Ketorolac Injections for Musculoskeletal Conditions: A Narrative Review

  • Clinical Medicine & Research
  • March 2024,
  • 22
  • (1)
  • 19-
  • 27;
  • DOI: https://doi.org/10.3121/cmr.2024.1847
PDF

Abstract

Musculoskeletal conditions of the upper and lower extremities are commonly treated with corticosteroid injections. Ketorolac, a parenteral nonsteroidal anti-inflammatory drug, represents an alternative injectant for common shoulder, hip, and knee conditions. A review of the current literature was conducted on the efficacy of ketorolac injection in musculoskeletal diseases. Several studies support the use and efficacy of ketorolac injection in subacromial bursitis, adhesive capsulitis, and hip and knee osteoarthritis. Given the systemic effects of glucocorticoid injections, ketorolac may be a safe and effective alternative in patients with musculoskeletal disease. However, more evidence is required to better understand the effects ketorolac has on the human body during inflammatory processes.

Keywords:

Musculoskeletal disease affects a large portion of the US population (33.2% in 2009-2011, on the rise from previous years). The US health care system was burdened by an aggregate economic impact of $796.3 billion in annual treatment costs of musculoskeletal diseases over this period of time.1

Arthritis and associated rheumatologic conditions are the most frequent cause of disability and work limitation in adults in the United States.2 Most musculoskeletal conditions are managed nonoperatively, and the use of prescription medications for musculoskeletal conditions are increasing at a rapid rate. Common nonoperative treatment options include rest, ice, physical therapy, exercise, weight loss, pharmacotherapy, bracing, and injections.3 Pooled data from the National Health Interview Survey from 2013 to 2015 suggest about 54 million (23%) adults in the United States suffered from arthritis.4 This amount is likely to have increased since then,4 and estimates indicate that by 2030, numbers could be as high as one-fourth (67 million) of the entire adult US population.5 A large fraction of those people will have arthritis-attributable activity limitations.

Arthritis can lead to enormous health care costs, disability, and lost wages. In 2011, there were approximately 964,000 hospitalizations in the United States due to osteoarthritis.6 At an average cost of $15,400 per stay, this represented a collective cost of $14.8 billion, making it the second most expensive condition observed in hospital stays and the second most costly condition billed to both private and government insurance companies.7,8 The need for nonoperative treatment has created a growing demand for non-physician providers and home health care visits that exceeds the capacity of the current health care system. Ketorolac injections may be a safe, efficacious, and financially beneficial alternative mode of therapy in patients with musculoskeletal disease, especially as compared to more traditionally administered injections of corticosteroids.

Corticosteroid injections are frequently used as part of a multimodal approach to treating several common orthopedic conditions.9 Common nonarthritic conditions include subacromial impingement, carpal tunnel syndrome, extensor tendinopathy (tennis elbow), stenosing flexor tenosynovitis, and de Quervain tenosynovitis, among others.10 Common arthritic conditions include glenohumeral, carpometacarpal, hip, and knee osteoarthritis.11 Although the exact mechanism of relief in these conditions following corticosteroid injection is not well understood, it is widely attributed to the anti-inflammatory properties of corticosteroids.12

Adverse effects of corticosteroid use include tendon rupture, subcutaneous atrophy, and articular cartilage changes.13,14 Systemically, hyperglycemia is common despite localized delivery of the medication.15 These adverse effects can limit the use of corticosteroid injections, particularly among patients with underlying conditions, such as diabetes mellitus.

It is proposed that ketorolac, a parenteral nonsteroidal anti-inflammatory drug (NSAID), represents a class of drug that has similar anti-inflammatory benefits as corticosteroids without the same adverse effect profile. Our study aim was to provide a narrative review of the use of ketorolac to treat common articular and extra-articular musculoskeletal conditions (Table 1).16-28

View this table:
Table 1.

