Continuing Education Activity

Sulindac is a medication used as an anti-inflammatory and analgesic agent. It is in the class of non-steroidal anti-inflammatory drugs (NSAIDs). It is administered for the acute treatment of musculoskeletal shoulder pain,  acute gouty arthritis, wear and tear osteoarthritis, and inflammatory arthritic conditions, including both rheumatoid arthritis and ankylosing spondylarthritis. For the individual patient, the lowest effective dose and shortest duration are recommended for initial treatment. This activity reviews the indications, contraindications, mechanism of action, adverse events, and other key elements of sulindac therapy in the clinical setting, which is helpful for clinicians. It also highlights the role of the interprofessional team in managing diseases when using sulindac.

Objectives:

• Identify the mechanism of action of sulindac.
• Describe the adverse effects of sulindac.
• Review the appropriate monitoring for sulindac.
• Summarize interprofessional team strategies for improving care coordination and communication to advance sulindac and improve outcomes.

Indications

Sulindac is a non-steroidal anti-inflammatory drug (NSAID). Like other NSAIDs, sulindac is used primarily to treat conditions characterized by acute or chronic inflammation. However, as per the manufacturer, the indications are broad.

• Sulindac is indicated for a short duration for acute treatment of musculoskeletal shoulder pain (acute subacromial bursitis/supraspinatus tendinitis).
• Sulindac also has FDA approval for other forms of arthritis, including wear and tear osteoarthritis and inflammatory arthritic conditions, including rheumatoid arthritis and ankylosing spondylarthritis.[1]
• Sulindac also has approval for use in the treatment of acute gouty arthritis.[1]
• Familial adenomatous polyposis (FAP) is a condition characterized by pediatric adenomas in the lower gastrointestinal tract and frequently results in colonic adenocarcinomas. Several chemopreventive strategies have been the object of research in an attempt to delay the development of colonic adenomas and subsequent adenocarcinomas. Sulindac has been one of the most extensively studied drugs used in this chemopreventative strategy.[2]

Mechanism of Action

Sulindac is a non-selective COX (cyclooxygenase) inhibitor that reversibly inhibits both COX-1 and COX-2 enzymes. The COX pathways are one of the two main pathways involved in arachidonic acid metabolism (the other involves leukotriene synthesis). The COX pathway results in the synthesis of both prostaglandins and thromboxanes. These are both critical mediators of inflammation and platelet aggregation.[3]

Prostaglandin E2 (PGE2) is often a trigger of the cardinal signs of inflammation: rubor (erythema), calor (warmth), tumor (swelling), and dolor (pain)- this is accomplished through increased blood flow and vascular permeability. PGE2 also triggers systemic fever through a hypothalamic-mediated reaction. Sulindac and other NSAIDs are responsible for inhibiting the synthesis of this prostaglandin and others. Sulindac exists as a pro-drug that activates upon initial metabolism. Its metabolism forms both sulfide and sulfone derivatives; the sulfide derivative is the one that is responsible for inhibiting prostaglandin synthesis.[4][5]

Pharmacokinetics

Absorption: Sulindac tablets have a similar extent of absorption compared to sulindac solution. There is no information regarding food's effect on sulindac absorption. Antacids containing aluminum hydroxide 225 mg and magnesium hydroxide 200 mg per 5 mL do not change absorption extent.

Distribution: Sulindac, sulfone, and sulfide metabolites are highly protein bound (more than 90%), mainly to albumin.

Metabolism: Sulindac goes through two major biotransformations of its sulfoxide moiety: reduction to the pharmacologically active sulfide metabolite and oxidation to the inactive sulfone metabolite.

Elimination: Approximately half of the administered dose of sulindac is eliminated through urine with the conjugated sulfone metabolite. Approximately 25% of the administered dose of sulindac is excreted in the feces, the majority as the sulfone or sulfide metabolites. The mean plasma effective half-life for sulindac and its active sulfide metabolite is 7.8 hours and 16.4 hours, respectively.

Administration

For the individual patient, the lowest effective dose and shortest duration are recommended for initial treatment. Sulindac is available as 150 mg and 200 mg oral tablets. The maximum recommended daily dose is 400 mg. Sulindac is recommended to take with food or milk to decrease GI side effects in adults and pediatric patients. Healthcare providers should carefully consider the potential risk to the benefit of sulindac and other relevant treatment options before determining to use the sulindac therapy option. 

