Ketorolac

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Ketorolac
Ketorolac.svg
Ketorolac ball-and-stick.png
Clinical data
Trade names Toradol, Acular, Sprix, others
Other namesKetorolac tromethamine
AHFS/Drugs.com Monograph
MedlinePlus a693001
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
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
  • (±)-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 InfoCard 100.110.314 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H13NO3
Molar mass 255.273 g·mol−1
3D model (JSmol)
Chirality Racemic 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) Yes check.svgY
  • Key:OZWKMVRBQXNZKK-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Ketorolac, sold under the brand name Toradol 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]

Contents

Common side effects include sleepiness, dizziness, abdominal pain, swelling, and nausea. [4] Serious side effects may include stomach bleeding, kidney failure, heart attacks, bronchospasm, heart failure, and anaphylaxis. [4] Use is not recommended during the last part of pregnancy or during breastfeeding. [4] Ketorolac works by blocking cyclooxygenase 1 and 2 (COX1 and COX2), thereby decreasing production of prostaglandins. [4] [9]

Ketorolac was patented in 1976 and approved for medical use in 1989. [10] [4] It is available as a generic medication. [5] In 2022, it was the 223rd most commonly prescribed medication in the United States, with more than 1 million prescriptions. [11] [12]

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. [13] 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. [14]

Medical uses

Ketorolac package from Russia Ketorolac (Toradol).jpg
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, [15] [16] [17] [18] : 291  due to its potential to cause kidney damage. [18] : 280 

Ketorolac is effective when administered with paracetamol (acetaminophen) to control pain in newborns because it does not depress respiration as do opioids. [19] Ketorolac is also an adjuvant to opioid medications and improves pain relief. It is also used to treat dysmenorrhea. [18] : 291  Ketorolac is used to treat idiopathic pericarditis, where it reduces inflammation. [20]

Ketorolac also has antipyretic (fever-reducing) properties. [7] [8]

For systemic use, ketorolac can be administered orally, under the tongue, by intramuscular injection, intravenously, and by nasal spray. [15] 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. [15] [19]

Ketorolac is also used as an eye drop. It can be given during eye surgery to help with pain, [21] and is effective in treating ocular itching. [22] There is not enough evidence to decide that non-steroidal anti-inflammatory drugs help in preventing cystoid macular edema. [23] [24] Ketorolac eye drops have also been used to manage pain from corneal abrasions. [25]

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. [15] [16]

Contraindications

Ketorolac is contraindicated in those with hypersensitivity, allergies to the medication, cross-sensitivity to other NSAIDs, before surgery, history of peptic ulcer disease, gastrointestinal bleeding, alcohol intolerance, renal impairment, cerebrovascular bleeding, nasal polyps, angioedema, and asthma. [15] [16] 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. [15] [16]

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 the use of ketorolac. [18] : 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. [20]

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. [15] [16]

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. [26] [27] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. [26] [27]

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. [15] [16]

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. [15] [16]

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. [28] 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. [29] It is considered a first-generation NSAID, [18] : 279  a group of drugs that non-selectively inhibit both COX-1 and COX-2 enzymes, which can lead to gastrointestinal side effects. [30] In contrast, later generations of NSAIDs are designed to selectively inhibit COX-2, aiming to reduce inflammation with fewer gastrointestinal issues. [30]

History

In the US, ketorolac is the only widely available intravenous NSAID. [19]

The Syntex company, of Palo Alto, California developed the ophthalmic solution Acular [31] around 2006, which is currently licensed by Allergan, Inc. [32] [33]

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. [34]

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 fatal outcomes were reported worldwide. [35]

The eye-drop formulation was approved by the FDA in 1992. [36]

An intranasal formulation (Sprix) was approved by the FDA in 2010 [37] 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 while injured tends to result in more severe injuries. [38] [39] A lawsuit alleging widespread league-sanctioned abuse of painkillers was filed by former players against the National Football League in 2017. [40]

Related Research Articles

<span class="mw-page-title-main">Ketoprofen</span> NSAID analgesic medication

Ketoprofen is one of the propionic acid class of nonsteroidal anti-inflammatory drugs (NSAID) with analgesic and antipyretic effects. It acts by inhibiting the body's production of prostaglandin.

<span class="mw-page-title-main">Nonsteroidal anti-inflammatory drug</span> Class of therapeutic drug for relieving pain and inflammation

Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of use, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease.

An antipyretic is a substance that reduces fever. Antipyretics cause the hypothalamus to override a prostaglandin-induced increase in temperature. The body then works to lower the temperature, which results in a reduction in fever.

<span class="mw-page-title-main">Ibuprofen</span> Medication treating pain, fever, and inflammation

Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arteriosus in a premature baby. It can be taken orally or intravenously. It typically begins working within an hour.

<span class="mw-page-title-main">Cyclooxygenase</span> Class of enzymes

Cyclooxygenase (COX), officially known as prostaglandin-endoperoxide synthase (PTGS), is an enzyme that is responsible for biosynthesis of prostanoids, including thromboxane and prostaglandins such as prostacyclin, from arachidonic acid. A member of the animal-type heme peroxidase family, it is also known as prostaglandin G/H synthase. The specific reaction catalyzed is the conversion from arachidonic acid to prostaglandin H2 via a short-living prostaglandin G2 intermediate.

