Ketorolac

Summary

Synopsis

Ketorolac is a non-steroidal agent with potent analgesic and moderate anti-inflammatory activity. It is administered as the tromethamine salt orally, intramuscularly, intravenously, and as a topical ophthalmic solution. Clinical studies indicate single-dose efficacy greater than that of morphine, pethidine (meperidine) and pentazocine in moderate to severe postoperative pain, with some evidence of a more favourable adverse effect profile than morphine or pethidine. In single-dose studies ketorolac has also compared favourably with aspirin, paracetamol (acetaminophen) and a few other non-steroidal anti-inflammatory drugs. If further investigation confirms the initially favourable findings regarding efficacy and tolerability, ketorolac will be a useful alternative to vpioid agents in postsurgical pain. It may well also find use in acute musculoskeletal pain, where it appears at least as effective as other agents with which it has been compared. From the limited clinical data available, ketorolac also seems promising in the treatment of ocular inflammatory conditions. Additional multiple-dose studies are required to evaluate fully the potential of ketorolac in the management of chronic pain states where it has shown superior efficacy to aspirin.

In summary, ketorolac offers promise as an alternative to opioid and to other non-steroidal analgesics in ameliorating moderate to severe postsurgical pain, and with wider clinical experience may find a place in the treatment of acute musculoskeletal and other pain states, and ocular inflammatory conditions.

Pharmacodynamic Studies

Ketorolac, in common with other non-steroidal anti-inflammatory drugs, is an inhibitor of prostaglandin synthesis. However, it possesses greater systemic analgesic than anti-inflammatory potency. In standard animal models of analgesic activity, ketorolac has exhibited up to 800 times the potency of aspirin (weight for weight). In all assays ketorolac was also more potent than indomethacin and naproxen, and demonstrated equal or greater potency than phenylbutazone. Animal models of systemic anti-inflammatory activity have provided less consistent indications of the relative potency of ketorolac: ID50 was 0.35 mg/kg in one assay, and intermediate between that of indomethacin and naproxen, while other assays indicate anti-inflammatory activity equal to or greater than that of indomethacin, greater than that of naproxen, and much greater than that of phenylbutazone. Tests of ocular anti-inflammatory activity indicate significant potency without exacerbation of underlying ocular infection. Antipyretic activity of ketorolac in rats was greater than that of aspirin and phenylbutazone, and equal to that of indomethacin and naproxen. Ketorolac appears to inhibit platelet aggregation induced by arachidonic acid and collagen, but not that induced by adenosine diphosphate (ADP), and to prolong mean bleeding time.

Pharmacokinetic Properties

The single-dose pharmacokinetic properties of ketorolac have been investigated in several studies, but its pharmacokinetic properties after multiple doses have been less well studied.

Ketorolac is rapidly absorbed, with a time to maximal plasma concentration (t_max) of as early as 30 to 40 minutes after oral administration to healthy volunteers, and of 45 to 50 minutes after intramuscular administration. The systemic availability of ketorolac is approximately 80% after oral administration. Food appears to reduce the rate, but not the extent, of absorption. Ketorolac is almost totally bound to plasma proteins. In healthy subjects, its apparent volume of distribution is 0.25 L/kg or less, its plasma clearance 0.021 to 0.037 L/h/kg, and terminal elimination half-life 4 to 6 hours. Ketorolac appears to cross the placenta, to the extent of approximately 10%, but is not found in breast milk in significant amounts.

The major metabolic pathway in humans is glucuronic acid conjugation. Approximately 90% of the dose is recovered in urine, with the remainder in faeces. Preliminary studies report the percentage of the dose excreted as unchanged ketorolac to be approximately 60%.

The rate of elimination of ketorolac appears to be reduced in the elderly and in patients with renal impairment, with plasma clearance reduced and elimination half-life prolonged. The influence of hepatic disease on the pharmacokinetics of ketorolac requires further investigation, but it seems that any alteration is unlikely to be clinically significant.

Therapeutic Trials

Ketorolac has been studied in a number of single-dose trials in patients with moderate to severe postsurgical pain. Ketorolac, usually 30 to 90mg intramuscularly, has shown analgesic efficacy superior to that of the opioid analgesics morphine (6 to 12mg), pethidine (meperidine) [50 and 100mg], pentazocine 30mg and ketobemidone. The lower 10mg dose of ketorolac is at least as effective as the opioid analgesics. A multiple-dose study showed ketorolac 30mg to be equivalent to morphine 12mg and superior to morphine 6mg when administered for up to 5 days.

