Ketorolac: An Effective Non-Steroidal Anti-Inflammatory Drug

History and Mechanism of Action

Ketorolac tromethamine was first approved for medical use in the United States in 1989 and introduced as an injectable formulation for the short-term management of moderate to severe pain. The drug works by inhibiting both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, which are responsible for the production of prostaglandins that mediate pain and inflammation. By blocking these enzymes, ketorolac is able to reduce pain signals and lower inflammation. Unlike other nonsteroidal anti-inflammatory drugs (NSAIDs), ketorolac is considered a nonselective COX inhibitor as it equally inhibits both COX isozymes.

Approved Indications and Formulations

Ketorolac is currently approved by the FDA for short-term management (up to 5 days) of moderately severe acute pain that requires analgesic treatment, including postoperative pain and pain following oral and dental surgical procedures. It is available in both injectable and oral tablet formulations. The injectable form was the original formulation but is now primarily used in hospital settings for pain management following surgeries or medical procedures. The oral tablet form was introduced later and allowed for outpatient use by patients after being discharged from medical facilities. Both formulations provide rapid relief from pain symptoms.

Adverse Effects and Risks

While ketorolac is effective at reducing pain and inflammation, it does carry some risks like other NSAIDs due to its mechanism of action. Some common side effects include nausea, vomiting, abdominal pain, diarrhea, headache and dizziness. More serious risks include gastrointestinal ulceration and bleeding, as well as kidney toxicity with long-term or high-dose use. Because it inhibits platelet activity, ketorolac also increases the risk of bleeding complications. For this reason, it is contraindicated in patients with ischemic heart disease, cerebrovascular disease, or active peptic ulcers. Close monitoring is required when using ketorolac, especially in older patients or those with preexisting medical conditions.

Comparative Efficacy and Utilization Trends

Various clinical studies have demonstrated ketorolac’s comparable efficacy to opioid analgesics for treating acute moderate to severe pain. In particular, it has been shown to provide similar levels of postoperative pain relief as morphine when used intravenously. However, its adverse effect profile is relatively milder than opioids and it lacks the risks of abuse, addiction and respiratory depression associated with potent narcotics. As a result, ketorolac has seen increasing utilization as an alternative to opioids for acute pain management in both inpatient and outpatient settings. According to industry sales data, the U.S. ketorolac market was valued at over $50 million in 2020 and is projected to grow at a moderate pace of 2-4% annually through 2025. Its oral formulations make up the bulk of prescription fills filled in retail pharmacies and mail order channels.

Post-marketing Safety Concerns

After initial FDA approval, additional post-marketing studies revealed new safety risks with ketorolac use. Most notably, the drug was found to increase the risk of acute kidney injury even when used at recommended doses and for short periods as indicated. This prompted the removal of intravenous ketorolac and lowering the maximum allowable oral dose from 40mg to 30mg per day. Warnings were also strengthened regarding risks of cardiovascular events like heart attacks and strokes with ketorolac use, especially in patients with cardiac risk factors. More recently, studies have linked nonselective NSAIDs like ketorolac to increased hospitalizations for heart failure as well. While providing a less sedating alternative to opioids, balancing ketorolac’s analgesic benefits with its potential adverse effects remains an ongoing issue. Close clinical judgement is required.

Future Directions and Place in Therapy

As the opioid crisis has heightened in recent years, identifying safer non-narcotic options for treating acute pain remains a priority research area. While selective COX-2 inhibitors once held promise, their own cardiovascular risks ultimately limited clinical utility. For ketorolac, future research directions could involve evaluating lower oral doses that still provide adequate analgesia or developing formulations for longer term outpatient use. Combining it with proton pump inhibitors may help offset gastrointestinal risks as well. Overall, ketorolac maintains a niche role for short-term management of moderate to severe acute pain in both inpatient and select ambulatory settings. However, its nonselective mechanism requires close monitoring and restricts widespread use due to safety limitations compared to newer analgesic options. Careful patient selection balancing risks and benefits remains key to optimal clinical outcomes with this established non-opioid drug

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