Summary of included studies

Pharmacokinetics

Ketorolac tromethamine is an NSAID that provides analgesic and anti-inflammatory mechanisms of action through peripheral inhibition of prostaglandin synthesis from nonselective cyclooxygenase inhibitory activity.29,30 The medication is approved for oral, intramuscular, and intravenous administration. There is also a topical ophthalmic solution available. Off-label subcutaneous use has also been described.29 Common drug alternatives to ketorolac injections for musculoskeletal disease are corticosteroids and various formulations of hyaluronic acid. Corticosteroids are commonly injected both intra-articularly and extra-articularly; their mechanism of action is complex, with effects on the immune and inflammatory cascade at multiple levels. Injection of corticosteroids inhibits phagocytosis, neutrophil superoxide production, metalloprotease, metalloprotease activator, and prevents synthesis of inflammatory mediators, such as prostaglandin and leukotrienes.31 Unfortunately, corticosteroids also induce insulin resistance by glucose transporter type 4, leading to steroid hyperglycemia.32 Hyaluronic acid is reported to provide proteoglycan and glycosaminoglycan synthesis and mechanical, subchondral, analgesic, and anti-inflammatory effects through CD44-mediated actions.33

Ketorolac’s mean plasma half-life ranges from 5.21 to 5.56 hours, independent of route of administration and dose. The half-life is greatly impacted in patients with chronic kidney disease, but it is not affected by hepatic impairment.29 The bioavailability in adults following oral, intramuscular, or intravenous administration is estimated at 87%;29,34 however, pharmacokinetic properties of ketorolac delivered subcutaneously are not as clearly defined in the literature.34 Ketorolac is metabolized primarily through glucuronidation and hydroxylation in the liver, with the metabolic products excreted in the urine.29 Pregnancy and lactation also impact the pharmacokinetic characteristics of this drug; fetal risk in pregnancy cannot be ruled out, and infant risk has been demonstrated in breast feeding.29 No data are available on the pharmacokinetics of intra-articular ketorolac administration.

Subacromial Conditions

Shoulder pain is a common chief complaint in all age groups.35 Subacromial impingement syndrome frequently causes shoulder pain, representing 44% to 65% of all outpatient cases of shoulder discomfort.36 Subacromial shoulder pain includes conditions such as rotator cuff tendinopathy, subacromial impingement, and subacromial bursopathy.37 The pain and restriction in range of motion lead to disability and decreased quality of life,38 and irritation of the bursa against the coracoacromial arch is a common feature.39 Treatment is usually conservative, and subacromial bursa injections are commonly used.40

Goyal et al19 performed a randomized controlled study of 35 patients who received subacromial injections with 60 mg of ketorolac and 2% lidocaine, with the control arm receiving methylprednisolone (methylprednisolone 40 mg with 2% lidocaine). Both groups had statistically significant improvements in both visual analog scale (VAS) scores (evaluating shoulder pain) and disability index scores. No differences were found in the functional outcomes among either group (P=.16 for shoulder pain and disability index and P=.21 for VAS score).19

Taheri et al27 randomized 40 patients into two groups receiving either 40 mg of methylprednisolone or 60 mg of ketorolac as a subacromial injection, along with lidocaine. At 1-month and 3-month follow-ups, both groups had statistically significant reductions in VAS scores; however, no differences were found between the groups, suggesting both drugs were equally effective at relieving pain (P>.05).27

Kim et al21 randomized 60 patients with rotator cuff syndrome into two groups; one received a mixture of 1 mL of triamcinolone acetonide (40 mg/mL) and 1 mL of lidocaine hydrochloride 2%, while the other received a mixture of 1 mL of ketorolac tromethamine (30 mg/mL) and 1 mL of lidocaine hydrochloride 2%. Both groups showed similar clinical improvement at 3, 6, and 12 weeks after the procedure with no significant difference in outcomes between the two groups (P=.571).21

Min et al24 randomized 32 patients with external shoulder impingement to either a corticosteroid group treated with 40 mg triamcinolone or ketorolac group treated with 60 mg ketorolac into the subacromial space. At 4 weeks, they found that ketorolac resulted in greater improvement in the UCLA shoulder rating scale in both forward flexion and patient satisfaction. No significant difference was seen in other outcome measures.24

Glenohumeral Joint Conditions

Adhesive capsulitis, also known as frozen shoulder, is a medical condition in which the capsule of the shoulder joint gradually thickens over time, resulting in stiffness, dysfunction, immobility, and pain. The exact pathophysiology behind this process is not fully understood, but it is believed that it involves inflammation and excessive fibrosis, which causes capsular contraction (similar to Dupuytren disease) and reduced joint volume.41,42 This disease can be primary (idiopathic) or secondary (following surgery or trauma).