Osteoarthritis, Rheumatoid Arthritis, and Ankylosing Spondylitis

The initial recommended dose of sulindac is 150 mg twice a day. This dose can be increased or decreased based on the individual patient's response. The dose can be increased up to 400 mg daily. Half of the patient population may expect a prompt response within one week of treatment; other patients may require prolonged treatment.[6][7]

Acute Supraspinatus Tendinitis/ Subacromial Bursitis (Acute Painful Shoulder)

The initial recommended dose of sulindac is 200 mg twice a day. This dose can be increased or decreased based on the individual patient's response. The dose can be increased up to 400 mg daily. An adequate response may be achieved from 7 to 14 days of therapy.[8]

Acute Gouty Arthritis

The initial recommended dose of sulindac is 200 mg twice a day. This dose can be increased or decreased based on the individual patient's response. The dose can be increased up to 400 mg daily. An adequate response may be achieved within seven days of therapy.[9] 

Specific Patient Population

Pregnancy Considerations

NSAID treatment during pregnancy can lead to lower amniotic fluid and may cause complications like impaired lung maturation and limb contractures in newly born babies. However, if a healthcare provider likes to use NSAIDs during the 20 and 28 weeks of pregnancy, they should consider using the lowest effective dose for the shortest duration possible. Using sulindac can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction, and, in some cases, neonatal renal impairment. Therefore, FDA recommends avoiding sulindac use at about 30 weeks of gestation and later in pregnancy.

Breastfeeding Women

It is unknown if sulindac is present in breast milk. Some NSAID agents with established safety data and short half-lives are considered compatible with lactating patients to treat rheumatic and musculoskeletal diseases. Due to some potential side effects of sulindac in the breastfeeding infant, the manufacturer recommends discontinuing treatment or breastfeeding based on risk-benefit assessments.[10][11]

Hepatic Impairment

Use sulindac with caution and monitor treatment closely in patients with hepatic impairment. Reduction of dose may be needed due to extensive metabolism in the liver.[12]

Renal Impairment

Patients with impaired renal function should be used medication with caution and monitor treatment closely. Reduction of dose may be needed in patients with advanced renal disease.

• eGFR 30-60 mL/minute/1.73m: Discontinue the treatment temporarily in patients with acute kidney diseases.
• eGFR LT 30 mL/minute/1.73m: Avoid treatment.

Adverse Effects

Prostaglandins and thromboxanes have critical functions throughout the body. Unfortunately, the wide range of functions results in a host of side effects for NSAIDs like sulindac. Blood vessels, the gastrointestinal (GI) tract, and kidneys are a few examples of critical organ systems impacted by sulindac.

• Sulindac is commonly associated with nausea and vomiting, stomach pain, indigestion, diarrhea, constipation, gas, anxiety, dizziness, tinnitus, and urticaria.
• The most common and severe side effect of NSAID use involves ulceration of the GI tract, as GI mucosa appears to be protected by various prostaglandins. Sulindac is commonly thought to have associations with lower rates of GI-related complications when compared to other non-selective NSAIDs; however, this has come into question, and the GI side effects related to NSAID use appear to be primarily mediated through COX-1, as COX-2 selective NSAIDs are associated with lower risks of GI complications. These side effects become exacerbated by the simultaneous use of alcohol and or steroids.[13]
• Sulindac also correlates with renal side effects. Certain prostaglandins are involved in dilating the afferent arteriole- inhibition of this prostaglandin-mediated mechanism may result in a reduced GFR, thus, the risk of acute kidney injury. Sulindac and other NSAIDs may also be nephrotoxic and may induce renal papillary necrosis and interstitial nephritis. This condition may become exacerbated with the simultaneous use of other nephrotoxic agents.[14][15]
• Sulindac is associated with various critical adverse effects, including changes in vision, hepatoxicity, pancreatitis, anemia, and steven-johnson syndrome.[16]

Contraindications

• Per the manufacturer, there are few absolute contraindications to the use of sulindac. The first is a previous hypersensitivity reaction to sulindac or other NSAIDs. NSAID hypersensitivity can present in a variety of ways.[15]
  • It can result in chronic respiratory disease because of the formation of nasal polyps.
  • Cutaneously it can present with urticaria and angioedema, and in severe instances, it can even result in generalized anaphylaxis.
• The other absolute contraindication is in patients in status post coronary artery bypass graft (CABG) operations.

