Ketorolac

Abstract

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. 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. The oral bioavailability of ketorolac is about 80 to 100%, and peak plasma concentrations (C_max) 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) [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. 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).