Treatment for this disorder usually includes physical therapy, oral medications, local injections, and surgery, all with widely different rates of success. The main goals of therapy are to reduce pain and restore joint movement. Akhtar et al17 conducted a randomized controlled trial in which 160 patients with adhesive capsulitis randomly received intra-articular injections with either 60 mg of ketorolac and 6 mL of 1% lidocaine with epinephrine (8 mL total) or 4 mL of 1% hyaluronic acid and 6 mL of lidocaine with epinephrine (10 mL total). They found the mean decrease in shoulder pain score at 4 weeks was remarkably better in the ketorolac group.17

Similarly, Ahn et al16 performed a prospective trial of adhesive capsulitis comparing intra-articular injections with 4 mL of 0.5% lidocaine and 40 mg of triamcinolone to 19 mL of 0.5% lidocaine and 30 mg of ketorolac. All injections were administered under ultrasound guidance, with the goal of achieving capsular distension. Two additional injections were administered at 2-week intervals, unless the reduction in self-reported pain in the verbal numeric pain scale was 50% or more. Follow-up interviews to evaluate pain outcomes were conducted at 1, 3, and 6 months. The authors did not find any difference in pain relief between the groups at 1, 3, or 6 months, suggesting that ketorolac and corticosteroid intraarticular injections were equally effective at relieving pain in patients with adhesive capsulitis. Furthermore, they found superior mobility (passive external rotation and abduction) in the ketorolac injection group compared to the corticosteroid group at 3 and 6 months after injection.16

Osteoarthritis of the Carpometacarpal Joint

Koh et al22 compared the safety and efficacy profiles of ultrasound-guided intra-articular injections of ketorolac and hyaluronic acid versus hyaluronic acid alone in patients with osteoarthritis in the carpometacarpal joint of the thumb with the hypothesis that adding ketorolac to hyaluronic acid could provide more prompt pain relief than hyaluronic acid alone. Of 74 patients, 38 received 0.5 mL of sodium hyaluronate and 0.5 mL of ketorolac, while 36 received 0.5 mL of sodium hyaluronate alone. At 1 month, the onset of pain relief was remarkably quicker in patients who received hyaluronic acid and ketorolac. Movement limitation and verbal numeric pain scale scores for the hand, arm, and shoulder improved at 1, 3, and 6 months after injection in both cohorts. No significant difference in analgesic properties was found at 1, 3, or 6 months following either injection.22 Overall, the study indicates that ketorolac’s quick onset of pain relief was a key benefit of adding the medication to an intra-articular injection.

Hip and Knee Conditions

Osteoarthritis is characterized by progressive damage to cartilage, bone, and other joint tissues that causes stiffness, pain, and functional limitation.43,44 Most cases occur without a specific identifiable trigger, cause, or injury.45 Obesity, however, is a risk factor for both knee and hip osteoarthritis.3 The hips and knees are among the most commonly afflicted joints by this condition. As of 2010, 3.8% of the world’s population was affected by osteoarthritis in the knee joints and 0.85% suffered from this condition in the hips, accounting for a substantial global disease burden, which is likely increasing due to the obesity epidemic.46

Park et al25 performed a retrospective review of 98 patients with hip osteoarthritis who underwent ultrasound-guided injection of the hip with either ketorolac or corticosteroids. The Harris hip score and verbal numeric pain scale ratings improved at 1, 3, and 6 months in both groups. There were no statistical differences observed between the two groups, suggesting intra-articular ketorolac injection is as effective as intra-articular corticosteroid injection in the treatment of osteoarthritis of the hip.25

Jurgensmeier and colleagues20 conducted a double-blinded randomized controlled trial of 110 patients with moderate or severe primary osteoarthritis of the hip or knee assigned to either a group receiving intra-articular ketorolac injections or one receiving intra-articular triamcinolone injections. Symptoms were evaluated before the procedure and at 1 and 3 months after injection. Patients in both the ketorolac and triamcinolone groups reported statistically significant improvement in outcomes and showed no significant difference when comparing both groups to each other. Post hoc tests suggested a slightly increased durability of the triamcinolone injection for the knee.20

Similarly, Xu et al28 performed a retrospective cohort study of 84 patients with symptomatic unilateral knee osteoarthritis to compare the safety and pain relief profiles between ketorolac and corticosteroids as an adjunct therapy to intra-articular injections of sodium hyaluronic acid. All patients received weekly injections for 5 weeks by the same physician, who was blinded to the patients’ groupings or drug schedules. During the first 3 weeks, Group A received injections with 5 mL of 0.5% lidocaine and 25 mg of triamcinolone and Group B received injections with 5 mL of 0.5% lidocaine and 10 mg of ketorolac. For the last 2 weeks, both groups received injections of only 2.5 mL of sodium hyaluronate. Patient-reported outcomes were recorded at 1, 2, 5, and 12 weeks after the first injection. Both groups experienced similar knee function improvement and overall pain relief.28

