Ketorolac

Ketorolac: An Injectable NSAID More than a dozen nonsteroidal anti-inflammatory drugs (NSAIDs) are now being marketed in the United States. With so many products to choose from, it would seem that enough NSAIDs are available to satisfy every analgesic need. [1-3] However, none of these agents are approved for parenteral use. Injectable indomethacin is available, but it is indicated only for the treatment of patent ductus arteriosus in infants. A parenteral nonnarcotic analgesic as potent as the opiates, but without the disadvantages, has been needed. Ketorolac tromethamine (Toradol), a new, noncontrolled injectable NSAID, may meet this need.

Chemistry

As s pyrrolo-pyrrole, ketorolac differs chemically from other NSAIDs such as proprionic acid, the indoles and the fenamates. Its unique features are high water solubility and potency, which make it suitable for parenteral use. The tromethamine salt enhances the drug's water solubility. [4]

Mechanism of Action

Like salicylates and other NSAIDs, ketorolac has analgesic, anti-inflammatory and antipyretic activity. Inhibition of prostaglandin synthesis through blockade of the cyclo-oxygenase pathway of arachidonic acid metabolism is probably responsible for both the beneficial and the toxic effects of the drug. [3] Ketorolac has not been shown to combine with opiate receptors, and its analgesic action appears to be unrelated to enkephalin-like activity. Animal studies suggest that the analgesic effect of ketorolac is greater than the anti-inflammatory effect. [4] Various mechanisms for the analgesic activity of NSAIDs have been suggested, but the drugs' action on cyclo-oxygenase seems to be the most plausible.

Like most othet NSAIDs, ketorolac reversibly inhibits platelet aggregation and may prolong bleeding time slightly. It has no effect on platelet count, prothrombin time or partial thromboplastin time. [5,6]

Pharmacokinetics

Ketorolac is completely absorbed from an intramuscular site, reaching a peak plasma concentration in about one hour. Plasma half-life is four to six hours in normal adults but is prolonged in the elderly (4.7 to 8.6 hours) and in patients with renal impairment (3.2 to 15.7 hours). This pattern suggests that moderate biotransformation occurs and that the kidneys excrete 90 percent of a single dose. Ketorolac is strongly (99 percent) protein-bound, and this attribute, combined with the drug's high water solubility, limits distribution primarily to vascular and extracellular compartments. Salicylates in high doses can displace ketorolac from its binding site and thus increase the likelihood of toxicity.

Pain relief may occur within ten minutes after intramuscular injection of ketorolac, but peak analgesic effects do not occur until one hour and 15 minutes to two hours after administration. For this reason, a loading dose of twice the every-six-hour maintenance dose is recommended to prevent delay in pain relief. Steady-state plasma levels in the effective range can be achieved and maintained by administering a dose every six hours. [7]

Analgesic Efficacy

The many clinical trials that have assessed the analgesic effect of ketorolac have used oral, intramuscular, intravenous and topical ophthalmic solutions. [8] Most clinicians believe that intramuscular injection is the most useful and practical mode of delivery for acute pain.

Single-dose comparative trials show that ketorolac is as effective as equivalent analgesic doses of morphine or meperidine (Demerol) and is longer-lasting. [9.10] Analgesic doses of ketorolac are compared with the doses of commonly used opiate analgesics in Table 1. It is apparent that, on a weight basis, the potency of ketorolac is almost equivalent to that of morphine. In one study, [11] a 30-mg dose of ketorolac proved superior to 30 mg of pentazocine (Talwin). Among patients with renal colic, [12] a 10-mg dose of ketorolac was founf to be as effective as a 100-mg dose of meperidine.

The quality of analgesia provided by ketorolac has not yet been evaluated in clinical studies. Since ketorolac has few central nervous system actions, the euphoria and amnesia characteristics of morphine would not be expected to occur. Ketorolac causes some drowsiness, but this effect is more likely to be associated with other aspects of the postoperative period, once acute pain has been relieved. A "morphine-sparing effect" of ketorolac was demonstrated in one study [13]; in the 24-hour period following abdominal surgery, the ketorolac-treated group required less morphine (administered by a patient-controlled analgesia system).

Few studies have focused on the chronic administration of ketorolac. Over a short postoperative period, ketorolac is well tolerated out fully comparable to morphine. [9] Some trials suggest that ketorolac has a slightly slower onset of action than morphine. [10] In Europe, an oral formulation of ketorolac for chronic pain has demonstrated thesame advantages and disadvantages of other NSAIDs.

Adverse Reactions

Adverse reactions reported in various studies include somnolence, nausea, edema, abdominal pain, diarrhea, dizziness, sweating and pain at the injection site; these side effects have occurred in 1 to 3 percent of patients. [8-10] No gastric ulceration or gastrointestinal bleeding was recorded in chronic studies, but this complication may occur in susceptible patients or in those who have been receiving long-term NSAID therapy prior to ketorolac administration. The drug does not cause respiratory depression, and important advantage over opiates. Tolerance and physical dependence did not occur in clinical trials. Chronic administration of ketorolac (as well as other NSAIDs) has not resulted in reported drug dependence. In the acute studies, the incidence of gastrointestinal bleeding was less then 1 percent.

Liver function tests have shown slight elevations in as many as 15 percent of patients. [8] These elevations are usually inconsequential but may be important in patients with prior liver damage. Because long-term administration of large doses of NSAIDs results in renal damage in both animals and humans, caution is required if ketorolac is used in patients with liver or renal impairment. [8]

Although animal studies have shown no evidence of mutagenesis, carcinogenesis or impairment of fertility, ketorolac is not recommended for use in pregnancy. Ketorolac is excreted in breast milk and consequently should be avoided in nursing mothers.

