Pharmacology of Ketorolac

Introduction/Overview

Ketorolac tromethamine represents a significant agent within the nonsteroidal anti-inflammatory drug (NSAID) class, distinguished primarily by its potent analgesic properties. Developed in the 1970s and approved for clinical use in the United States in 1989, it occupies a unique therapeutic niche as the first injectable NSAID approved for systemic use in the management of moderate to severe acute pain. Its clinical relevance stems from its non-opioid mechanism, offering an alternative for pain control without the associated risks of respiratory depression, sedation, or physical dependence that characterize opioid analgesics. Consequently, it has become a cornerstone in multimodal analgesic regimens, particularly in postoperative settings, where it is employed to reduce opioid consumption and mitigate opioid-related adverse effects. The importance of understanding its pharmacology is underscored by its narrow therapeutic index and the potential for serious adverse events, particularly gastrointestinal bleeding and acute kidney injury, which mandate judicious, short-term use.

Learning Objectives

• Describe the chemical classification of ketorolac and its position within the broader NSAID category.
• Explain the molecular mechanism of action of ketorolac, detailing its inhibition of cyclooxygenase enzymes and the subsequent pharmacological effects.
• Outline the pharmacokinetic profile of ketorolac, including absorption, distribution, metabolism, and excretion, and relate these parameters to dosing regimens.
• Identify the approved clinical indications for ketorolac, its role in multimodal analgesia, and recognize its contraindications and major drug interactions.
• Analyze the spectrum of adverse effects associated with ketorolac, with particular emphasis on serious gastrointestinal, renal, and hematological risks, and apply this knowledge to patient-specific risk assessment.

Classification

Ketorolac is definitively classified as a nonsteroidal anti-inflammatory drug. More specifically, it belongs to the heterocyclic acetic acid derivative subclass of NSAIDs, sharing structural similarities with drugs such as indomethacin and diclofenac. Chemically, it is formulated and administered as the tromethamine salt (2-amino-2-(hydroxymethyl)-1,3-propanediol) of ketorolac to enhance its water solubility, a property critical for its parenteral administration. The active moiety is the (S)-enantiomer of ketorolac, which is responsible for its pharmacological activity. The drug is categorized as a non-selective, reversible inhibitor of cyclooxygenase enzymes. From a therapeutic perspective, it is primarily classified as an analgesic, with significant anti-inflammatory and antipyretic properties, although its clinical use overwhelmingly emphasizes its analgesic efficacy. Its classification as a potent analgesic with a non-opioid mechanism underpins its strategic use in pain management protocols.

Mechanism of Action

The pharmacological effects of ketorolac are mediated through the inhibition of the cyclooxygenase (COX) enzymes, which are central to the arachidonic acid metabolic pathway. This inhibition forms the basis of its analgesic, anti-inflammatory, and antipyretic actions.

Molecular and Cellular Mechanisms

Arachidonic acid, released from membrane phospholipids by phospholipase A₂ in response to cellular injury or inflammation, serves as the substrate for COX enzymes. Two primary isoforms, COX-1 and COX-2, are recognized. COX-1 is constitutively expressed in most tissues, including gastric mucosa, platelets, and renal vasculature, and is involved in physiological homeostasis, such as gastric cytoprotection and platelet aggregation. COX-2 is primarily inducible at sites of inflammation, though it also has constitutive roles in the kidney and brain. Ketorolac acts as a competitive, reversible inhibitor of both COX-1 and COX-2, with a slightly greater potency for COX-1 inhibition. By binding to the active site of these enzymes, ketorolac prevents the conversion of arachidonic acid to prostaglandin G₂ (PGG₂) and subsequently to prostaglandin H₂ (PGH₂).

