Ketorolac

Ketorolac
Clinical data
Trade names	Toradol, Acular, Sprix, others
Other names	Ketorolac tromethamine
AHFS/Drugs.com	Monograph
MedlinePlus	a693001
License data	US DailyMed: Ketorolac;
Pregnancy; category	AU: C; ;
Routes of; administration	By mouth, under the tongue, intramuscular, intravenous, eye drops, nasal spray
ATC code	M01AB15 (WHO) S01BC05 (WHO);
Legal status
Legal status	AU: S4 (Prescription only); CA: ℞-only; US: ℞-only;
Pharmacokinetic data
Bioavailability	80–100% (oral) 100% IV/IM
Metabolism	Liver
Elimination half-life	3.5 h to 9.2 h, young adults;; 4.7 h to 8.6 h, elderly (mean age 72)
Excretion	Kidney: 91.4% (mean); Biliary: 6.1% (mean)
Identifiers
	IUPAC name (±)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid;
CAS Number	74103-06-3 ;
PubChem CID	3826;
DrugBank	DB00465 ;
ChemSpider	3694 ;
UNII	YZI5105V0L;
KEGG	D08104 ;
ChEBI	CHEBI:6129 ;
ChEMBL	ChEMBL469 ;
PDB ligand	KTR (PDBe, RCSB PDB);
CompTox Dashboard (EPA)	DTXSID8023189 ;
ECHA InfoCard	100.110.314
Chemical and physical data
Formula	C15H13NO3
Molar mass	255.273 g·mol−1
3D model (JSmol)	Interactive image;
Chirality	Racemic mixture
	SMILES O=C(c1ccc2n1CCC2C(=O)O)c3ccccc3;
	InChI 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) ; Key:OZWKMVRBQXNZKK-UHFFFAOYSA-N ;
	(what is this?) (verify)

Ketorolac, sold under the brand name Toradol among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain.^[2]^[3] Specifically it is recommended for moderate to severe pain.^[4] Recommended duration of treatment is less than six days,^[3] and in Switzerland not more than seven days (parenterally two days).^[5] It is used by mouth, by nose, by injection into a vein or muscle, and as eye drops.^[3]^[4] Effects begin within an hour and last for up to eight hours.^[3] Ketorolac also has antipyretic (fever-reducing) properties.^[6]^[7]

Common side effects include sleepiness, dizziness, abdominal pain, swelling, and nausea.^[3] Serious side effects may include stomach bleeding, kidney failure, heart attacks, bronchospasm, heart failure, and anaphylaxis.^[3] Use is not recommended during the last part of pregnancy or during breastfeeding.^[3] Ketorolac works by blocking cyclooxygenase 1 and 2 (COX1 and COX2), thereby decreasing production of prostaglandins.^[3]^[8]

Ketorolac was patented in 1976 and approved for medical use in 1989.^[9]^[3] It is available as a generic medication.^[4] In 2021, it was the 210th most commonly prescribed medication in the United States, with more than 2 million prescriptions.^[10]^[11]

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.^[12] When ketorolac was introduced into Germany, it was often 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.^[13]

Medical uses

Ketorolac is used for short-term management of moderate to severe pain.^[2] It is usually not prescribed for longer than five days,^[14]^[15]^[16]^[17]^: 291 due to its potential to cause kidney damage.^[17]^: 280

Ketorolac is effective when administered with paracetamol (acetominophen) to control pain in newborns because it does not depress respiration as do opioids.^[18] Ketorolac is also an adjuvant to opioid medications and improves pain relief. It is also used to treat dysmenorrhea.^[17]^: 291 Ketorolac is used to treat idiopathic pericarditis, where it reduces inflammation.^[19]

Ketorolac also has antipyretic (fever-reducing) properties.^[6]^[7]

For systemic use, ketorolac can be administered orally, under the tongue, by intramuscular injection, intravenously, and by nasal spray.^[14] Usually, it is initially administered by intramuscular injection or intravenously,^[2] with oral therapy used as a continuation after the initial IM or IV dose.^[14]^[18]

Ketorolac is also used as an eye drop. It can be given during eye surgery to help with pain,^[20] and is effective in treating ocular itching.^[21] There is not enough evidence to decide that non-steroidal anti-inflammatory drugs help in preventing cystoid macular edema.^[22]^[23] Ketorolac eye drops have also been used to manage pain from corneal abrasions.^[24]

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.^[14]^[15]

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.^[14]^[15] 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.^[14]^[15]

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.^[17]^: 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.^[19]

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.^[14]^[15]

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.^[25]^[26] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.^[25]^[26]

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.^[14]^[15]

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.^[14]^[15]

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.^[27] 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.^[28] It is considered a first-generation NSAID,^[17]^: 279 a group of drugs that non-selectively inhibit both COX-1 and COX-2 enzymes, which can lead to gastrointestinal side effects.^[29] In contrast, later generations of NSAIDs are designed to selectively inhibit COX-2, aiming to reduce inflammation with fewer gastrointestinal issues.^[29]

History

In the US, ketorolac is the only widely available intravenous NSAID.^[18]

The Syntex company, of Palo Alto, California developed the ophthalmic solution Acular^[30] around 2006, which is currently licensed by Allergan, Inc.^[31]^[32]

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.^[2] Dosing guidelines were published at that time.^[33]

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.^[34]

The eye-drop formulation was approved by the FDA in 1992.^[35]

An intranasal formulation (Sprix) was approved by the FDA in 2010^[36] 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.^[37]^[38] A lawsuit alleging widespread league-sanctioned abuse of painkillers was filed by former players against the National Football League in 2017.^[39]

References

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^ ^a ^b ^c ^d 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. Archived from the original on 5 June 2018. Retrieved 2 June 2018.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ "Ketorolac Tromethamine Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Archived from the original on 8 April 2019. Retrieved 13 April 2019.
^ ^a ^b ^c British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 1144, 1302–1303. ISBN 9780857113382.
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^ 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.
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