<span class="mw-page-title-main">Diclofenac</span> Nonsteroidal anti-inflammatory drug

Diclofenac, sold under the brand name Voltaren among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout. It can be taken orally, inserted rectally as a suppository, injected intramuscularly, injected intravenously, applied to the skin topically, or through eye drops. Improvements in pain last up to eight hours. It is also available as the fixed-dose combination diclofenac/misoprostol (Arthrotec) to help protect the stomach.

<span class="mw-page-title-main">Naproxen</span> Nonsteroidal anti-inflammatory drug (NSAID) used to treat pain

Naproxen, sold under the brand name Aleve among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, and inflammatory diseases such as rheumatoid arthritis, gout and fever. It is taken orally. It is available in immediate and delayed release formulations. Onset of effects is within an hour and lasts for up to twelve hours. Naproxen is also available in salt form, naproxen sodium, which has better solubility when taken orally.

Anti-inflammatory or antiphlogistic is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as opposed to opioids, which affect the central nervous system to block pain signaling to the brain.

Cyclooxygenase-2 inhibitors, also known as coxibs, are a type of nonsteroidal anti-inflammatory drug (NSAID) that directly target cyclooxygenase-2 (COX-2), an enzyme responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration and is the main feature of celecoxib, rofecoxib, and other members of this drug class.

<span class="mw-page-title-main">Indometacin</span> Anti-inflammatory drug

Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of prostaglandins, endogenous signaling molecules known to cause these symptoms. It does this by inhibiting cyclooxygenase, an enzyme that catalyzes the production of prostaglandins.

<span class="mw-page-title-main">Nimesulide</span> Anti-inflammatory drug

Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID) with pain medication and fever reducing properties. Its approved indications are the treatment of acute pain, the symptomatic treatment of osteoarthritis, and primary dysmenorrhoea in adolescents and adults above 12 years old.

<span class="mw-page-title-main">Meloxicam</span> Nonsteroidal anti-inflammatory drug (NSAID)

Meloxicam, sold under the brand name Mobic among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammation in rheumatic diseases and osteoarthritis. It is taken by mouth or given by injection into a vein. It is recommended that it be used for as short a period as possible and at a low dose.

Cyclooxygenase-3 (COX-3) is an enzyme that is encoded by the PTGS1 (COX1) gene, but is not functional in humans. COX-3 is the third and most recently discovered cyclooxygenase (COX3050) isozyme, while the first two to be discovered were COX-1 and COX-2. The COX-3 isozyme is encoded by the same gene as COX-1, with the difference that COX-3 retains an intron that is not retained in COX-1.

<span class="mw-page-title-main">Etodolac</span> Nonsteroidal anti-inflammatory drug

Etodolac is a nonsteroidal anti-inflammatory drug (NSAID).

<span class="mw-page-title-main">Diflunisal</span> NSAID analgesic and anti-inflammatory drug

Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. It was developed by Merck Sharp & Dohme in 1971, as MK647, after showing promise in a research project studying more potent chemical analogs of aspirin. It was first sold under the brand name Dolobid, marketed by Merck & Co., but generic versions are now widely available. It is classed as a nonsteroidal anti-inflammatory drug (NSAID) and is available in 250 mg and 500 mg tablets.

<span class="mw-page-title-main">Nabumetone</span> NSAID analgesic and anti-inflammatory drug

Nabumetone, sold under the brand name Relafen among others, is a nonsteroidal anti-inflammatory drug (NSAID). Nabumetone was developed by Beecham and first received regulatory approval in 1991.

<span class="mw-page-title-main">Acemetacin</span> NSAID analgesic medication

Acemetacin is a non-steroidal anti-inflammatory drug (NSAID) used for the treatment of osteoarthritis, rheumatoid arthritis, lower back pain, and relieving post-operative pain. It is manufactured by Merck KGaA under the tradename Emflex. It is no longer available in the UK, however is available in other countries as a prescription-only drug.

<span class="mw-page-title-main">Mechanism of action of aspirin</span>

Aspirin causes several different effects in the body, mainly the reduction of inflammation, analgesia, the prevention of clotting, and the reduction of fever. Much of this is believed to be due to decreased production of prostaglandins and TXA2. Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX) enzyme. Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme. This makes aspirin different from other NSAIDs, which are reversible inhibitors; aspirin creates an allosteric change in the structure of the COX enzyme. However, other effects of aspirin, such as uncoupling oxidative phosphorylation in mitochondria, and the modulation of signaling through NF-κB, are also being investigated. Some of its effects are like those of salicylic acid, which is not an acetylating agent.

<span class="mw-page-title-main">Mofezolac</span> Chemical compound

Mofezolac (INN), sold under the name Disopain in Japan, is a nonsteroidal anti-inflammatory drug (NSAID) used for its analgesic and anti-inflammatory actions. It is often prescribed for rheumatoid arthritis, lower back pain, frozen shoulder, and pain management after surgery or trauma. It is also being investigated for potential use in the treatment of neuroinflammation.

Prostaglandin inhibitors are drugs that inhibit the synthesis of prostaglandin in human body. There are various types of prostaglandins responsible for different physiological reactions such as maintaining the blood flow in stomach and kidney, regulating the contraction of involuntary muscles and blood vessels, and act as a mediator of inflammation and pain. Cyclooxygenase (COX) and Phospholipase A2 are the major enzymes involved in prostaglandin production, and they are the drug targets for prostaglandin inhibitors. There are mainly 2 classes of prostaglandin inhibitors, namely non- steroidal anti- inflammatory drugs (NSAIDs) and glucocorticoids. In the following sections, the medical uses, side effects, contraindications, toxicity and the pharmacology of these prostaglandin inhibitors will be discussed.

References

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