Toradol

Ketorolac, sold under the brand names Toradol, Acular, and Sprix, among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain. Specifically, it is recommended for moderate to severe pain. The recommended duration of treatment is less than six days, and in Switzerland, it is not more than seven days, with parenteral use limited to two days. It is administered by mouth, under the tongue, by intramuscular injection, intravenously, as eye drops, and via nasal spray. Effects begin within an hour and last for up to eight hours. Ketorolac also has antipyretic (fever-reducing) properties.

Ketorolac was patented in 1976 and approved for medical use in 1989. It is available as a generic medication. In 2022, it was the 223rd most commonly prescribed medication in the United States, with more than 1 million prescriptions. In the US, ketorolac is the only widely available intravenous NSAID.

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. When introduced in 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 dependence, and a dose was effective for 7–8 hours compared to morphine's 3–4 hours. As a very potent prostaglandin inhibitor, ketorolac diminishes the kidney's own defenses against vasoconstriction-related effects, such as during blood loss or high endogenous catecholamine levels.

Medical uses

Ketorolac is used for the short-term management of moderate to severe pain, usually not prescribed for longer than five days due to its potential to cause kidney damage. It is effective when administered with paracetamol (acetaminophen) to control pain in newborns because it does not depress respiration as opioids do. Ketorolac is also an adjuvant to opioid medications and improves pain relief. It is used to treat dysmenorrhea and idiopathic pericarditis, where it reduces inflammation.

Ketorolac has antipyretic (fever-reducing) properties. For systemic use, it can be administered orally, under the tongue, by intramuscular injection, intravenously, and by nasal spray. Typically, it is initially administered by intramuscular injection or intravenously, with oral therapy used as a continuation after the initial IM or IV dose.

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

During treatment, clinicians monitor for adverse effects, using lab tests such as liver function tests, bleeding time, BUN, serum creatinine, and electrolyte levels to identify potential complications.

From additional sources, Toradol is indicated for the short-term treatment of moderate to severe pain, typically not exceeding five days. It can be administered orally, intramuscularly, or intravenously.

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. Recommendations exist for cautious use in those who have experienced cardiovascular disease, myocardial infarction, stroke, heart failure, coagulation disorders, renal impairment, and hepatic impairment.

Additional contraindications include chronic pain syndrome, nasal polyps, bronchial asthma, complete or partial nasal polypus syndrome, bronchial spasm, giant urticaria, history of stomach or duodenal ulcer, hypovolemia, dehydration, high risk of postoperative bleeding or incomplete hemostasis, hematopoietic disorders, hemorrhages in the brain, children under 2 years. Contraindicated in pregnancy, during childbirth, and during lactation (breastfeeding).

Use with caution in patients with chronic heart failure, arterial hypertension, erosive and ulcerative lesions of the gastrointestinal tract, impaired renal function, and elderly patients.

Side effects

Common side effects (occurring in more than 10% of users) include drowsiness. Infrequent side effects (less than 1%) 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, and itching. Platelet function can be decreased by the use of ketorolac.

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.

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. In October 2020, the U.S. Food and Drug Administration 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. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.

Additional side effects include dyspepsia, gastrointestinal pain, nausea, vomiting, diarrhea, peptic ulcers, abnormal liver function, gastrointestinal bleeding, stomatitis, headache, dizziness, drowsiness, sweating, swelling, pain at the injection site, flatulence, gastritis, constipation, dyspnea, bronchial asthma, urticaria, pruritus, rash, anaphylactic reactions, asthenia, purpura, myalgia, vasodilation, pallor, dry mouth, nervousness, depression, increased urination, oliguria, glomerulonephritis, nephrotic syndrome, acute renal failure.

Interactions

Ketorolac can interact with other medications, potentially increasing the risk of adverse effects or reducing effectiveness. 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 of ketorolac is decreased. Problematic gastrointestinal effects are additive and become more likely if potassium supplements, aspirin, other NSAIDs, corticosteroids, or alcohol is taken concurrently. 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 use of medications such as 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.

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.

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. As a result, inhibition of prostaglandin synthesis prevents inflammation. 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. It is considered a first-generation NSAID, a group of drugs that non-selectively inhibit both COX-1 and COX-2 enzymes, which can lead to gastrointestinal side effects. In contrast, later generations of NSAIDs are designed to selectively inhibit COX-2, aiming to reduce inflammation with fewer gastrointestinal issues.

From additional sources, Ketorolac acts by reducing hormones that produce swelling and pain, functioning as an analgesic through its inhibitory effect on the central nervous system, blocking the transmission of impulses along nerve fibers. It does not have anti-inflammatory or antipyretic effects and is used solely for pain relief. (Note: This contrasts with primary sources indicating it does have anti-inflammatory and antipyretic effects.)

Pharmacokinetics

Absorption: After oral administration, it is absorbed from the gastrointestinal tract, with maximum plasma concentration (Cmax) reached in 40-50 minutes, both orally and intramuscularly. Food intake does not impact absorption.

Protein Binding: More than 99% plasma protein binding.

Half-Life (T1/2): 4-6 hours, both after oral ingestion and intramuscular administration.

Excretion: About 90% is excreted renally, with 60% in unchanged form; the rest is excreted through the bowels. In patients with decreased kidney function and elderly patients, the elimination rate decreases, and T1/2 increases.

Storage: Store in a dark place at a temperature of 15-30°C.

Dosage

Forms: Available as film-coated tablets (10 mg Ketorolac tromethamine per tablet, in blisters of 10, boxes of 1 or 2 blisters) and injection solution (30 mg per 1 ml ampoule, in blister packs of 5, boxes of 1 blister).

Administration: Dosage is chosen individually based on pain severity. A single dose is 10-30 mg, with a frequency of up to 4 times a day (every 6-8 hours). The maximum daily intake for adults is 120 mg for injection (60 mg for elderly patients, those with renal insufficiency, or weighing less than 50 kg) and 40 mg for tablets (10 mg every 4 or 6 hours as needed).

Duration: Treatment should not exceed 7 days for tablets and 5 days for injections, with a maximum of 2 days for children (injections only). Prolonged intake or doses exceeding 40 mg per day are not recommended.

Special Populations: Elderly patients (over 65) should take doses close to the lower therapeutic limit, with intervals of 6-8 hours between doses. During transfer from parenteral to oral intake, the recommended daily intake is 90 mg, with no more than 40 mg per day orally in combined administration.

Onset and Duration: Pain relief begins within 30 minutes to 1 hour orally, or minutes if administered intramuscularly or intravenously, with effects lasting 4-6 hours, requiring dosing every 6-8 hours.

Society and culture

Trade names

Ketorolac is sold under the brand names Toradol, Acular, Sprix, and others.

Other names

It is also known as ketorolac tromethamine.

History

Ketorolac was patented in 1976 and approved for medical use in 1989. It is available as a generic medication. As of 2022, it was the 223rd most commonly prescribed medication in the United States, with more than 1 million prescriptions. In the US, ketorolac is the only widely available intravenous NSAID.

Acular, an ophthalmic formulation (eye drop), was developed by the Syntex company of Palo Alto, California around 2006, which is currently licensed by Allergan. The formulation was approved by the FDA in 1992. 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.

In 2007, there were concerns about the high incidence of reported side effects, leading 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. Dosing guidelines were published at that time. 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.

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. 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.

References

• Toradol (Ketorolac) – iMedix