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Ketorolac

A Reappraisal of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Use in Pain Management

Summary

Synopsis

Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) with strong analgesic activity. The analgesic efficacy of ketorolac has been extensively evaluated in the postoperative setting, in both hospital inpatients and outpatients, and in patients with various other acute pain states.

After major abdominal, orthopaedic or gynaecological surgery or ambulatory laparoscopic or gynaecological procedures, ketorolac provides relief from mild to severe pain in the majority of patients and has similar analgesic efficacy to that of standard dosages of morphine and pethidine (meperidine) as well as less frequently used opioids and other NSAIDs. The analgesic effect of ketorolac may be slightly delayed but often persists for longer than that of opioids. Combined therapy with ketorolac and an opioid results in a 25 to 50% reduction in opioid requirements, and in some patients this is accompanied by a concomitant decrease in opioid-induced adverse events, more rapid return to normal gastrointestinal function and shorter stay in hospital.

In children undergoing myringotomy, hernia repair, tonsillectomy, or other surgery associated with mild to moderate pain, ketorolac provides comparable analgesia to morphine, pethidine or paracetamol (acetaminophen).

In the emergency department, ketorolac attenuates moderate to severe pain in patients with renal colic, migraine headache, musculoskeletal pain or sickle cell crisis and is usually as effective as frequently used opioids, such as morphine and pethidine, and other NSAIDs and analgesics. Subcutaneous administration of ketorolac reduces pain in patients with cancer and seems particularly beneficial in pain resulting from bone metastases.

The acquisition cost of ketorolac is greater than that of morphine or pethidine; however, in a small number of studies, the higher cost of ketorolac was offset when treatment with ketorolac resulted in a reduced hospital stay compared with alternative opioid therapy.

The tolerability profile of ketorolac parallels that of other NSAIDs; most clinically important adverse events affect the gastrointestinal tract and/or renal or haematological function. The incidence of serious or fatal adverse events reported with ketorolac has decreased since revision of dosage guidelines. Results from a large retrospective postmarketing surveillance study in more than 20 000 patients demonstrated that the overall risk of gastrointestinal or operative site bleeding related to parenteral ketorolac therapy was only slightly higher than with opioids. However, the risk increased markedly when high dosages were used for more than 5 days, especially in the elderly. Acute renal failure may occur after treatment with ketorolac but is usually reversible on drug discontinuation. In common with other NSAIDs, ketorolac has also been implicated in allergic or hypersensitivity reactions.

In summary, ketorolac is a strong analgesic with a tolerability profile which resembles that of other NSAIDs. When used in accordance with current dosage guidelines, this drug provides a useful alternative, or adjuvant, to opioids in patients with moderate to severe pain.

Pharmacodynamic Properties

As a nonsteroidal anti-inflammatory drug (NSAID), ketorolac possesses analgesic, anti-inflammatory and antipyretic activity. The major mechanism by which ketorolac and other NSAIDs exert their pharmacological effects is inhibition of prostaglandin synthesis. NSAIDs are most active in the periphery but recent evidence suggests they may also act centrally.

In animal models of pain, ketorolac generally appears to have less analgesic activity than morphine; however, in single-dose clinical trials, it provided analgesia similar to that of morphine and other opioids. Ketorolac is significantly more effective than aspirin and paracetamol (acetaminophen), and at least as effective as pethidine (meperidine), ibuprofen or paracetamol combined with codeine or hydrocodone in the human dental pain model (extraction of third mandibular molars).

By virtue of its effect on prostaglandin synthesis, ketorolac may prolong bleeding times by inhibiting platelet aggregation. No significant differences in thromboelastographic parameters or prothrombin or partial thromboplastin times were evident between ketorolac and placebo recipients. This same mechanism of action may result in gastrointestinal (GI) ulceration or other adverse effects, either by a direct irritant effect or indirectly by decreasing prostaglandin-dependent gastric acid inhibition. However, the mucosal damage in the stomach of healthy volunteers induced by ketorolac 30mg intramuscularly is less than that seen with oral aspirin 650mg daily.

