Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) that works by blocking cyclooxygenase (COX) enzymes and reducing prostaglandin production. It is available both as an injectable solution and oral tablet formulation. Ketorolac comes under the class of NSAIDs known as arylalkanoic acids and is prescribed for short-term management of moderately severe acute pain that requires analgesia at the opioid level.
History and Development of Ketorolac
Ketorolac was first synthesized in 1976 by Syntex and approved for medical use by the US Food and Drug Administration (FDA) in 1988. Since then, it has become an important analgesic option for perioperative short-term pain management. Ketorolac works by inhibiting the enzymes cyclooxygenase-1 and cyclooxygenase-2, which are involved in prostaglandin synthesis. Prostaglandins are biochemicals that promote pain and fever sensations as well as constriction of blood vessels. By blocking their production, ketorolac exerts potent anti-inflammatory and analgesic effects.
Pharmacology and Mechanism of Action
Ketorolac is a nonselective COX-1 and COX-2 inhibitor, meaning it blocks both isoforms of the cyclooxygenase enzyme. At therapeutic doses, ketorolac inhibits prostaglandin synthesis by more than 90% via suppression of COX activity. The inhibition of prostaglandin production results in reduced sensitization of pain nerve endings and decreased inflammation. Ketorolac has a bioavailability of over 90% after oral administration and peak plasma concentrations are achieved within 1 hour. It is highly protein bound, around 99%, and has a plasma half-life of about 5-6 hours. Metabolism occurs primarily through hepatic pathways via glucuronidation and the metabolites are eliminated renally.
Approved Indications and Dosage
Ketorolac is approved by the FDA for short-term management (5 days or less) of moderately severe acute pain that requires analgesia at the opioid level. Some common indications where ketorolac may be used include:
- Postoperative pain management
- Traumatic bone and soft tissue injuries
- Dental pain
- Renal colic
- Migraine headache
The usual adult dose of ketorolac is 10 mg orally or intramuscularly/intravenously every 4 to 6 hours as needed for pain relief. The maximum daily dose should not exceed 40 mg. Dosage adjustments may be needed in elderly patients or those with renal impairment. Ketorolac is not recommended for continuous long-term use due to potential adverse effects.
Adverse Reactions and Safety Considerations
Ketorolac is generally well-tolerated in the short-term when used appropriately for approved indications. Some common adverse effects include nausea, vomiting, constipation, diarrhea, dyspepsia, abdominal pain, flatulence, and headache. More serious adverse reactions include gastrointestinal ulceration/bleeding and renal impairment. Ketorolac should be used with caution in patients with history of peptic ulcer disease, asthma, coagulation disorders, heart failure, and kidney disease. Concomitant use with other NSAIDs or anticoagulants may increase risk of gastrointestinal bleeding or bleeding complications. Prolonged therapy with ketorolac is contraindicated due to risk of potentially life-threatening toxic effects.
Special Populations and Drug Interactions
Ketorolac is classified as pregnancy category C by the FDA. It should only be used during pregnancy if benefits outweigh potential risks to the fetus. Ketorolac is excreted in breast milk but the amount transferred to a breastfed infant is very small. Alternative analgesics are generally preferred during breastfeeding. Ketorolac can interact with various other drugs through pharmacokinetic or pharmacodynamic mechanisms that may influence its efficacy or safety profile. Some clinically significant interactions include increased risk of bleeding when combined with anticoagulants or other NSAIDs and decreased antihypertensive effect with ACE inhibitors. Dose adjustment of interacting medications may be required.
Comparison with Other Analgesics
When compared to opioid analgesics, ketorolac provides comparable analgesia for postoperative pain but with reduced risk of adverse effects such as nausea, vomiting, respiratory depression, and constipation. However, ketorolac has a broader range of potential safety issues versus opioids as mentioned earlier. Other nonopioid analgesic options have advantages over ketorolac at times. Acetaminophen is safer for the liver than NSAIDs but provides less effective pain relief. Selective COX-2 inhibitors like celecoxib have lower gastrointestinal risk than ketorolac, but higher cardiovascular risks limit their use. Overall, ketorolac remains a valuable option for acute moderate to severe pain requiring an opioid-level analgesic when used judiciously for approved short-term indications.
New Research and Changing Perceptions
While ketorolac has long been used for postoperative pain, new research continues to expand understanding of its optimal role and risk-benefit profile. Studies evaluate use of ketorolac for managing specific acute painful conditions like migraine, renal colic, or sickle cell vaso-occlusive crisis. Multimodal analgesic regimens incorporating acetaminophen, gabapentinoids, and ketorolac have gained favor over excessive opioid monotherapy for certain surgeries to improve outcomes and reduce opioid side effects and dependence. Recent reviews conclude that ketorolac retains usefulness when used prudently according to prescribing information. However, long-term ketorolac therapy should generally be avoided due to accrual of adverse impacts from chronic COX inhibition that outweigh potential analgesia benefits. Overall opinions continue evolving on maximizing ketorolac's utility while circumventing safety issues with alternative agents and regimens when clinically feasible.
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