Ketorolac

Ketorolac, sold under the brand names Toradol, and Biorolac among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain.[1][2] Specifically it is recommended for moderate to severe pain.[3] Recommended duration of treatment is less than six days,[2] and in Switzerland not more than two days.[4] It is used by mouth, by nose, by injection into a vein or muscle, and as eye drops.[2][3] Effects begin within an hour and last for up to eight hours.[2]

Ketorolac
Clinical data
Trade namesToradol, Acular, Sprix, others
Other namesKetorolac tromethamine
AHFS/Drugs.comMonograph
MedlinePlusa693001
License data
Pregnancy
category
  • AU: C
Routes of
administration		By mouth, under the tongue, intramuscular, intravenous, eye drops, nasal spray
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability80–100% (oral) 100% IV/IM
MetabolismLiver
Elimination half-life3.5 h to 9.2 h, young adults;
4.7 h to 8.6 h, elderly (mean age 72)
ExcretionKidney: 91.4% (mean)
Biliary: 6.1% (mean)
Identifiers
  • (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.110.314
Chemical and physical data
FormulaC15H13NO3
Molar mass255.273 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  • O=C(c1ccc2n1CCC2C(=O)O)c3ccccc3
  • InChI=1S/C15H13NO3/c17-14(10-4-2-1-3-5-10)13-7-6-12-11(15(18)19)8-9-16(12)13/h1-7,11H,8-9H2,(H,18,19) checkY
  • Key:OZWKMVRBQXNZKK-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Common side effects include sleepiness, dizziness, abdominal pain, swelling, and nausea.[2] Serious side effects may include stomach bleeding, kidney failure, heart attacks, bronchospasm, heart failure, and anaphylaxis.[2] Use is not recommended during the last part of pregnancy or during breastfeeding.[2] Ketorolac works by blocking cyclooxygenase 1 and 2 (COX1 and COX2), thereby decreasing production of prostaglandins.[2][5]

Ketorolac was patented in 1976 and approved for medical use in 1989.[6][2] It is available as a generic medication.[3] In 2020, it was the 249th most commonly prescribed medication in the United States, with more than 1 million prescriptions.[7][8]

Due to a series of deaths due to gastrointestinal bleeding and kidney failure, ketorolac as a pain medication was removed from the German market in 1993.[9] When ketorolac was introduced into Germany, it was often mis-used as an opioid replacement in pain therapy because its side effects were perceived as much less severe, it did not produce any dependence, and a dose was effective for 7-8 hours compared to morphine with 3-4 hours. As a very potent prostaglandin inhibitor, ketorolac diminishes the kidney's own defenses against vasoconstriction-related effects, e.g. during blood loss or high endogenous catecholamine levels.[10]

Medical uses
Ketorolac package from Russia

Ketorolac is used for short-term management of moderate to severe pain.[1] It is usually not prescribed for longer than five days,[11][12][13][14]: 291  due to its potential to cause kidney damage.[14]: 280 

Ketorolac is effective when administered with paracetamol to control pain in newborns because it does not depress respiration as do opioids.[15] Ketorolac is also an adjuvant to opioid medications and improves pain relief. It is also used to treat dysmenorrhea.[14]: 291  Ketorolac is used to treat idiopathic pericarditis, where it reduces inflammation.[16]

For systemic use, ketorolac can be administered orally, under the tongue, by intramuscular injection, intravenously, and by nasal spray.[11] Usually, it is initially administered by intramuscular injection or intravenously,[1] with oral therapy used as a continuation after the initial IM or IV dose.[11][15]

Ketorolac is also used as an eye drop. It can be given during eye surgery to help with pain,[17] and is effective in treating ocular itching.[18] There is not enough evidence to decide that non-steroidal anti-inflammatory drugs help in preventing cystoid macular edema.[19][20] Ketorolac eye drops have also been used to manage pain from corneal abrasions.[21]

During treatment with ketorolac, clinicians monitor for the manifestation of adverse effects. Lab tests, such as liver function tests, bleeding time, BUN, serum creatinine and electrolyte levels are often used and help to identify potential complications.[11][12]