In patients with prostaglandin-dependent renal blood flow, the administration of ketorolac may adversely affect kidney function; this is minimal in patients without hypovolaemia or other risk factors for haemodynamic compromise. In one study in postoperative patients, no treatment-related changes in renal function occurred after treatment with ketorolac or placebo; however, significant differences between baseline and postoperative days 1 and 2 were seen in both treatment groups.

In contrast to opioid drugs, ketorolac does not alter gastric motility or haemodynamic variables or adversely affect respiration, nor is it associated with adverse CNS effects, abuse or addiction potential.

Pharmacokinetic Properties

The oral bioavailability of ketorolac is about 80 to 100%, and peak plasma concentrations (Cmax) are achieved within about 30 to 60 minutes after oral or parenteral administration. Food reduces the rate, but not the extent, of absorption. The bioavailability of the drug is similar after intramuscular or intravenous administration. The pharmacokinetic s of ketorolac are linear over the usual oral and parenteral dosage range. Steady-state plasma drug concentrations are about 50% higher than after single-dose administration.

As with other NSAIDs, ketorolac is almost entirely bound to plasma proteins (>99%), which results in a small apparent volume of distribution (Vd) [<0.3 L/kg]. It is extensively metabolised, primarily by conjugation with glucuronic acid, and excreted via the kidney. The metabolites have no significant analgesic activity. The mean terminal elimination half-life (t½β) of ketorolac in healthy volunteers is about 5 hours.

In the elderly, the absorption and plasma protein binding of ketorolac are unaffected; however, plasma drug clearance (CL) is reduced, which results in a moderate prolongation of t½β to about 6 to 7 hours. In paediatric patients, the Vd and CL of ketorolac appear to be greater than in adults and the t½β is similar; no correlation appears to exist between age (<1 to 18 years) and Vd, CL or t½β values.

As would be expected in patients with renal impairment, the plasma clearance of ketorolac is decreased, which results in an increased t½β (9 to 10 hours). Slight increases in t½β and time to Cmax are seen in patients with alcoholic cirrhosis.

Serum lithium concentrations increased, and resulted in toxic effects, in 2 patients after coadministration of lithium and ketorolac.

Therapeutic Use

The analgesic efficacy of ketorolac has been extensively evaluated in postoperative patients with moderate to severe pain after major abdominal, orthopaedic or gynaecological surgery. There is substantial interoperative and interpatient variation in patients’ response to therapy. Nevertheless, results indicate that single or multiple doses of intramuscular or intravenous ketorolac 10 to 30mg have similar analgesic efficacy to intramuscular morphine 10 to 12mg, pethidine 50 to 100mg, pentazocine 30mg or intravenous morphine 2 to 4mg, and greater efficacy than intramuscular diclofenac 75mg. The analgesic effect of ketorolac tends to be slower in onset than that of morphine or pethidine but persists for longer.

When administered via patient-controlled analgesia, ketorolac 5 mg/h provides similar pain relief to morphine 1 mg/h, dipyrone (metamisole, metamizole) 330 mg/h and lysine clonixinate (clonixin-lysinate) 15 mg/h in patients after major abdominal surgery, but may be less effective than tramadol 15 mg/h. Intermittent intramuscular administration of ketorolac results in analgesia which is much the same as that provided by nalbuphine, pethidine and a multi-ingredient product containing ketobemidone (Ketogan®) and slightly better than papaveretum.

Administration of a single oral dose of ketorolac 10mg to patients within 4 days after major surgery attenuates pain to the same extent as combination analgesic products containing paracetamol and ibuprofen, oxycodone (oxycone) or dextropropoxyphene (propoxyphene), or dextropropoxyphene, aspirin and phenazone (antipyrine). However, intramuscular morphine 10mg, but not 5mg, tends to provide greater pain relief than oral ketorolac 10mg in some patients after orthopaedic surgery.

Preoperative administration of ketorolac reduces pain in the immediate post-operative period. Combination therapy with ketorolac and opioids results in a significant 25 to 50% reduction in morphine and fentanyl requirements in the first 1 to 2 postoperative days and may be accompanied by a reduction in opioid-induced adverse events. In addition, some patients experience a more rapid return to normal GI function and shorter time in hospital.