Box Warnings

• NSAIDs increase the risk of serious and fatal cardiovascular thrombotic events, including stroke and myocardial infarction. This risk can occur in an early phase of treatment and may increase with the duration of administration.
• NSAIDs increase the risk of serious and fatal gastrointestinal bleeding, ulceration, and perforation of the stomach or intestines. These adverse events may occur at any time while using and without warning symptoms. Senior adults are at higher risk of serious gastrointestinal events.

Cautions/Warnings

• Sulindac can increase the risk of hypertension or exacerbate existing hypertension.[17]
• It increases the risk of hospitalizations for patients with heart failure.[18]
• Cholestatic hepatitis cases are reported in some patients. Therefore, if abnormal liver tests persist or worsen, clinical signs and symptoms consistent with liver disease develop, or systemic manifestations occur (e.g., eosinophilia, rash, etc.), sulindac should be discontinued.[19]
• Chronic use of NSAIDs is linked with renal papillary necrosis and other renal injuries. Therefore, caution must be exercised in patients with heart failure, impaired renal function, liver dysfunction, volume-depleted patients, those taking diuretics and ACE inhibitors, and the elderly.[17][20]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been observed in patients taking sulindac, so discontinue the use if any signs or symptoms of DRESS develops.[21]

Monitoring

Sulindac use, as is the case with other NSAIDs, does not involve any routine monitoring. No regular blood work is necessary; however, it is essential to note that sulindac is not free from toxic side effects. Adhering to the dosing regimen is critical in preventing some of the side effects discussed above.[22]

• If a patient develops signs of anemia, have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.[23]
• If pancreatitis develops while taking sulindac, monitor closely with appropriate laboratory studies (e.g., serum and urine amylase, amylase/creatinine clearance ratio, electrolytes, serum calcium, glucose, lipase, etc.[24]
• Patients with hepatic insufficiency need to be monitored closely.
• Pregnant women who use sulindac for more than 48 hours between 2 and 30 weeks of gestation should be monitored for oligohydramnios.[25]
• Patients on long-term treatment should have their CBC and chemistry profile checked periodically since sulindac might cause unexpected severe GI bleeding and ulcerations.

Toxicity

It is essential to note that sulindac toxicity is rare; few cases are reported in the literature. It is also important to note that though sulindac is an NSAID, the toxicity does not present similarly to salicylate (aspirin) toxicity with metabolic acidosis, respiratory alkalosis, and tinnitus. Cases in the literature have demonstrated hepatic and renal toxicity associated with sulindac overdose; a case of granulocytosis has also been shown secondary to sulindac toxicity. One of the cases with hepatorenal toxicity further resulted in ischemic skin changes and ulceration.[26][27]

Since there have been exceedingly few cases of sulindac toxicity reported, many of the implications of overdose have not had a thorough investigation. Other research has demonstrated the utility of activated charcoal in the acute treatment of sulindac toxicity. Charcoal can help minimize absorption and some of the later sequelae associated with the drug's toxicity. However, other studies have demonstrated that once the drug has been in the system, proper treatment protocol involves supportive care, which includes aggressive hydration, fluid replacement, and hemodialysis in some instances.[26]

Enhancing Healthcare Team Outcomes

NSAIDs like sulindac are a common therapy for patients with arthritis, spondylitis, and tendinitis. Clinicians should be vigilant while prescribing sulindac, as it has few long-term and toxic adverse effects. Nurses should understand the signs and symptoms of toxicities thoroughly and counsel the patients on the importance of adhering to scheduled dosing regimens. Pharmacists should check the dose, verify the appropriateness of the treatment with sulindac, and report to the clinicians any concerns. Nurses can counsel the patient and monitor for these adverse events, reporting to the prescriber if they note any concerns. All healthcare team members should be able to implement treatment protocols rapidly in the case of emergencies to improve patient care. Sulindac therapy needs an interprofessional healthcare team, including clinicians, specialists, specialty-trained nurses, and pharmacists, collaborating across disciplines to achieve optimal patient outcomes. [Level 5]