Sulindac
Sulindac is a nonsteroidal anti-inflammatory drug (NSAID) of the indene acetic acid class, developed by Merck & Co. and marketed under the brand name Clinoril for the symptomatic relief of pain and inflammation associated with osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and acute subacromial bursitis or supraspinatus tendinitis.[1][2] As a prodrug, sulindac is administered as an inactive sulfoxide that undergoes hepatic bioactivation to its active sulfide metabolite, which inhibits cyclooxygenase (COX) enzymes, thereby reducing prostaglandin synthesis responsible for inflammation and pain.[3] This pharmacokinetic profile contributes to its enterohepatic recirculation and potentially lower renal toxicity compared to some other NSAIDs, though it shares common class risks including gastrointestinal ulceration and cardiovascular events.[4][5] Notably, sulindac has been studied for chemopreventive effects in colorectal neoplasia, with evidence from clinical trials indicating polyp reduction in familial adenomatous polyposis (FAP) patients upon treatment cessation and recurrence, though it is not approved for this indication.[6][7] Approved by the FDA in the late 1970s, sulindac remains available by prescription for short-term and chronic use in arthritis management, balancing efficacy against NSAID-related adverse effects.[8][2]Pharmacology
Mechanism of action
Sulindac is a prodrug that requires metabolic activation in the liver via reduction of its sulfoxide group to form the active metabolite sulindac sulfide, which is responsible for its pharmacological effects.[2] This biotransformation occurs primarily through cytosolic enzymes, rendering sulindac itself pharmacologically inactive until converted.[9] An alternative oxidation pathway produces sulindac sulfone, which lacks significant cyclooxygenase inhibitory activity.[2] The primary mechanism of action of sulindac sulfide involves reversible, nonselective inhibition of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, thereby suppressing the synthesis of prostaglandins and thromboxanes from arachidonic acid.[2] [9] This reduction in prostaglandin levels mediates the drug's anti-inflammatory, analgesic, and antipyretic properties by decreasing sensitization of peripheral nociceptors and inhibiting inflammation at sites of tissue injury.[10] COX-1 inhibition contributes to effects on gastric mucosa and platelet aggregation, while COX-2 inhibition predominates in inducible inflammatory responses.[2] Although the precise molecular interactions are not fully elucidated, sulindac sulfide binds to the active sites of COX enzymes, preventing substrate access and downstream prostanoid production, consistent with the general class of nonsteroidal anti-inflammatory drugs (NSAIDs).[1] Unlike irreversible COX inhibitors such as aspirin, sulindac's effects are reversible, allowing recovery of enzyme function upon drug clearance.[9] Experimental studies indicate that sulindac sulfide exhibits greater potency against COX-1 compared to COX-2, though clinical efficacy reflects combined inhibition.[11]Pharmacokinetics
Sulindac, an inactive prodrug, is rapidly absorbed from the gastrointestinal tract after oral administration, achieving approximately 90% bioavailability unaffected by antacids containing aluminum and magnesium hydroxides.[9][2] The extent of absorption is comparable between tablet and solution formulations.[2] Sulindac exhibits high plasma protein binding, exceeding 93% for the parent compound and reaching 98% for the active sulfide metabolite, primarily to albumin.[9] It distributes widely, including penetration of the blood-brain and placental barriers.[2] Metabolism occurs primarily in the liver via the sulfoxide moiety, involving reversible reduction to the pharmacologically active sulindac sulfide (responsible for COX inhibition and anti-inflammatory effects) and irreversible oxidation to the inactive sulindac sulfone.[9][2] The sulfide metabolite undergoes enterohepatic recirculation, contributing to prolonged exposure.[9] Elimination follows biotransformation, with approximately 50% of the dose excreted in urine (mainly as conjugated sulfone metabolite) and 25% in feces (as sulfone or sulfide forms).[2] The mean plasma half-life is 7.8 hours for sulindac and 16.4 hours for the sulfide metabolite; renal clearance averages 68 mL/min in healthy adults.[9][2] In special populations, pharmacokinetics warrant caution: hepatic impairment may necessitate dose reduction due to altered metabolism, while renal insufficiency (eGFR <60 mL/min/1.73 m²) requires monitoring or avoidance, as sulindac disposition remains altered despite studied parameters in end-stage disease.[2] No significant pharmacokinetic differences due to race or age have been identified, though pediatric data are lacking.[12]Medical uses
Approved indications
