Indomethacin

Article Author:
Akul Munjal
Article Editor:
Abdallah Allam
Updated:
3/29/2020 10:13:17 AM
PubMed Link:
Indomethacin

Indications

Indomethacin is a potent nonsteroidal anti-inflammatory drug (NSAID) that is very versatile. Its utility lies primarily in its ability to function as an antipyretic, anti-inflammatory, analgesic agent. 

The Food and Drug Administration (FDA) approved the use of indomethacin for several disease processes. Clinicians can use indomethacin in the treatment of rheumatoid arthritis (RA); however more effective disease-modifying anti-rheumatic agents (DMARDs) have demonstrated greater effectiveness in halting the progression of RA; thus, indomethacin is rarely used in isolation, but rather often in combination with agents such as adalimumab, etanercept, infliximab, methotrexate, etc. Ankylosing spondylitis is a form of inflammatory arthritis primarily impacting the axial skeleton: one of the primary manifestations involves spinal fusion and rigidity. The disease primarily impacts males, and more than 90% of patients with the condition test positive the HLA-B27 haplotype. Clinicians often use indomethacin in conjunction with DMARDs and physical therapy in the treatment of ankylosing spondylitis. Osteoarthritis (OA), a noninflammatory type of arthritis characterized by joint stress from "wear and tear," can often be effectively treated with indomethacin. It is important to note that while indomethacin and other NSAIDs can be very effective in the treatment of OA, first-line treatment involves acetaminophen. Bursae are synovial fluid-filled sacs that lubricate joints- bursitis involves bursa inflammation. Bursitis can present with erythematous, painful joints. This pathology is also treatable with indomethacin. Gouty arthritis involves the deposition of urate crystals in joints- this presents with an acute erythematous joint- often the hallux and may also respond to indomethacin therapy. A patent ductus arteriosus is a non-cyanotic heart defect that results in left to right shunting. The clinical severity of the condition depends on several factors; however, often, it needs to be closed, and indomethacin can help accomplish this.[1][2][3]

Although the FDA approved the use of indomethacin for a variety of disease processes, other processes are treatable with indomethacin that do not have FDA approval. These conditions include but are not limited to, the following. Aphthous stomatitis is a pathology that is defined by frequent and recurrent oral ulcerations. Often these ulcers can be painful, and the cause of the ulcers is unknown. Treatment for his condition is symptomatic, and indomethacin is a therapeutic option. An ERCP is a procedure involving the insertion of an endoscope into the duodenum to visualize various portions of the GI tract. It can be useful in the removal of gallstones from the common bile duct; however, it correlates with a risk of post-procedural pancreatitis; indomethacin can mitigate this risk. Plantar fasciitis is an orthopedic pathology that involves pain on the plantar (heel) surface of the foot. Walking and bending may aggravate the condition, but indomethacin can help minimize the symptoms of this pathology. Indomethacin can also alleviate back pain. Indomethacin has also been shown to have possible anti-tumor effects and may potentiate the effects of various neoplastic agents.[4][5]

Mechanism of Action

Indomethacin is an NSAID and functions like most other NSAIDs. The effects of indomethacin occur because it inhibits the synthesis of prostaglandins. Prostaglandins are produced primarily by cyclooxygenase (COX) enzymes, and prostaglandins are critical mediators of inflammation, fever, and pain. They are also involved in maintaining renal function, GI mucosa, and platelet activity-inhibition of this enzyme by NSAIDs may explain some of these drugs' side effects. COX-1 has involvement in the production of thromboxane A2 (a critical mediator of platelet aggregation) - thus, inhibition of this enzyme is likely responsible for the anti-platelet effects of NSAIDs. COX-1 appears to be responsible for the maintenance of GI mucosa, while COX-2 seems to be upregulated in inflamed tissues, and responsible for the production of prostaglandins responsible for inflammation, fever, and pain. Although COX-2 selective NSAIDs may have fewer GI associated side effects, indomethacin is a non-selective COX inhibitor.[6][7]

Indomethacin has anti-viral activity; it down-regulates viral replication, and literature showed its anti-viral activity against rhabdovirus vesicular stomatitis virus, hepatitis B virus, and coronavirus.[8][9][10] No data supports its anti-viral activity against COVID-19 at present.

Administration

As a common drug, indomethacin has many methods of administration. Indomethacin can be administered orally in both immediate and extended-release formulations. An oral suspension is also available. Indomethacin administration can also be via an IV injection. A rectal suppository of indomethacin is also available.[11][12]

Adverse Effects

As a commonly used drug, researchers have conducted numerous studies on the side effects of indomethacin. Hypersensitivity reactions have been noted to occur because of indomethacin- these reactions can have a plethora of symptoms including but not limited to anaphylaxis, urticaria, angioedema. Indomethacin (and most other NSAIDs) can impact most organ systems of the body, including the gastrointestinal, neurological, renal, hematologic, and cardiopulmonary systems. As previously mentioned indomethacin is a non-selective COX inhibitor, and COX-1 is responsible for the production of prostaglandins involved in the maintenance of the gastric mucosa. Inhibition of this process can result in dyspepsia (indigestion), nausea, constipation, and diarrhea. However, the most severe gastric side effect of indomethacin involves the formation of peptic ulcers. Peptic ulcers can present as mid-epigastric pain that is either relieved or exacerbated by eating depending on their location- the pain with gastric ulcers is exacerbated by eating, while the pain associated with duodenal ulcers is relieved by eating. Ulcers can rupture and result in acute surgical abdomen. Indomethacin can also affect the liver resulting in elevated liver enzymes and jaundice. Indomethacin can also impact the neurologic system resulting in tinnitus, vertigo, depression, dizziness, and headaches. More severe side effects have also been demonstrated, including aseptic meningitis, psychosis, and cognitive dysfunction. COX enzymes are responsible for the synthesis of prostaglandins involved in renal function. Inhibition of this process can result in renal insufficiency. Indomethacin can also result in acute interstitial nephritis. Indomethacin can have several effects on the hematologic system, including agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, thrombocytopenia, and thrombocytopenic purpura.  Indomethacin can impact the cardiopulmonary system and result in acute respiratory distress, Pulmonary edema, and congestive heart failure. Arachidonic acid is the precursor to prostaglandin synthesis via the COX enzymes, inhibition of COX enzymes results in shunting of arachidonic acid to the leukotriene synthesis pathway this can result in the formation of nasal polyps from indomethacin. This condition can also result in respiratory difficulties.  Indomethacin can also result in generalized fatigue and somnolence:[13]

