Ketorolac, sold under the brand name Toradol, Acular and Sprix, among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain.[3][4] Specifically it is recommended for moderate to severe pain.[5] Recommended duration of treatment is less than six days,[4] and in Switzerland not more than seven days (parenterally two days).[6] It is used by mouth, by nose, by injection into a vein or muscle, and as eye drops.[4][5] Effects begin within an hour and last for up to eight hours.[4] Ketorolac also has antipyretic (fever-reducing) properties.[7][8]
Ketorolac was patented in 1976 and approved for medical use in 1989. It is available as a generic medication. In 2023, it was the 228th most commonly prescribed medication in the United States, with more than 1million prescriptions[10].
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.[11] 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.[12]
Medical uses
Ketorolac package from Russia
Ketorolac is used for short-term management of moderate to severe pain.[3] It is usually not prescribed for longer than five days,[13][14][15][16]:291 due to its potential to cause kidney damage.[16]:280
Ketorolac is effective when administered with paracetamol (acetaminophen) to control pain in newborns because it does not depress respiration as do opioids.[17] Ketorolac is also an adjuvant to opioid medications and improves pain relief. It is also used to treat dysmenorrhea.[16]:291 Ketorolac is used to treat idiopathic pericarditis, where it reduces inflammation.[18]
For systemic use, ketorolac can be administered orally, under the tongue, by intramuscular injection, intravenously, and by nasal spray.[13] Usually, it is initially administered by intramuscular injection or intravenously,[3] with oral therapy used as a continuation after the initial IM or IV dose.[13][17]
Ketorolac is also used as an eye drop. It can be given during eye surgery to help with pain,[19] and is effective in treating ocular itching.[20] There is not enough evidence to decide that non-steroidal anti-inflammatory drugs help in preventing cystoid macular edema.[21][22] Ketorolac eye drops have also been used to manage pain from corneal abrasions.[23]
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.[13][14]
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.[13][14]
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.[24][25] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.[24][25]
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.[13][14]
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.[26] 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 enzymecyclooxygenase (COX). Ketorolac is a non-selective COX inhibitor.[27] It is considered a first-generation NSAID,[16]:279 a group of drugs that non-selectively inhibit both COX-1 and COX-2 enzymes, which can lead to gastrointestinal side effects.[28] In contrast, later generations of NSAIDs are designed to selectively inhibit COX-2, aiming to reduce inflammation with fewer gastrointestinal issues.[28]
History
Ketorolac was patented in 1976 and approved for medical use in 1989.[29][4] It is available as a generic medication.[5] As of 2022, it was the 223rd most commonly prescribed medication in the United States, with more than 1million prescriptions.[30][31] In the US, ketorolac is the only widely available intravenous NSAID.[17]
Sprix, an intranasal formulation (nasal spray), was approved by the FDA in 2010 for short-term management of moderate to moderately severe pain requiring analgesia at the opioid level.[36]
In 2007, there were concerns about the high incidence of reported side effects. This led to restrictions on 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.[3] Dosing guidelines were published at that time.[37] Concerns over the high incidence of reported side effects with ketorolac 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 fatal outcomes were reported worldwide.[38]
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 while injured tends to result in more severe injuries.[39][40] A lawsuit alleging widespread league-sanctioned abuse of painkillers was filed by former players against the National Football League in 2017.[41]
1 2 3 British national formulary: BNF 76 (76ed.). Pharmaceutical Press. 2018. pp.1144, 1302–1303. ISBN9780857113382.
↑ "TORA-DOL Inj Lös 30 mg/ml". Kompendium (in German). 1 March 2022. Archived from the original on 7 June 2023. Retrieved 24 March 2023. Die Behandlung mit Ampullen ist bei akuten und schweren Schmerzzuständen angezeigt und sollte nicht länger als 2 Tage dauern.
1 2 Gillis JC, Brogden RN (January 1997). "Ketorolac. A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management". Drugs. 53 (1): 139–88. doi:10.2165/00003495-199753010-00012. PMID9010653.
↑ "Ketorolac". PubChem. National Center for Biotechnology Information, U.S. National Library of Medicine. Archived from the original on 13 August 2020. Retrieved 18 April 2020.
↑ "Ketoprofen and ketorolac: gastrointestinal risk"(PDF). MHRA Drug Safety Update. 1 (3). Medicines and Healthcare products Regulatory Agency (MHRA): 3–4. October 2007. Archived(PDF) from the original on 26 January 2023. Retrieved 15 October 2022.
↑ Committee on Safety of Medicines (1993). "Ketorolac: new restrictions on dose and duration of treatment". Current Problems in Pharmacovigilance. 19: 5–6.
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