The blockade of prostaglandin synthesis has several downstream consequences. Prostaglandins, particularly PGE₂ and PGI₂, are key mediators of pain and inflammation. They sensitize peripheral nociceptors to mechanical and chemical stimuli (hyperalgesia) and lower the firing threshold of pain-transmitting neurons in the spinal cord. By reducing prostaglandin levels at sites of tissue injury, ketorolac diminishes pain signal generation and transmission. Its anti-inflammatory effect results from inhibiting prostaglandin-mediated vasodilation, edema, and leukocyte infiltration. The antipyretic action is mediated in the hypothalamus, where inhibition of prostaglandin synthesis resets the elevated temperature set-point induced by endogenous pyrogens.

Receptor Interactions and Secondary Effects

Beyond COX inhibition, ketorolac may influence other pathways. Some evidence suggests it can inhibit the lipoxygenase pathway, potentially modulating leukotriene production, though this effect is not considered clinically significant at therapeutic doses. The drug’s potent analgesic effect, disproportionate to its anti-inflammatory efficacy in some models, has led to speculation about potential central nervous system actions, possibly involving interactions with opioid or monoaminergic systems, but these remain areas of investigation without definitive clinical correlation. The primary therapeutic and toxic effects are overwhelmingly attributable to systemic COX inhibition.

Pharmacokinetics

The pharmacokinetics of ketorolac are characterized by rapid absorption, extensive distribution, hepatic metabolism, and renal excretion. Its pharmacokinetic profile necessitates careful consideration of dosing, especially in special populations.

Absorption

Ketorolac is well-absorbed following both oral and intramuscular administration. Oral bioavailability is high, approximately 80-100%. Following oral administration, peak plasma concentrations (C_max) are achieved within 30 to 60 minutes under fasting conditions. Intramuscular injection results in a more rapid onset, with C_max reached in about 45 to 50 minutes. Absorption from intramuscular sites is complete. The presence of food may delay the rate of oral absorption but does not significantly alter the extent of bioavailability.

Distribution

Ketorolac exhibits a relatively low volume of distribution, approximately 0.15 to 0.33 L/kg, suggesting limited tissue penetration beyond the plasma compartment. The drug is highly bound to plasma proteins (>99%), primarily albumin. This high degree of protein binding has implications for potential drug interactions with other highly protein-bound agents, as competition for binding sites may transiently increase free, pharmacologically active drug concentrations. Ketorolac crosses the placenta and is excreted in breast milk, though in small quantities.

Metabolism

Ketorolac undergoes extensive hepatic metabolism. The primary metabolic pathway is conjugation with glucuronic acid to form an acyl glucuronide metabolite. A minor pathway involves p-hydroxylation of the pyrrole ring. The major glucuronide conjugate is pharmacologically inactive. The metabolism is not primarily dependent on the cytochrome P450 system, which minimizes its potential for pharmacokinetic interactions mediated by CYP enzyme induction or inhibition. However, the formation of the acyl glucuronide may be subject to competition with other drugs undergoing glucuronidation.

Excretion

Elimination of ketorolac is predominantly renal. Approximately 90% of a given dose is excreted in the urine, with about 60% as metabolites and 40% as unchanged drug. A small fraction (less than 10%) is eliminated in the feces via biliary secretion. The elimination half-life (t_1/2) ranges from 4 to 6 hours in healthy young adults with normal renal function. This half-life is independent of the route of administration but is significantly prolonged in the elderly and in patients with renal impairment. Total systemic clearance is approximately 0.02 to 0.04 L/hr/kg.

The relationship between dose and plasma concentration is linear within the therapeutic range. Steady-state concentrations are typically achieved within 24 hours with multiple dosing. The pharmacokinetics can be described by a one-compartment model with first-order elimination: C(t) = C₀ × e^-k_elt, where C(t) is concentration at time t, C₀ is initial concentration, and k_el is the elimination rate constant.

Therapeutic Uses/Clinical Applications

The use of ketorolac is strictly limited to the short-term management of moderate to severe acute pain. Its approval and application are governed by stringent guidelines due to its adverse effect profile.