In general, pre-, intra- or postoperative parenteral administration of a single dose of ketorolac 30 to 60mg appears to be an effective alternative to parenterally administered opioid agents such as fentanyl 50 to 100µg, pethidine 100mg, dezocine 6mg or other NSAIDs such as diclofenac 75 to 100mg (intramuscular or rectal), indomethacin 100mg (rectal) and piroxicam 40mg (oral) after various outpatient laparoscopic or orthopaedic procedures associated with mild to moderate pain. Intravenous or intra-articular administration of ketorolac combined with bupivacaine or lidocaine (lignocaine) provides better analgesia than either agent alone in patients after knee arthroscopy or hand surgery.

In paediatric patients, intramuscular or intravenous ketorolac 0.5 to 1.5 mg/kg provided similar analgesia to morphine 0.1 mg/kg, pethidine 1 mg/kg or paracetamol 35 mg/kg (rectal) after outpatient surgical procedures usually associated with mild to moderate pain, such as bilateral myringotomy, hernia repair and tonsillectomy.

In the emergency room, parenteral administration of ketorolac 10 to 60mg provides effective pain relief in the majority of patients with acute pain resulting from various causes including renal colic, sickle cell crisis, migraine headache, fractures, strains, sprains and gout. As in the postoperative setting, no significant difference in response to therapy is seen between patients treated with ketorolac and standard doses of morphine, pethidine, pentazocine, ibuprofen, diclofenac or indomethacin.

Subcutaneous administration of ketorolac 60 to 120 mg/day was beneficial in the treatment of some patients with cancer pain, especially those with a component of pain resulting from bone metastases, and was accompanied by a concomitant reduction in opioid dosage. However, in other cancer patients, morphine was more effective than ketorolac but less well tolerated.

Pharmacoeconomic Considerations

The pharmacoeconomic consequences of using ketorolac in the treatment of acute pain have not been extensively investigated. The acquisition cost of ketorolac ($US5.76 to 5.85/30mg; currency year not stated) is markedly higher than that of the commonly used opioids morphine ($US0.42 to 0.49/10mg; currency year not stated) or pethidine ($US0.59 to 1.30/100mg; currency year not stated). Nevertheless, results from some retrospective cohort studies indicated that, from a hospital perspective, the cost of therapy with ketorolac was favourable compared with that of control groups (patients typically received morphine or pethidine). Sensitivity analyses were not conducted. Cost savings arose primarily as a result of reduced length of stay in hospital.

As expected, the mean cost of hospitalisation varied with operative procedure, and duration of stay was the largest cost determinant. Procedures such as cholecystectomy, abdominal hysterectomy, major limb surgery/limb reattachment and lumbar laminectomy were associated with lower costs per patient treated with ketorolac than control. However, the reverse cost scenario was seen in patients who underwent intestinal resection, back and neck procedures and lumbar fusion. In a paediatric hospital, about $US52 000 (currency year not stated) was saved over a 3-year period by repackaging unit dose ketorolac 60mg syringes into smaller 7.5 to 30mg increments.

Tolerability

The tolerability profile of ketorolac and other NSAIDs is well defined and relates directly to the pharmacological action of these drugs, particularly with respect to effects on the GI tract and on renal and haematological function. The number and severity of adverse events which occurred in ketorolac recipients in the 3 years after the drug was released prompted regulatory review of drug labelling and usage in several countries. This subsequently led to revised prescribing guidelines and dosage recommendations.

Most adverse events with ketorolac involve the GI tract and range from mild upset to serious ulceration and haemorrhage. Results from a large postmarketing surveillance study (n > 20 000) indicate that, overall, parenteral ketorolac is associated with only a slightly increased risk of GI or operative site bleeding compared with opioids [odds ratios (OR): 1.30 and 1.02, respectively]. The risk of bleeding with ketorolac is strongly linked to increasing age, high dosages and treatment for more than 5 days. For example, elderly patients (aged ≥65 years) who receive ketorolac >120 mg/day have a significantly higher risk of GI bleeding than if they receive a lower dosage of ketorolac 30 mg/day (OR: 6.69 vs 1.13). In children who underwent tonsillectomy, parenteral administration of ketorolac was associated with a similar incidence of bleeding episodes to placebo but with a greater incidence than morphine, paracetamol or codeine. Ketorolac usually causes less nausea and vomiting than opioids.

