Continuing Education Activity

Ketorolac is a medication used in the management and treatment of acute moderate to severe pain. It is in the nonsteroidal anti-inflammatory drug class. This activity outlines the indications, actions, and contraindications for ketorolac as a valuable agent in treating acute pain. It will also highlight the mechanism of action, adverse event profile, and other key factors (e.g., contraindications, monitoring, toxicity) pertinent for members of the interprofessional team in treating patients with acute moderate to severe pain.

Objectives:

• Review the indications and appropriate dosing for ketorolac.
• Identify the most common adverse effects of ketorolac.
• Summarize the contraindications for ketorolac.
• Outline the importance of collaboration and coordination among the interprofessional team to enhance patient care when dosing, monitoring, and selecting appropriate patients for the use of ketorolac to improve outcomes for patients with acute moderate to severe pain.

Indications

Ketorolac is an FDA-approved medication used in the treatment of moderate to severe acute onset pain.[1] It is in the nonsteroidal anti-inflammatory drug (NSAID) drug class. Ketorolac is versatile, as it is available in multiple-dose forms: oral, nasal spray, IV, or IM. It is commonly used postoperatively for pain management. In combination with opioids, ketorolac results in a significant decrease in opioid requirement and lowers the incidence of adverse effects such as vomiting and decreased gastrointestinal motility.[1] In children, ketorolac is as effective as major opioid analgesics.[2] Thus, it is a great pain management alternative or adjunct for pediatric (off-label for acute moderate to severe pain) or adult individuals for whom there is concern regarding opioid dependence. In the emergency department, it is used to successfully treat musculoskeletal pain, migraines, and sickle cell crisis. Lastly, NSAIDs such as ketorolac are effective for pain associated with cancer that has metastasized to bones.[3]

Mechanism of Action

The exact mechanism for ketorolac is not known. Ketorolac, like other NSAIDs, blocks cyclooxygenases (COX), which are enzymes that convert arachidonic acid into prostaglandins, prostacyclin, and thromboxane. The inhibition of these substances decreases pain, fever, and inflammation.[4] Ketorolac does so by inhibiting both cyclooxygenase-1 and cyclooxygenase-2. It has higher demonstrated potency than most other NSAIDs.[3]

Administration

The administration of ketorolac can be done via oral, nasal spray, IV, or IM routes. The oral version should be administered only following IV or IM ketorolac. Ketorolac administration should not be for longer than five days, given an increased risk of cardiac thrombotic events, renal failure, peptic ulcers, and increased risk of bleeding beyond this point.

Dosage Formulations 

• Ketorolac tromethamine IV injection solution: 15 mg/mL; 30 mg/mL
• Ketorolac tromethamine IM injection solution: 60 mg/2 mL
• Oral tablets: 10 mg

Adult Dosing

• IV and IM dosing for adults are recommended at 30 mg single dose or 30 mg every 6 hours, not exceeding 120 mg in 24 hours.
• The recommended oral dosing in adults is a 20 mg single dose after IV or IM therapy, then 10 mg every 4 to 6 hours, not exceeding 40 mg in 24 hours.
• Half-life: 5.6 hours for a single 30 mg IM or single 10 mg oral dose

Pediatric Dosing (off-label for acute moderate to severe pain; ketorolac has no approval for use under the age of 17)

• Less than two years
  • Not recommended
• 2 to 16 years
  • Single-dose: 0.5 mg/kg IV/IM once; not to exceed 15 mg
  • Multiple-dose: 0.5 mg/kg IV/IM q6h; not to exceed 5 days
• Over 16 years, less than 50 kg
  • IV: 15 mg in a single dose or 15 mg every 6 hours; do not exceed 60 mg/day
  • IM: 30 mg in a single dose or 15 mg every 6 hours; do not exceed 60 mg/day
  • PO: 10 mg once after IV/IM therapy, then 10mg every 6 hours; do not exceed 40 mg/day
• Over 16 years, greater than 50 kg
  • Adult dosing as described above

Geriatric Dosing: Because this group is more sensitive to the dose-related adverse effects of NSAIDs, and ketorolac may be eliminated more slowly by the elderly, extreme caution and reduced dosages with careful clinical monitoring must be used when treating the elderly with ketorolac tromethamine.

• Single Dosing regimen
  • IM Dosing: Renally impaired and/or less than 50 kg (110 lbs) of body weight: One dose of 30 mg.
  • IV Dosing: Renally impaired and/or less than 50 kg (110 lbs) of body weight: One dose of 15 mg.
• Multiple-Dose Treatment (IV or IM)
  • For patients with renal impairment and less than 50 kg (110 lbs) of body weight: 15 mg ketorolac injection every 6 hours, and the maximum daily dose for senior adults should not exceed 60 mg.

Pregnancy Considerations

• Based on animal studies, ketorolac is a Pregnancy Category C medicine. Since nonsteroidal anti-inflammatory drugs have the potential for causing the fetal cardiovascular adverse reaction (closure of ductus arteriosus), using ketorolac during pregnancy (particularly late trimester) should be avoided. There are no well-controlled adequate studies of ketorolac in pregnant women. Therefore, ketorolac should be administered during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
• Ketorolac administration is contraindicated in labor and/or delivery because of its prostaglandin synthesis inhibitory effect; it may adversely impact fetal blood circulation and prevent uterine contractions, increasing the risk of uterine hemorrhage.
• Ketorolac inhibits cyclooxygenase/ prostaglandin synthesis, may decrease fertility, and should not be recommended in women planning to conceive.

