Introduction
Mefenamic acid is a nonsteroidal anti-inflammatory drug (NSAID) belonging to the fenamate class. It is commonly prescribed for its analgesic, anti-inflammatory, and antipyretic properties. First approved by the FDA in 1967, mefenamic acid remains a therapeutic option primarily for short-term management of mild to moderate pain, particularly menstrual pain (dysmenorrhea).
Mechanism of Action
Mefenamic acid exerts its therapeutic effects through reversible inhibition of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes. This inhibition prevents the conversion of arachidonic acid to prostaglandin precursors (prostaglandin G2 and prostaglandin H2), thereby reducing the synthesis of prostaglandins, thromboxanes, and prostacyclins. These mediators play key roles in pain perception, inflammation, and fever. The drug's particular affinity for uterine prostaglandin synthesis makes it especially effective for menstrual pain management.
Indications
- Primary dysmenorrhea: Short-term treatment of pain associated with menstrual periods
- Mild to moderate pain: Management of acute pain when therapy will not exceed 7 days
- Off-label uses: Some clinicians may prescribe for migraine headaches, osteoarthritis, and rheumatoid arthritis, though these are not FDA-approved indications
Dosage and Administration
Adults:- Dysmenorrhea: 500 mg as initial dose, followed by 250 mg every 6 hours as needed
- Mild to moderate pain: 500 mg as initial dose, then 250 mg every 6 hours as needed
- Maximum daily dose: 1,250 mg
- Duration: Not to exceed 7 days of continuous therapy
- Renal impairment: Use with caution; contraindicated in advanced renal disease
- Hepatic impairment: Use with caution; consider reduced dosing
- Elderly: Start with lowest effective dose due to increased risk of adverse effects
- Pediatrics: Safety and effectiveness not established for children under 14 years
- Should be taken with food or milk to minimize gastrointestinal upset
- Tablets should be swallowed whole with adequate fluid
Pharmacokinetics
Absorption: Rapidly absorbed from the gastrointestinal tract with peak plasma concentrations occurring within 2-4 hours post-administration. Food may delay absorption but does not significantly affect bioavailability. Distribution: Highly protein-bound (>90%), primarily to albumin. Volume of distribution is approximately 1.06 L/kg. Crosses placenta and is excreted in breast milk. Metabolism: Extensively metabolized in the liver via cytochrome P450 enzymes, primarily CYP2C9. Major metabolites include 3-hydroxymethyl mefenamic acid and 3-carboxymefenamic acid. Elimination: Primarily excreted in urine (52-67%) as metabolites, with fecal elimination accounting for 20-25% of the dose. Elimination half-life is approximately 2 hours.Contraindications
- Hypersensitivity to mefenamic acid, other NSAIDs, or any component of the formulation
- History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs
- Peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery
- Third trimester of pregnancy
- Active peptic ulcer disease or gastrointestinal bleeding
- Advanced renal impairment or progressive renal disease
- Severe hepatic impairment or active liver disease
Warnings and Precautions
Cardiovascular Risk: NSAIDs may increase the risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use and in patients with cardiovascular disease or risk factors. Gastrointestinal Risk: NSAIDs cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Renal Effects: Long-term administration may result in renal papillary necrosis and other renal injury. Use with caution in patients with renal impairment, heart failure, hepatic impairment, those taking diuretics or ACE inhibitors, and the elderly. Hepatic Effects: May cause hepatic toxicity. Monitor patients for signs and symptoms of liver dysfunction. Hematological Effects: May inhibit platelet aggregation and prolong bleeding time. Pregnancy: Avoid use during third trimester due to risk of premature closure of ductus arteriosus.Drug Interactions
- Anticoagulants (warfarin): Increased risk of bleeding
- Aspirin: Decreased mefenamic acid efficacy; increased GI adverse effects
- ACE inhibitors/ARBs: Reduced antihypertensive effect; potential renal impairment
- Diuretics: Reduced diuretic and antihypertensive effects; potential renal impairment
- Lithium: Increased lithium levels and toxicity
- Methotrexate: Increased methotrexate levels and toxicity
- Cyclosporine: Increased nephrotoxicity risk
- Corticosteroids: Increased GI ulceration risk
- SSRIs/SNRIs: Increased bleeding risk
- CYP2C9 inhibitors (fluconazole, amiodarone): May increase mefenamic acid levels
Adverse Effects
Common (≥1%):- Gastrointestinal: Nausea, dyspepsia, abdominal pain, diarrhea, constipation, flatulence
- Central nervous system: Dizziness, headache, nervousness
- Dermatological: Rash, pruritus
- Other: Edema, tinnitus
- Gastrointestinal bleeding, ulceration, or perforation
- Cardiovascular thrombotic events
- Renal impairment or failure
- Hepatic toxicity
- Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)
- Anaphylactoid reactions
- Hematologic disorders (anemia, leukopenia, thrombocytopenia)
- exacerbation of asthma in aspirin-sensitive patients
Monitoring Parameters
- Efficacy: Pain relief, functional improvement
- Renal function: Serum creatinine, BUN, especially in at-risk patients
- Hepatic function: Liver enzymes periodically with long-term use
- Hematologic: CBC if signs of bleeding or infection occur
- Gastrointestinal: Signs and symptoms of bleeding or ulceration
- Cardiovascular: Blood pressure monitoring, especially in hypertensive patients
- Fluid retention: Monitor for edema and weight gain
Patient Education
- Take with food or milk to reduce stomach upset
- Do not exceed prescribed dosage or duration of treatment
- Report any signs of gastrointestinal bleeding (black stools, vomiting blood, abdominal pain)
- Report signs of allergic reactions (rash, itching, swelling, difficulty breathing)
- Be aware of potential dizziness or drowsiness; avoid driving or operating machinery if affected
- Avoid concurrent use of other NSAIDs, including over-the-counter products
- Inform all healthcare providers of mefenamic acid use, especially before surgery
- Report any unusual bruising or bleeding
- Monitor for signs of cardiovascular events (chest pain, shortness of breath, weakness)
- Notify physician if pregnancy is suspected or planned
- Store at room temperature away from moisture and heat
References
1. Drugs.com. Mefenamic Acid Monograph. 2023. 2. Lexicomp Online. Mefenamic Acid: Drug Information. Wolters Kluwer Clinical Drug Information, Inc. 2023. 3. Micromedex Solutions. Mefenamic Acid. IBM Watson Health, 2023. 4. FDA Prescribing Information: Ponstel (mefenamic acid). 2022. 5. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's: The Pharmacological Basis of Therapeutics. 13th ed. McGraw-Hill Education; 2017. 6. American College of Obstetricians and Gynecologists. Dysmenorrhea: Painful Periods. ACOG Patient Education, 2022. 7. Laine L, et al. NSAID-associated gastrointestinal toxicity: new insights into risk management and prevention. Am J Gastroenterol. 2021;116(5):899-913. 8. Harirforoosh S, et al. Adverse effects of nonsteroidal antiinflammatory drugs: an update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci. 2022;25:68-85.