Sulindac, a nonsteroidal anti-inflammatory drug (NSAID), is approved by the U.S. Food and Drug Administration (FDA) for acute or long-term symptomatic relief of osteoarthritis, rheumatoid arthritis (excluding patients classified as Functional Class IV by the American Rheumatism Association, indicating severe incapacity), ankylosing spondylitis, acute painful shoulder (specifically acute subacromial bursitis or supraspinatus tendinitis), and acute gouty arthritis.[1] These approvals emphasize its role in reducing pain, inflammation, and associated symptoms rather than altering disease progression.[13] In osteoarthritis, sulindac addresses joint pain and stiffness from cartilage degradation, typically used when other analgesics prove insufficient.[1] For rheumatoid arthritis, efficacy is supported by clinical trials showing improvements in joint tenderness and swelling, though long-term use requires monitoring due to potential cardiovascular and gastrointestinal risks inherent to NSAIDs.[5] Ankylosing spondylitis approval targets spinal and sacroiliac inflammation, with dosing aimed at maintaining mobility.[1] Acute indications include gouty arthritis, where sulindac mitigates severe joint flares from uric acid crystal deposition, often as an alternative to other anti-inflammatories.[14] Similarly, for acute shoulder conditions like subacromial bursitis or supraspinatus tendinitis, it provides short-term relief of localized pain and inflammation, with recommendations to limit duration to minimize adverse effects.[1] All uses mandate the lowest effective dose for the shortest period to balance benefits against risks such as gastrointestinal ulceration or renal impairment.[13]Off-label and investigational uses
Sulindac has been used off-label for the management of colorectal polyps in patients with familial adenomatous polyposis (FAP), a genetic condition predisposing individuals to numerous adenomatous polyps and high risk of colorectal cancer. In a 1993 randomized trial involving FAP patients post-colectomy, sulindac at 400 mg daily reduced the mean number of rectal polyps from 18.5 to 8.5 after one year and the size from 3.3 mm to 2.2 mm, though effects were incomplete and polyps recurred upon discontinuation.[15] Long-term administration (up to 9 years) at 150-200 mg twice daily has demonstrated sustained reduction in polyp number and prevention of higher-grade adenoma recurrence in retained rectal segments, with endoscopic surveillance recommended due to incomplete regression.[16] Combination therapy with sulindac and erlotinib resulted in a 69% reduction in colorectal polyp burden after 6 months in FAP patients, outperforming placebo in a phase II trial.[17] However, a phase III trial combining sulindac with eflornithine did not show superior prevention of disease progression compared to either agent alone.[18] Investigational applications of sulindac extend to cancer chemoprevention and treatment, leveraging its non-cyclooxygenase-dependent mechanisms such as induction of apoptosis and inhibition of cell proliferation. In preclinical models, sulindac sulfide metabolite has inhibited growth of colon cancer cells independent of COX inhibition and enhanced oxidative stress-induced killing in colon and lung cancer cells.[19][20] For prostate cancer, sulindac derivatives induced apoptosis in cell lines via COX-independent pathways.[21] A phase II trial explored sulindac in acute myeloid leukemia (AML), hypothesizing COX inhibition could target leukemic stem cells, though results remain unpublished as of 2025.[22] Sulindac combined with tamoxifen was investigated for desmoid tumors in FAP patients, aiming to block tumor growth enzymes.[23] Recent studies suggest potential synergy with chemotherapeutics in prostate cancer models, reducing proliferation and invasion.[24] Despite promising preclinical data, clinical efficacy for these indications requires further validation through randomized trials, given sulindac's primary approval for inflammatory conditions and associated cardiovascular risks.[2]Safety and adverse effects
Common adverse effects
Gastrointestinal disturbances represent the most frequent adverse effects associated with sulindac use, occurring in up to 10% of patients for abdominal pain specifically, with other symptoms such as dyspepsia, nausea, diarrhea, constipation, flatulence, anorexia, and cramps reported in 3-9% of cases.[1] These effects are milder and less frequent compared to aspirin in clinical trials for osteoarthritis and rheumatoid arthritis, though they remain a primary reason for discontinuation in some patients.[1] Central nervous system effects, including dizziness, headache, and nervousness, occur in 3-9% of users, while dermatologic reactions such as rash and pruritus are similarly prevalent at 3-9%.[1] Tinnitus and peripheral edema are also noted as common, though specific incidence rates vary across studies.[2] Sulindac's prodrug nature, requiring hepatic bioactivation, may contribute to a relatively lower overall gastrointestinal toxicity profile versus other nonsteroidal anti-inflammatory drugs, but empirical data from controlled trials confirm these symptoms as dose-dependent and more pronounced with long-term use.[1][2]- Gastrointestinal: Abdominal pain (10%), dyspepsia (3-9%), nausea (3-9%), constipation (3-9%), diarrhea (3-9%).
- Neurological: Headache (3-9%), dizziness (3-9%).
- Dermatological: Rash (3-9%).
- Other: Tinnitus, edema.[1][2]