Ketorolac should not be used for obstetric analgesia, because the inhibition of prostaglandin synthesis is likely to affect uterine contractility and may decrease fetal circulation. [14] The drug should also be avoided or used cautiously in patients with a history of hypersensitivity to aspirin or other NSAIDs.

Drug Interactions

To date, few drug interactions have been reported. Since ketorolac is highly bound to plasma proteins, drugs that are capable of displacing ketorolac significantly increase its potential for toxicity. Likely candidates are warfarin, salicylates and, possibly, other NSAIDs. It is reasonable to avoid simultaneous administration of these drugs with ketorolac.

Clinical Use

Parenteral ketorolac is a potent NSAID that has been approved for the short-term management of pain. Most studies have demonstrated its effectiveness in alleviating postoperative pain. The drug is of particular benefit in patients with chronic obstructive pulmonary disease or other respiratory problems, since it does not depress respiration.

Limited data suggest a possible role of ketorolac in the management of other forms of acute pain, such as renal colic, biliary colic, sickle cell crisis or migraine headaches. Ketorolac is also useful in patients with a history of opiate dependency. It can be combined with opiate analgesia to achieve a sparing effect, although it will not prevent opiate withdrawal symptoms. If a patient receiving a low dose of ketorolac (e.g., 15 mg every six hours) experiences a return of pain before the next dose, the dose may be increased to 30 mg before a narcotic analgesic is added or substituted.

Ketorolac tromethamine is available for single-dose administration as 1-mL Cartrix syringes containing 15 or 30 mg and 2-mL syringes containing 60 mg. The drug is approximately ten times more expensive than morphine in equivalent dosage. [15] However, the use of ketorolac could save personnel costs associated with the control of injectable narcotics. [16]

REFERENCES

[1.] Facts and comparisons. ST. Louis: Facts and Comparisons Div., Lippincott, 1990:1016-24.

[2.] Zarro V. Nonsteroidal anti-inflammatory drugs: a review. Am Farm Physician 1984;30(5):243-6.

[3.] Ross JM, DeHoratius RJ. Nonnarcotic analgesics. In: DiPalma JR, DiGregorio GJ, eds. Basic pharmacology in medicine. 3d ed. New York: McGraw-Hill, 1990:309-23.

[4.] Rooks WH 2d, Tomolonis AJ, Maloney PJ, Wallach MB, Schuler ME. The analgesic and anti-inflammatory profile of (+/-)-5-benzoyl-1,2-dihydro-3H-prrrolo[1,2a]pyrrole-1-carboxylic acid (RS-37619). Agents Actions 1982;12:684-90.

[5.] Gannon R. Focus on ketorolac: a nonsteroidal anti-inflammatory agent for the treatment of moderate to severe pain. Hosp Formul 1989;24:695-702.

[6.] Conrad KA, Fagan TC, Mackie MJ, Mayshar PV. Effects of ketorolac tromethamine on hemostasis in volunteers. Clin Pharmacol Ther 1988;43:542-6.

[7.] Honig WJ, Van Ochten J. A multiple-dose comparison of ketorolac tromethamine with diflunisal and placebo in postmeniscectomy pain. J Clin Pharmacol 1986;26:700-5.

[8.] Buckley MM, Brogden RN. Ketorolac. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs 1990;39(1):86-109.

[9.] Yee JP, Koshiver JE, Allbon C, Brown CR. Comparison of intramuscular ketorolac tromethamine and morphine sulfate for analgesia of pain after major surgery. Pharmacotherapy 1986;6:253-61.

[10.] O'Hara DA, Fragen RJ, Kinzer M, Pemberton D. Ketorolac tromethamine as compared with morphine sulfate for treatment of postoperative pain. Clin Pharmacol Ther 1987;41:556-61.

[11.] Estenne B, Julien M, Charleux H, Arsac M, Arvis G, Loygue J. Comparison of ketorolac, pentazocine and placebo in treating postoperative pain. Curr Ther Res 1988;43:1173-82.

[12.] Oosterlinck W, Philp NH, Charig C, Gillies G, Hetherington JW, Lloyd J. A double-blind single dose comparison of intramuscular ketorolac tromethamine and pethidine in the treatment of renal colic. J Clin Pharmacol 1990;30:336-41.

[13.] Gillies GW, Kenny GN, Bullingham RE, McArdle CS. The morphine sparing effect of ketorolac tromethamine. A study of a new, parenteral non-steroidal anti-inflammatory agent after abdominal surgery. Anaesthesia 1987;42:727-31.

[14.] Walker JJ, Johnstone J, Lloyd J, Rocha CL. The transfer of ketorolac tromethamine from maternal to foetal blood. Eur J Clin Pharmacol 1988;34:509-11.

[15.] Ketorolac tromethamine. Med Lett Drugs Ther 1990;32(825):79-81.

[16.] Koffer H, Hildebrand JR 3d, Connell ML. Potential for nonnarcotic analgesics to save personnel costs associated with controlling injectable morphine and meperidine. Am J Hosp Pharm 1990;47:1084-8.

JOSEPH R. DIPALMA, M.D., coordinator of this series, is emeritus professor of pharmacology and medicine at Hahnemann University School of Medicine, Philadelphia.

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