Breastfeeding Considerations

• Use ketorolac with caution when administered to a nursing woman. No adverse events are reported on ketorolac use in lactating women and its effect on breastfed babies; however, instruct patients to contact their pediatrician if there are any adverse events.[5]

Patients with Renal Impairment

• The majority of ketorolac and its metabolites are eliminated via the kidneys. Around 92% of a dose is excreted in urine as 60% as unchanged ketorolac and 40% as metabolites. According to Kidney Disease Improving Global Outcomes guidelines (KDIGO Guidelines), all NSAIDs should be avoided in patients with creatinine clearance less than 30 mL/min.

Patients with Hepatic Impairment

• The manufacturer has provided no information on ketorolac dose adjustment in patients with hepatic impairment.

Adverse Effects

Adverse effects of ketorolac increase significantly when used in higher doses, for durations over five days, and in patients who are over 75 years old. Like other NSAIDs, ketorolac shows correlations with significant gastrointestinal (GI), renal, and cardiovascular risks.[3] In the GI system, it can cause peptic ulcers and/or perforations of the stomach or intestines. In an extensive pooled data set, all NSAIDs, including COX2 inhibitors, were shown to increase the relative risk for peptic ulcers, with ketorolac having the highest RR at 11.5.[6] Because of its antiplatelet properties, ketorolac increases the risk of GI bleeding. It also increases postoperative bleeding risk when compared with opioids.[7] 

Ketorolac can cause an increased risk of cardiovascular thrombotic events, myocardial infarctions, and hemorrhagic stroke. Heart failure is a significant risk factor for the adverse effects of NSAIDs. A large case-controlled study spanning multiple European countries tested the risk of heart failure for 27 different NSAIDs, including 92,163 hospital admissions for heart failure and 824,6403 control patients. Seven NSAIDs were shown to increase the risk of heart failure, with ketorolac having the highest odds ratio of 1.83 vs. the lowest odds ratio of 1.16 for naproxen.[8] Lastly, ketorolac can cause renal damage and failure. In a population-based case-controlled study conducted in southern Italy, ketorolac was shown to have the highest odds ratio of increasing the cumulative risk for chronic kidney disease ( OR 2.58 after 0 to 90-day use vs. 1.08 for any NSAID).[9]

Contraindications

Ketorolac is contraindicated in individuals who have adverse reactions or are allergic to NSAIDs. It is not recommended to be given intraoperatively or preoperatively due to the increased risk for bleeding. It is not recommended during labor and delivery, as it negatively affects fetal circulation and decreases uterine contraction.[10] Ketorolac is contraindicated in patients with renal disease or renal failure because it may increase fluid retention and worsen renal function. GI-related contraindications for ketorolac include patients with active peptic ulcer disease, recent GI bleed, or GI perforations. Extreme caution is necessary when administering ketorolac to the geriatric population.[3]

Monitoring

As per the manufacturer's prescribing label, due to the increased bleeding risk, patients should be closely monitored for GI bleeding; the recommendation is to obtain a complete blood count (CBC) at baseline and periodically after that. Since this medication primarily undergoes hepatic metabolism, liver function tests should be checked at baseline and regularly monitored, especially in patients with liver compromise. Renal function assessment is necessary via creatinine and urine output before administering this medication and followed closely, given that ketorolac is excreted renally and can cause renal damage.

Toxicity

High quantities or prolonged use of ketorolac can lead to hepatotoxicity and renal toxicity.[11] In addition, ketorolac can cause multiple skin issues, such as toxic epidermal necrolysis. In combination with lithium, it increases the risk of lithium toxicity, given that lithium also gets excreted renally.

Enhancing Healthcare Team Outcomes

In light of the present opioid epidemic in the United States, seeking alternative pain reduction methods that either reduce or obviate the need for administering opioids is essential. Higher-risk populations for opioid abuse include young males, individuals with a history of misuse, and individuals with significant mental health histories.[12] Clinicians should make a deliberate effort to identify patients in these populations and, as a whole, decrease their opioid prescribing practices where possible. The recent general trend of emergency room prescription practices shows a decrease in opioid prescriptions, but much room remains for improvement.[13] 

Ketorolac has demonstrated effectiveness equal to that of morphine when used postoperatively. It has significant potential to be useful in emergency room settings for moderate to severe pain, for which opioids are often regularly prescribed. When considering opioids for acute pain, a multimodal approach can be beneficial to decrease opioid administration to the extent possible. An interprofessional team can also be helpful in correctly identifying individuals who might benefit from alternative pain management medications or interventions and coordinating or assisting in implementing these alternate strategies. Given the relatively high toxicity profile of ketorolac and the oral form is recommended for administration only after IV or IM dosage, highly fluid inter-professional collaboration is ideally maintained to reduce adverse outcomes and ensure the right individuals receive this medication.

Health care providers are first and foremost responsible for identifying individuals who could benefit from non-opioid pain medications, both in the emergency department and in the postoperative setting. Recommendations include pharmacists in this process, as their expertise in medication pharmacokinetics and proper dosing. Pharmacists can also ensure that adverse drug-to-drug interactions are detected and addressed and help decide which patients are ideal for ketorolac. Nurses play a vital role, given that they spend the most time with patients and are the individuals responsible for administrating ketorolac in its oral, IV, and IM forms. They assist in monitoring for toxicity, as well. Nurses can also liaise between the ordering provider and the patient, informing clinicians of any adverse effects and advocating for patients who might be appropriate candidates for ketorolac. Both nurses and pharmacists are responsible for reporting any concerns or issues to the rest of the health care team.

Coordination of communication between all the above individuals on the interprofessional team is essential to ensure that the patient receives the proper care regarding this medication, thereby optimizing outcomes with its use. [Level 5]