Bellamy et al18 conducted a double-blinded randomized controlled clinical trial comparing intra-articular ketorolac to corticosteroid injection among 35 patients with knee osteoarthritis verified clinically and radiographically. Patients randomly received an intra-articular injection of either 30 mg of ketorolac or 80 mg of triamcinolone acetonide. Patient-reported symptoms were measured at 0, 2, 6, 12, and 24 weeks after the injections. Both groups experienced similar functional improvement and pain relief in all timeframes; however, the authors noted at their institution, the cost of a single injection of triamcinolone was $12.28, while the cost of a ketorolac injection was $2.01 (a 143% difference in drug prices). Therefore, they argued it would be very cost-effective for an institution that performs high volumes of intra-articular injection procedures per year to consider ketorolac over corticosteroids.18

In a single-blind study, Lee et al23 evaluated the effectiveness of intra-articular injections of ketorolac compared to hyaluronic acid in patients with osteoarthritis of the knee. Individuals in the ketorolac group were given hyaluronic acid and ketorolac intra-articular injections once a week for 3 weeks, followed by 2 weeks of only hyaluronic acid injections. Patients in the hyaluronic acid group were given a weekly intra-articular injection of hyaluronic acid for 5 weeks. Patient-reported symptoms were recorded at baseline and after the first, third, fifth, and sixteenth week of injection protocol initiation. VAS and pain rating score reductions 1 week after initiating the ketorolac and hyaluronic acid injections, while 5 weeks was necessary to note improvement in the hyaluronic acid group. Five patients in the ketorolac group experienced focal knee pain for approximately 8 hours after the injections.23

Stalman et al26 examined local metabolism and inflammatory markers of the knee’s synovial fluid and subjective pain levels in patients who underwent knee arthroscopy following the administration of intra-articular injection with ketorolac, morphine, or placebo. Sixty patients were scheduled to undergo knee arthroscopy and randomly assigned into 3 groups of 20 patients. Each group was injected with either 10 mg of morphine, 60 mg of ketorolac, or 90 mg of sodium chloride into the knee joint approximately 10 minutes prior to surgery, as per protocol defined in the study. Both patients and surgeons were blinded by using unmarked syringes. The mean body mass index (BMI) was similar among the morphine (24 kg/m²), ketorolac (25 kg/m²), and placebo (23.3 kg/m²) groups with no statistically significant difference between them. Mean age was also similar at 37.7, 40.7, and 37.3 years among the morphine, ketorolac, and placebo groups, respectively. All surgeries were performed by the same surgeon. Pain measurements were assessed using VAS scores taken before and 4 hours after surgery. Upon discharge, each patient completed a questionnaire to assess their pain level at rest, during physical activity, and in general for the previous day using a numeric rating scale from 0 to 10. The questionnaire was also given once per day for the first week and on days 14 and 30 following the surgical procedure.

To assess the interstitial fluid, a subset of 30 patients (n=10 from each group) received microdialysis catheter implants under arthroscopic visual control in the synovial membranes of both the knee that underwent intervention and the contralateral knee for comparison. The metabolic status of the synovial fluid of both knees was assessed by collecting samples of lactate, glucose, glycerol, ethanol ratio, prostaglandin E2, and glutamate every 40 minutes during the first 4 hours after the surgical procedure. In all three groups, there was a comparable decrease in levels of pain intensity (based on the numeric rating scale) reported during days 1 through 7 and 14 (day 30 was excluded due to missing values). Preoperative and postoperative VAS scores were similar between the three groups.26

Prostaglandin E2 levels were significantly higher in the postoperative knee than the contralateral side in the morphine and placebo groups. The ketorolac group had significantly lower prostaglandin E2 levels; however, a comparable level was observed in both knees, implying ketorolac may have been absorbed systemically after injection into the surgical knee (this could not be confirmed, since plasma samples were not taken).26 It has been suggested that prostaglandin E2 and excitatory amino acids, such as glutamate, are important mediators of inflammatory pain.47

A time-dependent elevation in glycerol levels was observed in the ketorolac group; however, this was not the case for the placebo or the morphine groups.26 Glycerol is a constituent of cell membranes and may indicate toxicity in tissue with cellular damage.48 Hence, despite having well-known anti-inflammatory properties, ketorolac may also carry metabolically unfavorable effects that need to be further studied.