Contraindications

Ketorolac is contraindicated in those with hypersensitivity, allergies to the medication, cross-sensitivity to other NSAIDs, prior to surgery, history of peptic ulcer disease, gastrointestinal bleeding, alcohol intolerance, renal impairment, cerebrovascular bleeding, nasal polyps, angioedema, and asthma.[11][12] Recommendations exist for cautious use of ketorolac in those who have experienced cardiovascular disease, myocardial infarction, stroke, heart failure, coagulation disorders, renal impairment, and hepatic impairment.[11][12]

Adverse effects

A common (>10%) side effect is drowsiness. Infrequent (<1%) side effects include paresthesia, prolonged bleeding time, injection site pain, purpura, sweating, abnormal thinking, increased production of tears, edema, pallor, dry mouth, abnormal taste, urinary frequency, increased liver enzymes, itching and others. Platelet function can be decreased by use of ketorolac.[14]: 279 

Though uncommon, potentially fatal adverse effects include stroke, myocardial infarction, GI bleeding, Stevens–Johnson syndrome, toxic epidermal necrolysis and anaphylaxis. In terms of safety, ketorolac has been assessed to be a relatively higher-risk NSAID when compared to aceclofenac, celecoxib, and ibuprofen.[16]

Like all NSAIDs, ketorolac can cause premature constriction of the ductus arteriosus in the infant if taken by the mother during the third trimester of pregnancy.[11][12]

In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.[22][23] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.[22][23]

Interactions

Ketorolac can interact with other medications. Probenecid can increase the probability of having an adverse reaction when taken with ketorolac. Pentoxifylline can increase the risk of bleeding. When aspirin is taken at the same time as ketorolac, the effectiveness is decreased. Problematic GI effects are additive and become more likely if potassium supplements, aspirin, other NSAIDs, corticosteroids, or alcohol is taken at the same time. The effectiveness of antihypertensives and diuretics can be lowered. The use of ketorolac can increase serum lithium levels to the point of toxicity. Toxicity to methotrexate is more likely if ketorolac is taken at the same time. The risk of bleeding increases with the concurrent medications clopidogrel, cefoperazone, valproic acid, cefotetan, eptifibatide, tirofiban, and ticlopidine. Anticoagulants and thrombolytic medications also increase the likelihood of bleeding. Medications used to treat cancer can interact with ketorolac along with radiation therapy. The risk of toxicity to the kidneys increases when ketorolac is taken with cyclosporine.[11][12]

Interactions with ketorolac also exist with some herbal supplements. The use of Panax ginseng, clove, ginger, arnica, feverfew, dong quai, chamomile, and Ginkgo biloba increases the risk of bleeding.[11][12]

Mechanism of action

Chemically ketorolac functions as a carboxylic acid derivative serving non-selectively to block the prostaglandin synthesis by inhibition of prostaglandin G/H synthesis 1 and 2. Prostaglandin functions in the body as a messenger for contraction/relaxation of smooth muscle and modulation of inflammation. Resultant, inhibition of prostaglandin synthesis prevents inflammation.[24] The primary mechanism of action responsible for ketorolac's anti-inflammatory, antipyretic, and analgesic effects is the inhibition of prostaglandin synthesis by competitive blocking of the enzyme cyclooxygenase (COX). Ketorolac is a non-selective COX inhibitor.[25] It is considered a first-generation NSAID.[14]: 279 

History

In the US, ketorolac is the only widely available intravenous NSAID.[15]

The Syntex company, of Palo Alto, California developed the ophthalmic solution Acular[26] around 2006, which is currently licensed by Allergan, Inc.[27][28]

In 2007, there were concerns about the high incidence of reported side effects. This led to restriction in its dosage and maximum duration of use. In the UK, treatment was initiated only in a hospital, although this was not designed to exclude its use in prehospital care and mountain rescue settings.[1] Dosing guidelines were published at that time.[29]

Concerns over the high incidence of reported side effects with ketorolac trometamol led to its withdrawal (apart from the ophthalmic formulation) in several countries, while in others its permitted dosage and maximum duration of treatment have been reduced. From 1990 to 1993, 97 reactions with a fatal outcome were reported worldwide.[30]

The eye-drop formulation was approved by the FDA in 1992.[31]

An intranasal formulation (Sprix) was approved by the FDA in 2010[32] for short-term management of moderate to moderately severe pain requiring analgesia at the opioid level.