Similarly, the single-dose efficacy of ketorolac 5 to 30mg orally appeared equal or superior to that of aspirin 650mg, paracetamol (acetaminophen) 500 to 1000mg, glafenine 400mg and naproxen 550mg after major surgery. Ketorolac 10 or 20mg was superior to aspirin 650mg, paracetamol 500mg and ibuprofen 400mg in alleviating pain associated with oral surgery. A 5-day multiple-dose study which compared oral ketorolac 20 or 40mg daily with diflunisal 1000mg daily found ketorolac superior to placebo in the acute postoperative phase. However, no significant difference in pain relief between the active treatments or placebo was observed during the chronic phase of the study. Additionally, no differences in efficacy were found between ketorolac 10 or 20mg, aspirin 650mg, paracetamol 500mg and ibuprofen 400mg when assessed on a repeated-dose basis.

There have been a small number of single-dose comparisons of ketorolac with combinations of opioid and non-steroidal or simple analgesics, and in these studies ketorolac 20mg has demonstrated efficacy equal to or greater than that of either aspirin or paracetamol plus codeine. A multiple-dose trial comparing ketorolac 10mg with paracetamol 1000mg + codeine 60mg up to 4 times daily showed both treatments to be similar in relieving pain. No differences in efficacy were found between ketorolac 10mg, dihydrocodeine 30mg or placebo, and repeated doses of ketorolac were equivalent to pentazocine 100mg.

Oral ketoroloc 10mg 4 times daily for up to 7 days tended to relieve acute musculo-skeletal pain better than ibuprofen 400mg, paracetamol 600mg + codeine 60mg or floc-tafenine 200mg in similar regimens, and was superior to diflunisal 500mg twice daily. Efficacy of ketorolac in other pain states, such as postpartum or labour pain, cancer pain, sciatica, renal colic or post-traumatic pain has not been fully investigated, although several preliminary single-dose or repeated dose comparisons with non-steroidal or opioid analgesics have been conducted. The limited experience with ketorolac in these indications at present does not permit any conclusions to be drawn regarding its efficacy.

Ketorolac 10mg up to 4 times daily appears superior to aspirin 650mg in the same regimen in chronic pain (mostly osteoarthritis), as evidenced by a multicentre trial in more than 800 patients.

In several studies of ketorolac ophthalmic solution administered after cataract surgery, marked anti-inflammatory efficacy was apparent in comparison with placebo and with dexamethasone. A further trial of ketorolac solution in cystoid macular oedema also indicated a potential role for ketorolac in this condition.

Adverse Effects

The overall incidence of adverse effects in published studies employing single intramuscular doses of ketorolac 10 to 90mg has ranged from 17 to 41%, in comparison with 17 to 62% for morphine 6 to 12mg, and 59% for pethidine 50 and 100mg. In a 5-day trial of oral ketorolac 20 to 40mg daily, the incidence of adverse effects was approximately twice that observed with placebo. Single-dose comparison of oral ketorolac with paracetamol has indicated a lower incidence of adverse effects overall with ketorolac (30 to40% compared with 50 to 57%). Nausea and headache were the unwanted effects most frequently reported by patients receiving ketorolac.

Overall, oral and intramuscular ketorolac would appear to be at least as well tolerated as alternative analgesics used to treat moderate to severe pain. Adverse effects reported after multiple intramuscular doses of ketorolac include somnolence (7%), injection site pain (2%), increased sweating (1%) and nausea (1%). Headache, dizziness, vomiting, pruritus, vasodilatation, and dysgeusia have also been reported, each with an incidence of less than 1%. Similarly, after oral ketorolac 10mg 4 times daily for up to 10 days post-operatively, adverse events reported to occur with a probable causal relationship to treatment included: somnolence (4% incidence); nausea, gastrointestinal pain, dyspepsia, diarrhoea, headache, or dizziness (each 2% incidence); constipation, nervousness, dry mouth, increased sweating, abnormal dreams, hyperkinaesia, myalgia, asthenia, or palpitations (1% each event). The only adverse effects which appear to increase with time (after 30 mg/day for up to 1 year in patients with chronic pain) include gastrointestinal pain (12%), dyspepsia (11%), and nausea (7%).

Dosage and Administration

In postoperative pain, single intramuscular doses of 10 to 90mg, and oral doses of 5 to 30mg, have usually been employed. A 4-times-daily regimen for longer term administration has been used. Ketorolac has also been administered topically in ocular inflammatory conditions in a 0.5% solution 3 or 4 times daily. It appears that systemic dosage should be reduced in the elderly and in patients with renal impairment; it is unclear whether hepatic disease necessitates dosage reduction.