Ketorolac

Article Author:
Ahmad Mahmoodi
Article Editor:
Peggy Kim
Updated:
8/30/2019 1:40:02 PM
PubMed Link:
Ketorolac

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. Ketorolac, in combination with opioids, 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 setting, it is successful in treating 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 more demonstrated potency than most other NSAIDs.[3]

Administration

The administration of ketorolac is 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.

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 recommendation for 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 2 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 50kg

  • 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

Adverse Effects

Like other NSAIDs, ketorolac has associations 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 a large 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.[5] Because of its antiplatelet properties, ketorolac increases the risk of GI bleeding. It also increases postoperative bleeding risk when compared with opioids.[6] 

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, which included 92163 hospital admissions for heart failure and 8246403 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.[7] 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).[8]

Adverse effects increase significantly when used in higher doses, for durations over 5 days, and in patients who are over 75 years old.

Contraindications

Ketorolac is contraindicated in individuals who have adverse reactions or are allergic to NSAIDs. It 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.[9] In patients with renal disease or renal failure, ketorolac is contraindicated 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 in the geriatric population.[3]

Monitoring

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 monitored. 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. 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, it is essential to seek out alternative methods of pain reduction that either reduce or obviate the need for administering opioids. Higher-risk populations for opioid abuse include young males, individuals with a history of misuse, and individuals with significant mental health histories.[10] Clinicians should make a deliberate effort to identify patients in these populations and as a whole, decrease their opioid prescribing practices where possible. When examining emergency room prescription practices, the recent general trend shows a decrease in opioid prescriptions, but much room remains for improvement.[11] 

Ketorolac has demonstrated effectiveness equal to that of morphine when used postoperatively and has significant potential to be useful in emergency room settings for moderate to severe pain for which opioids are often regularly prescribed. When opioids are considered for acute pain, a multimodal approach can be beneficial to decrease opioid administration to the extent possible. A multidisciplinary team can also be helpful to correctly identify individuals who might benefit from alternative pain management medications or interventions, as well as coordinate or assist in implementing these alternate strategies. Given the relatively high toxicity profile of ketorolac, and the fact that 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 are to include pharmacists in this process, given their expertise in medication pharmacokinetics and proper dosing. Pharmacists can also ensure that adverse drug to drug interactions are decreased and can help decide which patients would be ideal candidates for ketorolac. Nurses play a vital role, given that they spend the most amount of 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 serve as a liaison between the ordering provider and the patient, informing providers 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 V]


References

[1] Gillis JC,Brogden RN, Ketorolac. A reappraisal of its pharmacodynamic and pharmacokinetic properties and therapeutic use in pain management. Drugs. 1997 Jan;     [PubMed PMID: 9010653]
[2] Forrest JB,Heitlinger EL,Revell S, Ketorolac for postoperative pain management in children. Drug safety. 1997 May;     [PubMed PMID: 9187531]
[3] Vacha ME,Huang W,Mando-Vandrick J, The role of subcutaneous ketorolac for pain management. Hospital pharmacy. 2015 Feb;     [PubMed PMID: 25717205]
[4] Hiľovská L,Jendželovský R,Fedoročko P, Potency of non-steroidal anti-inflammatory drugs in chemotherapy. Molecular and clinical oncology. 2015 Jan;     [PubMed PMID: 25469262]
[5] Drini M, Peptic ulcer disease and non-steroidal anti-inflammatory drugs. Australian prescriber. 2017 Jun;     [PubMed PMID: 28798512]
[6] Strom BL,Berlin JA,Kinman JL,Spitz PW,Hennessy S,Feldman H,Kimmel S,Carson JL, Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. A postmarketing surveillance study. JAMA. 1996 Feb 7;     [PubMed PMID: 8569017]
[7] Arfè A,Scotti L,Varas-Lorenzo C,Nicotra F,Zambon A,Kollhorst B,Schink T,Garbe E,Herings R,Straatman H,Schade R,Villa M,Lucchi S,Valkhoff V,Romio S,Thiessard F,Schuemie M,Pariente A,Sturkenboom M,Corrao G, Non-steroidal anti-inflammatory drugs and risk of heart failure in four European countries: nested case-control study. BMJ (Clinical research ed.). 2016 Sep 28;     [PubMed PMID: 27682515]
[8] Ingrasciotta Y,Sultana J,Giorgianni F,Fontana A,Santangelo A,Tari DU,Santoro D,Arcoraci V,Perrotta M,Ibanez L,Trifirò G, Association of individual non-steroidal anti-inflammatory drugs and chronic kidney disease: a population-based case control study. PloS one. 2015;     [PubMed PMID: 25880729]
[9] Bloor M,Paech M, Nonsteroidal anti-inflammatory drugs during pregnancy and the initiation of lactation. Anesthesia and analgesia. 2013 May;     [PubMed PMID: 23558845]
[10] Cragg A,Hau JP,Woo SA,Kitchen SA,Liu C,Doyle-Waters MM,Hohl CM, Risk Factors for Misuse of Prescribed Opioids: A Systematic Review and Meta-Analysis. Annals of emergency medicine. 2019 Jun 19;     [PubMed PMID: 31229388]
[11] Gleber R,Vilke GM,Castillo EM,Brennan J,Oyama L,Coyne CJ, Trends in emergency physician opioid prescribing practices during the United States opioid crisis. The American journal of emergency medicine. 2019 Jun 6;     [PubMed PMID: 31227419]