Contraindications

NSAIDs have relatively few contraindications; however, according to the package insert, they are as follows: 

  1. A history of NSAID or salicylate induced hypersensitivity including atopic reactions after taking NSAIDS (examples of atopic reactions include urticaria and asthma)
  2. A previous history of coronary artery bypass graft (CABG) surgery
  3. The third trimester of pregnancy

Monitoring

Indomethacin is not a benign substance- as noted above, there are many potential side effects of the medication; however, there is no need for routine monitoring.

Toxicity

Indomethacin toxicity is rare; there are only a few cases reported in the literature. Cases in the literature have demonstrated acute kidney injury (AKI) secondary to indomethacin toxicity.[14]

Enhancing Healthcare Team Outcomes

All healthcare personnel should understand that although widely used indomethacin and other NSAIDs are not benign substances free of any adverse reactions. Understanding the risks associated with Indomethacin and other NSAIDs can serve to improve patient outcomes, as NSAID use can be tailored more adequately (i.e., avoid NSAIDs in patients with a history of gastric or other peptic ulcers).  


References

[1] Pacifici GM, Clinical pharmacology of indomethacin in preterm infants: implications in patent ductus arteriosus closure. Paediatric drugs. 2013 Oct;     [PubMed PMID: 23754139]
[2] Helleberg L, Clinical Pharmacokinetics of indomethacin. Clinical pharmacokinetics. 1981 Jul-Aug;     [PubMed PMID: 7249487]
[3] Yoshimoto S,Sakai H,Ueda M,Yoshikata M,Mizobuchi M,Nakao H, Prophylactic indomethacin in extremely premature infants between 23 and 24 weeks gestation. Pediatrics international : official journal of the Japan Pediatric Society. 2010 Jun;     [PubMed PMID: 19843236]
[4] Zhou Y,Wang S,Ying X,Wang Y,Geng P,Deng A,Yu Z, Doxorubicin-loaded redox-responsive micelles based on dextran and indomethacin for resistant breast cancer. International journal of nanomedicine. 2017;     [PubMed PMID: 28883726]
[5] Geng C,Li X,Li Y,Song S,Wang C, Nonsteroidal anti-inflammatory drugs alleviate severity of post-ERCP pancreatitis by inhibiting inflammation and reducing apoptosis. Journal of gastroenterology and hepatology. 2020 Feb 16;     [PubMed PMID: 32064683]
[6] Lucas S, The Pharmacology of Indomethacin. Headache. 2016 Feb;     [PubMed PMID: 26865183]
[7] Draper MP,Martell RL,Levy SB, Indomethacin-mediated reversal of multidrug resistance and drug efflux in human and murine cell lines overexpressing MRP, but not P-glycoprotein. British journal of cancer. 1997;     [PubMed PMID: 9062400]
[8] Amici C,La Frazia S,Brunelli C,Balsamo M,Angelini M,Santoro MG, Inhibition of viral protein translation by indomethacin in vesicular stomatitis virus infection: role of eIF2╬▒ kinase PKR. Cellular microbiology. 2015 Sep     [PubMed PMID: 25856684]
[9] Kapicio─člu S,Sari M,Kaynar K,Baki A,Ozoran Y, The effect of indomethacin on hepatitis B virus replication in chronic healthy carriers. Scandinavian journal of gastroenterology. 2000 Sep     [PubMed PMID: 11063156]
[10] Amici C,Di Caro A,Ciucci A,Chiappa L,Castilletti C,Martella V,Decaro N,Buonavoglia C,Capobianchi MR,Santoro MG, Indomethacin has a potent antiviral activity against SARS coronavirus. Antiviral therapy. 2006     [PubMed PMID: 17302372]
[11] El-Mashad AE,El-Mahdy H,El Amrousy D,Elgendy M, Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. European journal of pediatrics. 2017 Feb;     [PubMed PMID: 28004188]
[12] Lindo Ricce M,Rodríguez López-Salazar T,Mendoza Jiménez-Ridruejo J,Moreno Monteagudo JA,Santander Vaquero C, Effectiveness of rectal indomethacin in the prevention of acute pancreatitis after endoscopic retrograde cholangiopancreatography in unselected patients. Revista espanola de enfermedades digestivas : organo oficial de la Sociedad Espanola de Patologia Digestiva. 2020 Feb 5;     [PubMed PMID: 32022572]
[13] Hoppmann RA,Peden JG,Ober SK, Central nervous system side effects of nonsteroidal anti-inflammatory drugs. Aseptic meningitis, psychosis, and cognitive dysfunction. Archives of internal medicine. 1991 Jul;     [PubMed PMID: 2064481]
[14]     [PubMed PMID: 19192282]