Approved Indications

• Postoperative Pain: This is the primary indication for parenteral ketorolac. It is highly effective as a component of multimodal analgesia following surgical procedures, including orthopedic, abdominal, gynecological, and dental surgeries. It is typically administered via intramuscular or intravenous injection, often as a loading dose followed by scheduled or as-needed doses for a maximum of 5 days.
• Acute Musculoskeletal Pain: Ketorolac is indicated for the short-term relief of severe pain associated with conditions such as fractures, sprains, and acute flares of chronic conditions like rheumatoid arthritis.
• Renal Colic: The drug is particularly effective in managing the severe pain of ureteral colic due to kidney stones, as it reduces ureteral smooth muscle contraction and associated inflammation.
• Oral Formulation for Continuation of Therapy: Following initial parenteral therapy, treatment may be transitioned to oral ketorolac tablets. The total combined duration of parenteral and oral therapy must not exceed 5 days, as the risk of serious adverse events increases with prolonged use.

Off-Label Uses

While not FDA-approved for these purposes, ketorolac has been studied or used in other contexts. Its use in migraine headaches, often administered intranasally or intramuscularly, is a common off-label application due to its potent analgesic effect. Topical ophthalmic formulations of ketorolac are approved for the reduction of ocular pain and photophobia following corneal refractive surgery and for the inhibition of intraoperative miosis during cataract surgery, representing a distinct and localized route of administration with minimal systemic exposure.

Adverse Effects

The adverse effect profile of ketorolac is consistent with that of non-selective NSAIDs but is often more pronounced due to the higher doses used for analgesic effect and its potent COX-1 inhibition. Adverse effects are generally dose-dependent and duration-dependent.

Common Side Effects

• Gastrointestinal: Nausea, dyspepsia, epigastric pain, diarrhea, and constipation are frequently reported. Gastrointestinal ulceration and bleeding can occur even with short-term use.
• Central Nervous System: Headache, dizziness, and drowsiness are common. Somnolence occurs in a notable percentage of patients.
• Renal: Fluid retention, peripheral edema, and mild elevations in serum creatinine may be observed.
• Injection Site Reactions: Pain, burning, or induration can occur with intramuscular administration.

Serious and Rare Adverse Reactions

• Gastrointestinal Bleeding, Ulceration, and Perforation: This is a major risk, which can occur at any time, with or without warning symptoms, and may be fatal. Risk factors include advanced age, history of peptic ulcer disease, concomitant use of corticosteroids, anticoagulants, or other NSAIDs, longer duration of use, smoking, and alcohol use.
• Renal Toxicity: Acute kidney injury, including interstitial nephritis and nephrotic syndrome, can occur. Inhibition of COX-1 and COX-2 in the kidney reduces the synthesis of vasodilatory prostaglandins (PGE₂, PGI₂), compromising renal blood flow and glomerular filtration rate, particularly in states of volume depletion or pre-existing renal compromise.
• Hematological Effects: By inhibiting platelet COX-1, ketorolac irreversibly blocks thromboxane A₂ production for the lifespan of the platelet, impairing aggregation and prolonging bleeding time. This increases the risk of perioperative and post-traumatic bleeding, including intracranial hemorrhage.
• Cardiovascular Risk: As with other NSAIDs, ketorolac may increase the risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke.
• Hepatic Effects: Rare cases of hepatotoxicity, including hepatitis and liver failure, have been reported.
• Hypersensitivity Reactions: Anaphylactoid reactions, severe skin reactions (e.g., Stevens-Johnson syndrome), and exacerbation of asthma in aspirin-sensitive patients can occur.