Glutamate was observed to have increased only in the postoperative synovial fluid and not the contralateral knee in all three groups.26 Furthermore, even though there was a reduction in glutamate levels in all the cohorts over time, it only reached statistical significance in the ketorolac and morphine groups. The authors posited that ketorolac affected the metabolism of glutamate, a substance that plays a crucial role in the process of inflammation and nociception.26 Of note, however, 60 mg of ketorolac given intra-articularly also has a systemic effect.

Safety

The safety profile of ketorolac is similar to that of other NSAIDs.49 The most important adverse effects involve the gastrointestinal tract, hematologic function, and renal function.30 The most common gastrointestinal events include gastritis and gastrointestinal distress; less common events include peptic ulcers, gastrointestinal hemorrhage, and gastrointestinal perforation. Reduced platelet aggregation is also associated with a decline in renal function.34 Rare, but serious renal adverse effects include kidney injury, nephrotic syndrome, renal failure, and tubulointerstitial nephritis. The advent of soluble and injectable NSAIDs has offered the potential advantage of delivering these anti-inflammatory agents to the local sites of inflammatory processes and enabled physicians to bypass the gastrointestinal tract. Local delivery may circumvent the systemic adverse effects of these medications.

As an alternative to intra-articular corticosteroids, intraarticular administration of ketorolac seems to have a safe profile. Animal model studies using knee intra-articular administration of NSAIDs have revealed no destructive effects on articular ligaments or cartilage or unfavorable kinematic function.50-52 In vitro bovine experiments seem to suggest that not only does ketorolac not damage cartilaginous tissue, but it may have protective benefits by inhibiting cytokines such as interleukin-1, a known trigger for cartilage damage during inflammatory processes.53

In a study comparing the safety profile and analgesic effects of ketorolac and corticosteroids as adjuncts to sodium hyaluronate intra-articular injections for the treatment of knee osteoarthritis symptoms, no serious adverse effects were found among the 42 patients who received 5 weekly ketorolac injections.28 Only three patients developed mild, focal, postinjection pain for about 1 to 3 days. All pain complaints were self-limiting and subsided with no supplemental treatment.28 Table 2 summarizes suggested ketorolac doses and preparations, routes of administration for various musculoskeletal entities seen in clinic, and possible adverse effects.29,54

View this table:
Table 2.

Suggested ketorolac dose, preparation, and routes of administration for various clinical entities, and possible adverse effects

Limitations of Ketorolac

Ketorolac may not be appropriate for all patients. Like other NSAIDS, ketorolac can have deleterious effects on the renal, gastrointestinal, and cardiovascular system. It may increase risk of hypertension and cerebrovascular or cardiovascular disease. It is also important to note that NSAIDs are the second most common cause of drug-induced hypersensitivity reactions, and clinicians should give special consideration to patients with asthma, nasal polyps, and chronic urticaria, where hypersensitivity may be as high as 27% to 35%.55 In patients who fit these risk profiles, other injectates may be preferred. It is important for the treating physician to approach the patient holistically when considering which, if any, injection is appropriate.

Conclusion

Intra-articular or intrabursal ketorolac injection may be a safe, efficacious, and cost-effective alternative to corticosteroids or other forms of conservative management for treatment of musculoskeletal conditions. Although the number of studies evaluating ketorolac injection are limited, its efficacy has been demonstrated in subacromial bursopathy, adhesive capsulitis, first carpometacarpal joint, and hip and knee osteoarthritis. While the safety profile of intra-articular ketorolac is not well described in the literature, the localized chondrotoxicity and systemic effects of intra-articular corticosteroids make ketorolac an appealing alternative. Further studies are warranted to better understand the intraarticular effects of ketorolac in the management of musculoskeletal conditions.

Footnotes

  • Disclosures: The have reported no financial support or other conflicts of interest related to this work. Data will be made available upon request of the authors. Dr. Pujalte is the guarantor of this manuscript.

  • Received April 27, 2023.
  • Revision received December 18, 2023.
  • Accepted January 9, 2024.

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In this Issue
Clinical Medicine & Research
Clinical Medicine & Research

Vol. 22, Issue 1

1 Mar 2024

Table of Contents Cover (Photo) Index by author
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Keywords

Anti-inflammatory agents, Arthritis, Glucocorticoids, Ketorolac, Musculoskeletal diseases, Nonsteroidal