infection, where mefenamic acid (100 mg/kg/day for 5 days) reduced worm burden by 82% in patent infections (p<0.001) and also decreased egg production and organomegaly, suggesting antischistosomal potential warranting human trials.^[90] Research gaps persist, including limited long-term (>7 days) efficacy and safety data due to labeling restrictions for short-term use only, and insufficient cardiovascular risk assessments in Asian populations where genetic factors may influence NSAID metabolism.^[16]

Formulation and analytical advances

Recent advances in the formulation of mefenamic acid have focused on improving its solubility, dissolution rate, and patient acceptability, particularly for populations with swallowing difficulties. In 2025, orodispersible tablets (ODTs) were developed using direct compression with croscarmellose sodium as a superdisintegrant, achieving disintegration times as low as 14.5 seconds and near-complete dissolution (99.9%) within 15 minutes.^[91] This approach enhances bioavailability by promoting rapid absorption in the oral cavity and improves compliance, especially in pediatric patients, by eliminating the need for water and masking the drug's bitter taste.^[91] Additionally, continuous antisolvent sonocrystallization has enabled the production of microparticles with controlled sizes of 2.6–3.5 μm, resulting in narrower particle size distributions and improved dissolution profiles compared to unprocessed material (mean size 33.4 μm).^[92] These microparticles maintain the Form I crystal structure while enhancing apparent solubility, potentially doubling bioavailability through better wettability and reduced aggregation.^[92] Prodrug and codrug strategies for mefenamic acid, spanning the 1990s to the 2020s, have emphasized ester derivatives to mitigate gastrointestinal (GI) irritation associated with the parent compound. Mutual prodrugs, such as hydroxyethyl esters and mefenamic-guaiacol esters, demonstrate prolonged half-lives (up to 38 hours in alkaline conditions) and reduced GI toxicity by masking the carboxylic acid group until enzymatic cleavage in vivo.^[93] These modifications retain anti-inflammatory efficacy while improving tolerability, with examples like N-arylhydrazone derivatives showing enhanced permeation across biological membranes.^[93] In production methods, wet milling optimization has advanced continuous manufacturing processes for mefenamic acid, enabling scalable particle size reduction and integration with downstream crystallization steps. A 2025 study utilized design of experiments and simulation to refine wet milling parameters, achieving high yields and consistent polymorph control suitable for industrial-scale operations.^[94] Furthermore, carboranyl analogues synthesized in 2022 via Pd-catalyzed B–N coupling introduce boron clusters, conferring potential for boron neutron capture therapy (BNCT) by accumulating 10B in tumor cells for targeted neutron irradiation.^[95] These analogues exhibit COX-1/COX-2 inhibition (IC50 values of 40 μM and 33 μM, respectively) comparable to mefenamic acid, alongside enhanced cytotoxicity against colon cancer cells.^[95] Analytical techniques have evolved to ensure purity and structural integrity in mefenamic acid formulations. A 2025 liquid chromatography-tandem quadrupole mass spectrometry (LC-TQ-MS/MS) method detects N-nitroso drug substance-related impurities (NDSRI) with a limit of detection (LOD) of 0.005 ng/mL and limit of quantification (LOQ) of 0.01 ng/mL (equivalent to ~0.01 ppm at 1 mg/mL concentration), using positive electrospray ionization and multiple reaction monitoring.^[96] This validates compliance with ICH guidelines for nitrosamine control in tablets and pediatric suspensions.^[96] For conformational analysis, two-dimensional nuclear Overhauser effect spectroscopy (2D-NOESY) in supercritical CO2-DMSO mixtures reveals equilibrium between two conformer groups (A+C and B+D, proportions ~48%/52%), providing insights into solvent-dependent flexibility that aids the design of novel polymorphic forms.^[97] Looking ahead, the discovery of mefenamic acid's dual effects on the cardiac IKs channel (KCNQ1/KCNE1)—potentiation at low concentrations and inhibition at higher ones—suggests opportunities for cardioprotective reformulations targeting arrhythmias like long QT syndrome.^[98] This bidirectional modulation influences pore kinetics and voltage sensor coupling at the extracellular interface, potentially guiding dosage adjustments for safer cardiac applications.^[98] Concurrently, pediatric ODTs address compliance challenges by offering taste-masked, water-free dosing, with formulations achieving rapid disintegration to reduce refusal rates in children.^[91]

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