Black Box Warnings

Ketorolac labeling carries several boxed warnings, the strongest safety designation issued by regulatory agencies. These warnings mandate that the drug is contraindicated for perioperative pain in the setting of coronary artery bypass graft (CABG) surgery due to an increased risk of cardiovascular and bleeding complications. Furthermore, the labeling emphasizes the increased risk of serious gastrointestinal adverse events (bleeding, ulceration, perforation), which may be fatal. The warning also stresses that ketorolac is indicated for short-term use (≤5 days) only, as the risk of serious adverse events increases with duration of use. Finally, it highlights the risk of serious renal adverse events, including acute renal failure.

Drug Interactions

Ketorolac has the potential for significant pharmacokinetic and pharmacodynamic interactions, which must be carefully managed in clinical practice.

Major Pharmacodynamic Interactions

• Anticoagulants and Antiplatelet Agents (e.g., Warfarin, Heparin, Clopidogrel, Aspirin): Concomitant use significantly increases the risk of bleeding due to additive effects on hemostasis. Ketorolac may also increase warfarin levels by displacing it from protein binding sites, further potentiating anticoagulation.
• Other NSAIDs and Corticosteroids: Concurrent use with other NSAIDs, including aspirin for cardioprotection, or with corticosteroids (e.g., prednisone) markedly increases the risk of gastrointestinal ulceration and bleeding.
• Angiotensin-Converting Enzyme (ACE) Inhibitors, Angiotensin II Receptor Blockers (ARBs), and Diuretics: Ketorolac can attenuate the antihypertensive effect of these agents. Furthermore, when used with diuretics or in patients who are volume-depleted, the risk of acute renal failure is substantially increased due to synergistic inhibition of renal prostaglandin-mediated compensatory mechanisms.
• Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): These antidepressants may increase the risk of gastrointestinal bleeding when combined with NSAIDs like ketorolac.

Pharmacokinetic Interactions

Ketorolac is not a significant inducer or inhibitor of cytochrome P450 enzymes. However, its high degree of protein binding creates a potential for interactions with other highly protein-bound drugs (e.g., phenytoin, valproic acid, sulfonylureas), leading to transient increases in free concentrations of either agent. Probenecid inhibits the renal tubular secretion of ketorolac, potentially doubling its plasma levels and prolonging its half-life, which necessitates dose reduction or avoidance of the combination.

Contraindications

Ketorolac is contraindicated in patients with a known hypersensitivity to ketorolac, aspirin, or other NSAIDs, including those who experience asthma, urticaria, or allergic-type reactions after taking these drugs. It is absolutely contraindicated in the setting of active peptic ulcer disease, recent gastrointestinal bleeding or perforation, and a history of these conditions. It must not be used as a prophylactic analgesic before any major surgery, for perioperative pain in CABG surgery, in patients with advanced renal impairment or at risk for renal failure, in patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis, or a high risk of bleeding. It is also contraindicated during labor and delivery, in nursing mothers, and as concomitant therapy with other NSAIDs, including low-dose aspirin.

Special Considerations

The use of ketorolac requires careful patient selection and dose adjustment in specific populations due to altered pharmacokinetics or increased susceptibility to adverse effects.

Pregnancy and Lactation

Ketorolac is classified as Pregnancy Category C in the first and second trimesters and Category D in the third trimester. Use during the first two trimesters may be considered if the potential benefit justifies the potential risk to the fetus, but it is generally avoided. Use in the third trimester is contraindicated due to the risk of premature closure of the ductus arteriosus, which can lead to persistent pulmonary hypertension of the newborn, and the potential to inhibit uterine contractions and prolong labor. Ketorolac is excreted in human milk in low concentrations. Because of the potential for serious adverse reactions in nursing infants, including the potential for prostaglandin-mediated effects, the use of ketorolac is contraindicated in lactating women.

Pediatric Considerations

The safety and efficacy of ketorolac in children under 2 years of age have not been established. For pediatric patients aged 2 to 16 years, a single intramuscular dose of 1 mg/kg (up to 30 mg) or a single intravenous dose of 0.5 mg/kg (up to 15 mg) may be used for moderate to severe acute pain. Multiple-dose regimens are not recommended due to limited safety data. Dosing must be carefully calculated based on body weight, and the total duration of therapy should not exceed 48 hours. Close monitoring for bleeding and renal function is essential.