Ketorolac has also been used in collegiate and professional sports, and is reported to be routinely used in the National Football League and National Hockey League. Competitive athletes, particularly in contact sports, are often expected by their coaches and/or teammates to play through injuries, generally with the help of painkillers. However, more recent research has indicated that encouraging players to play in an injured state tends to result in more severe injuries.[33][34] A lawsuit alleging widespread league-sanctioned abuse of painkillers was filed by former players against the National Football League in 2017.[35]

References
  1. Mallinson T (2017). "A review of ketorolac as a prehospital analgesic". Journal of Paramedic Practice. 9 (12): 522–526. doi:10.12968/jpar.2017.9.12.522. Retrieved 2 June 2018.
  2. "Ketorolac Tromethamine Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 13 April 2019.
  3. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 1144, 1302–1303. ISBN 9780857113382.
  4. "TORA-DOL Inj Lös 30 mg/ml". Kompendium (in German). 1 March 2022. Die Behandlung mit Ampullen ist bei akuten und schweren Schmerzzuständen angezeigt und sollte nicht länger als 2 Tage dauern.
  5. "DailyMed - ketorolac tromethamine tablet, film coated". dailymed.nlm.nih.gov. Retrieved 14 April 2019.
  6. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 521. ISBN 9783527607495.
  7. "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  8. "Ketorolac - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
  9. "Abverkauf von Ketorolac (TORATEX) gestoppt" [Sale of Ketorolac (TORATEX) stopped]. 1993.
  10. "Warnhinweis: Wie lange noch Analgetikum Ketorolac (Toratex)?" [Warning notice: How long anymore analgesic Ketorolac (Toratex)?] (in German). Arznei-Telegramm. 1993.
  11. Vallerand AH (2017). Davis's Drug Guide for Nurses. Philadelphia: F.A. Davis Company. p. 730. ISBN 9780803657052.
  12. Physician's Desk Reference 2017. Montvale, New Jersey: PDR, LLC. 2017. pp. S–474–5. ISBN 9781563638381.
  13. "Ketorolac-tromethamine". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
  14. Henry N (2016). RN pharmacology for nursing : review module. Overland Park, KS: Assessment Technologies Institute. ISBN 978-1-56533-573-8.
  15. Martin LD, Jimenez N, Lynn AM (2017). "A review of perioperative anesthesia and analgesia for infants: updates and trends to watch". F1000Research. 6: 120. doi:10.12688/f1000research.10272.1. PMC 5302152. PMID 28232869.
  16. Schwier N, Tran N (March 2016). "Non-Steroidal Anti-Inflammatory Drugs and Aspirin Therapy for the Treatment of Acute and Recurrent Idiopathic Pericarditis". Pharmaceuticals. 9 (2): 17. doi:10.3390/ph9020017. PMC 4932535. PMID 27023565.
  17. Gonzalez-Salinas R, Guarnieri A, Guirao Navarro MC, Saenz-de-Viteri M (2016). "Patient considerations in cataract surgery - the role of combined therapy using phenylephrine and ketorolac". Patient Preference and Adherence. 10: 1795–1801. doi:10.2147/PPA.S90468. PMC 5029911. PMID 27695298.
  18. Karch A (2017). Focus on nursing pharmacology. Philadelphia: Wolters Kluwer. p. 272. ISBN 9781496318213.
  19. Lim BX, Lim CH, Lim DK, Evans JR, Bunce C, Wormald R (November 2016). "Prophylactic non-steroidal anti-inflammatory drugs for the prevention of macular oedema after cataract surgery". The Cochrane Database of Systematic Reviews. 11 (11): CD006683. doi:10.1002/14651858.CD006683.pub3. PMC 6464900. PMID 27801522.
