Chemistry:Ketorolac

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Short description: Nonsteroidal anti-inflammatory drug (NSAID; analgesic)
Ketorolac
Ketorolac.svg
Ketorolac ball-and-stick.png
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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
Chemical and physical data
FormulaC15H13NO3
Molar mass255.273 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
 ☒N☑Y (what is this?)  (verify)

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]

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. ↑ 1.0 1.1 1.2 1.3 "A review of ketorolac as a prehospital analgesic" (in en). Journal of Paramedic Practice 9 (12): 522–526. 2017. doi:10.12968/jpar.2017.9.12.522. https://www.researchgate.net/publication/321640488. Retrieved 2 June 2018. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 "Ketorolac Tromethamine Monograph for Professionals" (in en). American Society of Health-System Pharmacists. https://www.drugs.com/monograph/ketorolac-tromethamine.html. 
  3. ↑ 3.0 3.1 3.2 British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 1144, 1302–1303. ISBN 9780857113382. 
  4. ↑ "TORA-DOL Inj Lös 30 mg/ml" (in de). 2022-03-01. https://compendium.ch/product/30303-tora-dol-inj-los-30-mg-ml/mpro. "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". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2837a082-3a34-6f81-5e43-45a70295686b. 
  6. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 521. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA521. 
  7. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  8. ↑ "Ketorolac - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Ketorolac. 
  9. ↑ "Abverkauf von Ketorolac (TORATEX) gestoppt". 1993. https://www.arznei-telegramm.de/html/1993_08/9308084_02.html. 
  10. ↑ "Warnhinweis: Wie lange noch Analgetikum Ketorolac (Toratex)?" (in de). Arznei-Telegramm. 1993. https://www.arznei-telegramm.de/html/1993_06/9306061_05.html. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 Davis's Drug Guide for Nurses. Philadelphia: F.A. Davis Company. 2017. p. 730. ISBN 9780803657052. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 12.6 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. https://www.drugs.com/monograph/ketorolac-tromethamine.html. 
  14. ↑ 14.0 14.1 14.2 14.3 14.4 RN pharmacology for nursing : review module. Overland Park, KS: Assessment Technologies Institute. 2016. ISBN 978-1-56533-573-8. 
  15. ↑ 15.0 15.1 15.2 "A review of perioperative anesthesia and analgesia for infants: updates and trends to watch". F1000Research 6: 120. 2017. doi:10.12688/f1000research.10272.1. PMID 28232869. 
  16. ↑ 16.0 16.1 "Non-Steroidal Anti-Inflammatory Drugs and Aspirin Therapy for the Treatment of Acute and Recurrent Idiopathic Pericarditis". Pharmaceuticals 9 (2): 17. March 2016. doi:10.3390/ph9020017. PMID 27023565. 
  17. ↑ "Patient considerations in cataract surgery - the role of combined therapy using phenylephrine and ketorolac". Patient Preference and Adherence 10: 1795–1801. 2016. doi:10.2147/PPA.S90468. PMID 27695298. 
  18. ↑ Focus on nursing pharmacology. Philadelphia: Wolters Kluwer. 2017. p. 272. ISBN 9781496318213. 
  19. ↑ "Prophylactic non-steroidal anti-inflammatory drugs for the prevention of macular oedema after cataract surgery". The Cochrane Database of Systematic Reviews 2016 (11): CD006683. November 2016. doi:10.1002/14651858.CD006683.pub3. PMID 27801522. PMC 6464900. http://discovery.ucl.ac.uk/1529414/. 
  20. ↑ "Non-steroidal anti-inflammatory agents for treating cystoid macular oedema following cataract surgery". The Cochrane Database of Systematic Reviews 2022 (12): CD004239. December 2022. doi:10.1002/14651858.CD004239.pub4. PMID 36520144. 
  21. ↑ "Topical non-steroidal anti-inflammatory drugs for analgesia in traumatic corneal abrasions". The Cochrane Database of Systematic Reviews 2017 (5): CD009781. May 2017. doi:10.1002/14651858.CD009781.pub2. PMID 28516471. 
  22. ↑ 22.0 22.1 "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. This article incorporates text from this source, which is in the public domain.
  23. ↑ 23.0 23.1 "NSAIDs may cause rare kidney problems in unborn babies". 21 July 2017. https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic.  This article incorporates text from this source, which is in the public domain.
  24. ↑ "Ketorolac" (in en). PubChem. National Center for Biotechnology Information, U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/3826. 
  25. ↑ "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. March 2008. doi:10.1213/ane.0b013e318163f602. PMID 18292448. 
  26. ↑ "Acular (Ketorolac Tromethamine): Uses, Dosage, Side Effects, Interactions, Warning" (in en). https://www.rxlist.com/acular-drug.htm. 
  27. ↑ "Label: ACULAR® Eye Drops (ketorolac trometamol)". December 2011. https://allergan-web-cdn-prod.azureedge.net/allergan/allergannewzealand/media/allergannewzealand/products/acular-nz-cmi.pdf. 
  28. ↑ "Label: ACULAR® (ketorolac tromethamine ophthalmic solution)". Allergan, Inc.. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019700s028lbl.pdf. 
  29. ↑ "Ketoprofen and ketorolac: gastrointestinal risk". MHRA Drug Safety Update (Medicines and Healthcare products Regulatory Agency (MHRA)) 1 (3): 3–4. October 2007. https://webarchive.nationalarchives.gov.uk/ukgwa/20150110161836mp_/http://www.mhra.gov.uk/home/groups/pl-p/documents/publication/con2032519.pdf. 
  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. https://www.drugs.com/mtm/ketorolac-ophthalmic.html. 
  32. ↑ "Sprix Information from". Drugs.com. https://www.drugs.com/sprix.html. 
  33. ↑ "Toradol Lawsuit: NFL Can't Outrun Legacy of Abuse" (in en-us). Sports Illustrated. https://www.si.com/nfl/2017/03/28/nfl-toradol-lawsuit-painkillers-nflpa-union-team-doctor-conflict-interest. Retrieved 18 April 2020. 
  34. ↑ "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. September 2012. doi:10.1177/1941738112457154. PMID 23016110. 
  35. ↑ "NFL abuse of painkillers and other drugs described in court filings" (in en-US). Washington Post. 9 March 2017. ISSN 0190-8286. https://www.washingtonpost.com/sports/redskins/nfl-abuse-of-painkillers-and-other-drugs-described-in-court-filings/2017/03/09/be1a71d8-035a-11e7-ad5b-d22680e18d10_story.html. 

Further reading

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

External links



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