Geriatric Considerations

Patients aged 65 years and older are at increased risk for adverse events, particularly gastrointestinal bleeding, peptic ulceration, and acute renal failure. This population often has reduced renal function, even with normal serum creatinine levels, due to decreased muscle mass. Consequently, the elimination half-life of ketorolac is prolonged. For patients ≥65 years, and particularly those with low body weight (<50 kg), lower doses are recommended. The maximum daily dose for such patients is often limited to 60 mg (e.g., 15 mg every 6 hours) for parenteral therapy, and the oral dose should not exceed 40 mg daily. Extreme caution and the shortest possible duration of therapy are warranted.

Renal and Hepatic Impairment

In patients with renal impairment (serum creatinine >1.5 mg/dL or creatinine clearance <30 mL/min), ketorolac is contraindicated due to the high risk of drug accumulation and exacerbation of renal dysfunction. In patients with mild to moderate renal impairment, dose reduction and close monitoring of renal function are mandatory, and use should be avoided if possible. In patients with hepatic impairment, ketorolac should be used with caution. While its metabolism may be impaired in severe liver disease, leading to increased exposure, the primary concern is the increased risk of gastrointestinal bleeding due to coagulopathy and possible portal hypertensive gastropathy. Dose adjustment may be necessary, and therapy should be initiated at the low end of the dosing range.

Summary/Key Points

• Ketorolac tromethamine is a potent non-opioid analgesic belonging to the nonsteroidal anti-inflammatory drug class, specifically a heterocyclic acetic acid derivative.
• Its mechanism of action involves reversible, competitive inhibition of both COX-1 and COX-2 enzymes, thereby reducing the synthesis of prostaglandins that mediate pain, inflammation, and fever.
• Pharmacokinetically, it is well-absorbed orally and parenterally, highly protein-bound, metabolized primarily by glucuronidation, and renally excreted with a half-life of 4-6 hours in healthy adults.
• The drug is indicated only for the short-term (≤5 days) management of moderate to severe acute pain, most commonly postoperative pain, and is a key component of multimodal analgesic regimens to reduce opioid requirements.
• Serious adverse effects, including gastrointestinal bleeding, acute kidney injury, and impaired platelet function leading to bleeding, are significant risks that limit its use. These risks are highlighted in its boxed warnings.
• Major drug interactions occur with anticoagulants, other NSAIDs, corticosteroids, ACE inhibitors, and diuretics. It is contraindicated in many clinical scenarios, including active peptic ulcer disease, advanced renal impairment, CABG surgery, and the third trimester of pregnancy.
• Special populations, including the elderly, those with renal or hepatic impairment, and pediatric patients, require dose adjustments, heightened vigilance, and often avoidance of therapy due to increased susceptibility to toxicity.

Clinical Pearls

• Ketorolac should be viewed as a short-term analgesic bridge, not for chronic pain management. Adherence to the 5-day maximum duration rule is critical for patient safety.
• In postoperative patients, a single dose of ketorolac may be as effective as morphine 10-12 mg IM, but without opioid-related sedation or respiratory depression, making it valuable for enhancing recovery.
• Always assess renal function (e.g., serum creatinine) prior to initiation, especially in patients over 65, and consider lower doses (e.g., 15 mg IV/IM) in this population.
• The concomitant use of a proton pump inhibitor may be considered in patients at high risk for gastrointestinal complications, but this does not eliminate the risk and does not justify prolonged use.
• Intravenous administration should be given as a slow bolus over no less than 15 seconds to minimize injection site discomfort and potential vascular irritation.

References

1. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
2. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
3. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
4. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
5. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
6. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
7. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.