FAQ’s

• Mefenamic acid is the only NSAID which acts on the E-type prostanoid (EP) receptors in addition to the prostaglandin (PG) synthesis inhibition.
• Additionally, it has inhibitory action on the Nod-like receptor protein-3 (NLRP3) inflammasome.

• Mefenamic acid is indicated for the treatment of fever.
• It is used for managing acute and chronic painful conditions like primary dysmenorrhea, menstrual migraine, post-partum pain, dental pain, post-operative pain, musculoskeletal pain, arthritis, low back pain and spondylitis.
• It has also been found to be effective in menorrhagia.

The recommended dose of Mefenamic acid for adolescents and adults is 250-500 mg three time daily to be administered preferably with or after food.

Mefenamic acid can be safely used and is recommended for children from 06 months of age for the relief of fever and pain. The recommended dose is 4 – 6.5 mg/kg body weight three times daily.

Use of Mefenamic acid is not recommended below the age of 6 months, however it has been evidenced to be effective and safe for the closure of patent ductus arteriosus in preterms and neonates at a 12 hourly dose of 2 mg/kg.

• Mefenamic acid exhibits a dual mode of action acting at both central and peripheral levels. Primarily it inhibits cyclooxygenase (COX) enzyme thus inhibiting PG synthesis. In addition it has the ability to block the EP receptors, thereby blocking the pre-formed PGs as well which makes it unique amongst all the NSAIDs.
• Recent evidences also suggests its action on NLRP3 inflammasome inhibition which is a cellular protein.

Of all the NSAIDs only Mefenamic acid is known to inhibit NLRP3 inflammasome which is responsible for the release of pro-inflammatory cytokines namely IL-1β augmenting its anti-inflammatory action.

Mefenamic acid selectively inhibits the NLRP3 inflammasome and IL-β release by blocking the membrane volume-regulated anion (chloride) channel (VRAC) and volume-modulated transient receptor potential melastatin-related 2 (TRPM2) channels.

• NSAIDs particularly selective COX-2 inhibitors are associated with an increased risk of adverse cardiovascular (CV) events namely myocardial infarction, stroke or thrombotic event.
• Mefenamic acid being a preferential COX inhibitor is less likely to interfere with the COX system thereby presenting a lower CV risk than other NSAIDs. Like all NSAIDs, use of Mefenamic acid should be exercised with caution in patients with a pre-existing CV disease.

• Gastrointestinal adverse events like upper GI ulcers, GI bleeding and perforations are known to be associated with chronic use of NSAIDs particularly non-selective COX inhibitors.
• Mefenamic acid is a preferential COX-2 inhibitor and a recent meta-analysis has reported Mefenamic acid to be the safest NSAID as compared to other NSAIDs in terms of GI safety.

As NSAIDs are associated with increased risk of GI related adverse events, Mefenamic acid should not be used in patients with a history of peptic / duodenal ulcer or GI bleeding.

• Prostaglandins (PGE2 and PGI2) are important in renal function and renal PG synthesis inhibition may lead to decreased blood supply to the nephrons causing acute ischemic renal insufficiency.
• Use of NSAIDs has been associated with dose-dependent renal side effects like acute interstitial renal injury and hematuria.
• During volume depletion, renal PGs are responsible for vasodilation thereby maintaining normal glomerular filtration rate (GFR).
• Renal PG inhibition by NSAIDs compromise normal GFR leading to acute tubular necrosis. However, these side-effects are transient and reversible upon their withdrawal.
• There are no studies of Mefenamic acid affecting renal function in the long term, whether through kidney-mediated processes or others; therefore short-term use of Mefenamic acid is unlikely to lead to renal side effects if adequate hydration is maintained.

• Mefenamic acid is eliminated primarily by the kidneys (urine 66% and feces 20-25%).
• Therefore, use of Mefenamic acid is contraindicated in patients with pre-existing renal disease/renal impairment.

• Under normal physiological conditions the renal blood flow is independent of PG actions and therefore inhibition of PG synthesis by NSAIDs at therapeutic dosages is unlikely to cause nephrotoxicity.
• In conditions such as dehydration, pre-existing renal disease and compromised intravascular volume, the role of PG seems to be significant as a counter regulatory response.
• Thus, inhibition of renal PG synthesis by NSAIDs may decrease renal perfusion leading to acute interstitial nephritis presenting with hematuria.
• As per the evidence, incidence of hematuria with Mefenamic acid is reported to be either an occasional occurrence or less than 1% and is transient in nature.
• In conclusion, if enough hydration is maintained at the beginning of NSAID (Mefenamic acid) therapy, the possibility of potential hematuria can be avoided.

• According to prospective studies, transient serum aminotransferase increases were recorded in about 5% of individuals receiving Mefenamic acid.
• The abnormalities usually resolved even while continuing the drug and without dose modification.
• Rare cases of Mefenamic acid induced liver injury have been reported. The mechanism of Mefenamic acid hepatotoxicity is not known, but is likely to be idiosyncratic hypersensitivity.
• In conclusion, possible rare clinically apparent liver injury is associated with Mefenamic acid.