  20. Wingert AM, Liu SH, Lin JC, Sridhar J (December 2022). "Non-steroidal anti-inflammatory agents for treating cystoid macular oedema following cataract surgery". The Cochrane Database of Systematic Reviews. 2022 (12): CD004239. doi:10.1002/14651858.CD004239.pub4. PMC 9754896. PMID 36520144.
  21. Wakai A, Lawrenson JG, Lawrenson AL, Wang Y, Brown MD, Quirke M, et al. (May 2017). "Topical non-steroidal anti-inflammatory drugs for analgesia in traumatic corneal abrasions". The Cochrane Database of Systematic Reviews. 2017 (5): CD009781. doi:10.1002/14651858.CD009781.pub2. PMC 6481688. PMID 28516471.
  22. "FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications". U.S. Food and Drug Administration (FDA) (Press release). 15 October 2020. Retrieved 15 October 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  23. "NSAIDs may cause rare kidney problems in unborn babies". U.S. Food and Drug Administration. 21 July 2017. Retrieved 15 October 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  24. "Ketorolac". PubChem. National Center for Biotechnology Information, U.S. National Library of Medicine. Retrieved 18 April 2020.
  25. Lee IO, Seo Y (March 2008). "The effects of intrathecal cyclooxygenase-1, cyclooxygenase-2, or nonselective inhibitors on pain behavior and spinal Fos-like immunoreactivity". Anesthesia and Analgesia. 106 (3): 972–7, table of contents. doi:10.1213/ane.0b013e318163f602. PMID 18292448. S2CID 5894373.
  26. "Acular (Ketorolac Tromethamine): Uses, Dosage, Side Effects, Interactions, Warning". RxList. Retrieved 6 May 2021.
  27. "Label: ACULAR® Eye Drops (ketorolac trometamol)" (PDF). December 2011.
  28. "Label: ACULAR® (ketorolac tromethamine ophthalmic solution)" (PDF). Allergan, Inc. U.S. Food and Drug Administration.
  29. "Ketoprofen and ketorolac: gastrointestinal risk" (PDF). MHRA Drug Safety Update. Medicines and Healthcare products Regulatory Agency (MHRA). 1 (3): 3–4. October 2007.
  30. Committee on Safety of Medicines (1993). "Ketorolac: new restrictions on dose and duration of treatment". Current Problems in Pharmacovigilance. 19: 5–6.
  31. "Ketorolac ophthalmic medical facts from". Drugs.com. Retrieved 6 October 2013.
  32. "Sprix Information from". Drugs.com. Retrieved 6 October 2013.
  33. Klemko R. "Toradol Lawsuit: NFL Can't Outrun Legacy of Abuse". Sports Illustrated. Retrieved 18 April 2020.
  34. Matava M, Brater DC, Gritter N, Heyer R, Rollins D, Schlegel T, et al. (September 2012). "Recommendations of the national football league physician society task force on the use of toradol(®) ketorolac in the national football league". Sports Health. 4 (5): 377–383. doi:10.1177/1941738112457154. PMC 3435943. PMID 23016110.
  35. Maese R (9 March 2017). "NFL abuse of painkillers and other drugs described in court filings". Washington Post. ISSN 0190-8286. Retrieved 18 April 2020.

Further reading
  • AHFS drug information. Bethesda, MD: American Society of Health-System Pharmacists. 2011. ISBN 9781585282609.
  • Hamilton R (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 9. ISBN 9781284057560.
  • Handley DA, Cervoni P, McCray JE, McCullough JR (February 1998). "Preclinical enantioselective pharmacology of (R)- and (S)- ketorolac". Journal of Clinical Pharmacology. 38 (2S): 25S–35S. doi:10.1002/j.1552-4604.1998.tb04414.x. PMID 9549656. S2CID 22508540.
  • Henry N (2016). RN pharmacology for nursing : review module. Overland Park, KS: Assessment Technologies Institute. ISBN 9781565335738.
  • Kizior R (2017). Saunders nursing drug handbook 2017. St. Louis, MO: Elsevier. ISBN 9780323442916.
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