All NSAIDs have the potential to cause nephropathies, but these occur more frequently in patients with hypovolaemia or other medical conditions which predispose them to haemodynamic compromise. Ketorolac-mediated renal toxicity is associated with increasing levels of serum creatinine, blood urea nitrogen and potassium, and decreased urine output. Importantly, nephrotoxicity is usually reversible on discontinuation of drug therapy; however, it may occur rarely in low-risk patients after a single dose.

As with other NSAIDs, ketorolac has been implicated in allergic or hypersensitivity reactions, ranging from bronchospasm to anaphylaxis.

Many of the reports of serious toxicity with ketorolac predated the revised manufacturers’ dosage guidelines and occurred at high dosages and in patients in whom drug therapy would not currently be recommended. The increased risk of GI events compared with opioids appears to be decreased by appropriate patient selection and prescribing.

Dosage and Administration

Ketorolac is available for intramuscular, intravenous or oral administration and is indicated for the short term treatment of moderate to severe pain which requires analgesia at the opioid level. In the US, the maximum recommended intramuscular single-dose treatment of ketorolac is 60mg. In healthy adults, the usual parenteral dosage is 10 to 30mg every 4 to 6 hours. The total daily dosage should not exceed 90 (UK, Italy, Spain, Belgium, Switzerland) or 120 mg/day (US, Mexico, Canada, Finland and Sweden). Parenteral therapy should be limited to 2 (e.g. UK) or 5 days (e.g. US) and oral therapy should replace parenteral treatment as soon as possible. The usual oral dosage is ketorolac 10mg every 4 to 6 hours to a maximum of 40 mg/day. In the US, oral administration of ketorolac is indicated only as continuation therapy after parenteral administration and the maximum duration of combined therapy is 5 days. In the UK, treatment with oral ketorolac may be initiated without prior parenteral therapy and should not exceed 7 days.

The total daily dosage of parenteral ketorolac should not exceed 60mg in patients aged ≥65 years or those with renal impairment (creatinine clearance of 1.2 to 3 L/h in the UK; not defined in the US) or bodyweight <50kg. The use of ketorolac is not currently recommended in children.

Treatment with ketorolac is contraindicated in patients with congestive heart failure, hepatic impairment, hypertension or conditions that may lead to a reduction in blood volume and in those who are hypersensitive to aspirin or other NSAIDs. Ketorolac should not be coadministered with other NSAIDs, probenecid, pentoxifylline or lithium and should be administered cautiously to patients on anticoagulation therapy (including low dose heparin).

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Correspondence to Jane C. Gillis.

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Various sections of the manuscript reviewed by: E. Alon, Department of Anesthesiology, Zurich University Hospital, Zurich, Switzerland; B. Bastani, Department of Internal Medicine, Health Sciences Center School of Medicine, St Louis University, St Louis, Missouri, USA; A.L. Buchman, Division of Gastroenterology Baylor College of Medicine, Houston, Texas, USA; D.B. Carr, Department of Anesthesia, New England Medical Center, Boston, Massachusetts, USA; J.N. Cashman, Department of Anaesthesia, St George’s Hospital, London, England; D. Fletcher, Département d’Anesthésie-Réanimation Chirurgicale, Hôpital de Bicêtre, Paris, France; P.J. Hughes, Anaesthetist, Central Anaesthetic Group, Melbourne, Victoria, Australia; F. Jamali, Faculty of Pharmacy, University of Alberta, Edmonton, Alberta, Canada; S.H. Roth, Arthritis Center Limited, Phoenix, Arizona, USA; A. Stein, Department of Urology, The Lady Davis Carmel Medical Center, Haifa, Israel.

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Gillis, J.C., Brogden, R.N. Ketorolac. Drugs 53, 139–188 (1997). https://doi.org/10.2165/00003495-199753010-00012

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Keywords

  • Morphine
  • Adis International Limited
  • Ketorolac
  • Pethidine
  • Analgesic Efficacy