• Mefenamic acid is known to be metabolized by cytochrome enzyme and excreted through hepatic route by less than 20%.
• Therefore it is liable to get accumulated in patients with hepatic impairment.
• Since, there are no clinical studies in mild-moderate hepatic dysfunction, therefore it is advisable for dose reduction in such cases.
• However, as per clinical studies, Mefenamic acid should be avoided in patients with advance liver disease.

• Seizures occur when there is an excess of excitatory activity (glutamate) relative to inhibitory activity [gamma-aminobutyric acid (GABA)].
• Preclinical studies indicate that Mefenamic acid reduces glutamate-evoked excitotoxicity and activates GABAA receptors supporting its neuroprotective action.
• Preclinical studies on the effect of Mefenamic acid on seizures have found it to be neuroprotective at doses of 20 to 40 mg/kg, whereas at 60 mg/kg and above toxicity levels it can induce seizures.
• Literature also reveals dose-related CNS toxicity, especially convulsions with an overdose of >3.5 gm of Mefenamic acid.
• The above indicates that at therapeutic doses, Mefenamic acid has a protective action on the CNS.

• Recent clinical evidence suggests significantly increased levels of IL-1β and NLRP3 inflammasome in children with febrile seizures (FS)
• Since, Mefenamic acid is known to inhibit NLRP3 inflammasome and thereby decrease IL-β release, it may help in controlling FS. However, further exploration is required to corroborate the same.

Elderly patients are associated with declining physiological functions and comorbid conditions thus, it is advisable to start Mefenamic acid with lower dosage.

• Pregnancy category C
• Studies have suggested an increased risk of miscarriage and fetal cardiac malformations with use of NASIDs in early pregnancy. Thus, Mefenamic acid should not be used during the first trimester.
• Since there are limited studies with no any major adversities reported, it can be given in the second trimester depending on the benefit-risk ratio.
• Exposure to Mefenamic acid after 30 weeks of gestation has been associated with an increased risk of premature closure of the ductus arteriosus and oligohydramnios; therefore, its use after 30 weeks or more is usually not recommended unless prescribed by the treating physician.

The amount of Mefenamic acid excreted in the breast milk is clinically non-significant therefore the American Academy of Pediatrics classifies it as usually compatible with breastfeeding.

• COX-2-selective NSAIDs inhibit the synthesis of prostacyclin (PGI2) but not thromboxane A2 (TXA2), which leads to an increase in platelet aggregation.
• On the contrary, non-selective COX-2 NSAIDs block TXA2, which reduces platelet activation and increases bleeding.
• Mefenamic acid being a preferential COX inhibitor, has a balanced PG synthesis (PGE2, PGF2α, PGI2) inhibition, degranulates platelets and activates its aggregation, causing hemostasis.
• However, patients on anti-coagulants or platelet disorders should be monitored.

• Mefenamic acid has been shown through pre-clinical studies to have antiviral property.
• In-vitro studies have confirmed significant reduction in viral replication of dengue virus (DENV -infected cells) with Mefenamic acid
• Preclinical studies have demonstrated its antiviral effectiveness against Chikungunya virus (CHIKV) to be due to viral envelop interactions leading to virus inactivation.

• Mefenamic acid has an established antipyretic effect and is effective is reducing fever associated with viral/dengue infection.
• It also has an anti-inflammatory action which is augmented with its NLRP3 inflammasome inhibitory property.
• NLRP3 inflammasome have been found to be implicated in aggravating the pathophysiology of viral/dengue infection.
• Additionally, due to its antiviral property, Mefenamic acid may help reduce the viral load and accelerate the recovery.

• Though NSAIDs are known to induce bronchospasm in asthmatic patients, clinical studies of Mefenamic acid have found it to possess anti-bradykinin action which leads to bronchodilation.
• Evidence have found that Mefenamic acid led to an increase in forced expiratory volume (FEV1) in asthmatic individuals by 45% to 80%.
• Furthermore, patients with neutrophilic asthma were found to have elevated expression of NLRP3 inflammasome and IL-1β.
• The above indicates that Mefenamic acid may be beneficial in asthmatic patients.

• Recent studies have used Mefenamic acid in the dose of 500 mg thrice daily for 3 months in post-COVID syndrome and was found to be effective and safe.
• The above indicates that Mefenamic acid may not have any long term safety concerns.

• The maximum recommended dose of Mefenamic acid is 1500 mg/day in divided doses.
• However, the toxic dose has been determined at 3.5 gm (40 mg/kg)
• According to British National Formulary, the toxicity threshold is approximately 2 times (1.9 times) the maximum recommended daily dose.

• p-Cresol, a phenolic compound, is a highly protein-bound uremic toxin that is mainly originated from intestinal microbial metabolism of tyrosine and phenylalanine.
• Once formed, p-cresol undergoes extensive first-pass metabolism in the formation of p-cresol sulfate and p-cresol glucuronide.
• Sulfotransferases (SULT) enzymes in liver are responsible for catalyzing p-cresol sulfate & SULT1A1 are the primary enzymes responsible for formation of p-cresol sulfate.
• Mefenamic acid has shown to inhibit SULT1A1 in in-vitro studies and thus reduce the formation of p-cresol sulfate (pCS). This novel findings suggest that mefenamic acid can be potentially utilized therapeutically to attenuate pCS-associated toxicities.