FORMULARY FORUM

KETOROLAC: A PARENTERAL NONSTEROIDAL ANTIINFLAMMATORY DRUG Beth H. Resman-'Thrgoff

ABSTRACf: Ketorolac tromethamine is a pyrrolo-pyrrole nonsteroidal antiinflammatory drug (NSAID) with potent analgesic effects when administered intramuscularly for the treatment of acute pain. Ketorolac is well absorbed and has a rapid onset of action. Maximum plasma concentrations are achieved in 45-50 minutes and peak analgesic effects in about one to two hours following intramuscular injection. Ketorolac is more than 99 percent bound to plasma proteins and has a mean apparent volume of distribution of 0.11-0.25 I.Jkg. About 91 percent of a dose is excreted in urine, mostly as inactive metabolites, and approximately 6 percent is eliminated in feces. The elimination half-life, approximately four to six hours, increases in elderly patients and those with renal impairment. Its analgesic effectiveness was similar or superior to that of morphine, meperidine, or pentazocine in singledose studies of patients with postoperative pain or renal colic and greater than that of placebo in patients with chronic cancer pain. The adverse effects are generally mild to moderate, self-limiting, and similar to those seen with other prostaglandin inhibitors. Ketorolac has a reversible inhibitory effect on platelet aggregation. It can cause doserelated gastric ulcerations, even when administered parenterally. Ketorolac is a promising parenteral alternative to oral NSAIDs and a nonnarcotic alternative to opioid analgesics. Additional multiple-dose studies are needed to more clearly define its place in therapy. D/CP Ann Pharmacother 1990;24:1098-104. KETOROLAC TROMETHAMINE is a new nonsteroidal antiin-

flammatory drug (NSAID) indicated for the treatment of acute pain and recently approved by the Food and Drug Administration for intramuscular administration. It is a pyrrolo-pyrrole compound chemically related to tolmetin and zomepirac but it is a cyclized propionic acid derivative rather than an acetic acid derivative (Figure 1). 1 The tromethamine salt of ketorolac enhances its solubility; there are 6.8 mg of ketorolac in 10 mg of ketorolac tromethamine.2 The (-)-S enantiomer of the compound is responsible for its pharmacologic activity. 3 BETII H. RESMAN-TARGOFF, Pharm.D., is a Clinical Assistant Professor, Depart-

ment of Pharmacy Practice, College of Phannacy, University of Oklahoma, P.O. Box 26901, 1110 North Stonewall, Oklahoma City, OK 73190. Reprints: Beth H. ResrnanTargoff, Phann.D. Ketorolac tromethamine (foradol), Syntex Laboratories and Roche laboratories.

This article is approved for continuing education credit.

Figure I. Graphic formulas of ketorolac, tolmetin, and zomepirac.

Pharmacology Ketorolac is a potent inhibitor of the cyclooxygenase pathway of arachidonic acid metabolism, resulting in a decrease in prostaglandin and thromboxane production. 1 Other NSAIDs have additional effects on the lipoxygenase pathway of arachidonic acid metabolism with resultant decrease in leukotriene production. No studies have been published regarding the effects ofketorolac on leukotrienes or other mediators of pain or inflammation. Ketorolac was found to have potent analgesic, antiinflammatory, and antipyretic activity in animal models. 1•2 In those models, the analgesic activity is more prominent than the antiinflammatory effects. Ketorolac does not appear to have significant central nervous system effects or opioidlike activity nor does it enhance infection by inhibiting macrophage phagocytosis as do corticosteroids such as

1098 • DICP, The Annals of Pharmacotherapy • 1990 November, Volume 24

dexamethasone. 4 These beneficial effects of ketorolac are thought to be mediated, at least in part, by its inhibition of prostaglandin synthesis. The adverse pharmacologic effects of ketorolac, such as decreased platelet aggregation and gastric mucosal injury, are also believed to occur because of cyclooxygenase inhibition.

Biopharmaceutics and Pharmacokinetics The pharmacokinetic parameters for intramuscular ketorolac are summarized in Table I. Most pharmacokinetic determinations reported thus far have involved single-dose studies. Samples are analyzed for ketorolac by a reversedphase high-performance liquid chromatography assay method. ABSORPTION AND DISTRIBUTION

Ketorolac is rapidly and almost completely absorbed when administered intramuscularly, with a maximum plasma concentration achieved in 45-50 minutes. The mean peak plasma concentration with a 30-mg dose is 2.24 j.J.g/mL. 8 It exhibits a high degree of protein binding with about 99 percent being protein-bound in plasma. 5 It has a small mean steady-state volume of distribution of 0.11 L!kg with a volume of distribution of0.17-0.25 L!kg during the elimination phase. 9 •10 METABOLISM AND EXCRETION

Following intravenous injection or absorption after intramuscular or oral administration, ketorolac tromethamine dissociates into the anionic form ofketorolac at physiologic pH. 9 The decline in plasma concentration of ketorolac is best described by a two- or three-compartment model with elimination from the central compartment. Ketorolac appears to follow linear pharmacokinetics. 11 When single oral doses of 10-234 mg are administered, plasma concentrations increase in proportion to the dose while the elimination half-life remains constant. Similar linearity occurs when comparing pharmacokinetic parameters for intramuscular doses of 10-90 mg. 8 •9 Clearance did not change with multiple dosing. When Mroszczak et al. administered doses of 12.5 mg tid for 28 days, steadystate trough concentrations were achieved in 24 hours and remained similar throughout the study. 11 Approximately 91 percent of a dose of ketorolac is excreted in urine and 6 percent in feces regardless of whether the drug is administered orally or intravenously. The major metabolic pathway is thought to be glucuronide conjugation to an inactive metabolite. Since the glucuronide conjugate is found in urine but not in plasma, conjugation may occur in the kidney. It is estimated that at least 5-10 percent is excreted in the urine as unchanged ketorolac. The percentage of unchanged ketorolac is much higher if analysis is delayed because the glucuronide conjugate is unstable and undergoes hydrolysis. This has also been reported for other drugs such as naproxen and ketoprofen, which also contain a carboxylic acid group. A minor metabolic pathway for ketorolac is hydroxylation at the para-position tophydroxyketorolac,10 the only ketorolac metabolite found in plasma. 8 The amount of circulatingp-hydroxyketorolac is small relative to ketorolac and it is essentially inactive. It has less than 115 the antiinflammatory and less than 11100 the analgesic activity of ketorolac in animal models and

Table l. Pharmacokinetic Parameters Following a Single Intramuscular Dose of Ketorolac Tromethamine 30 mg to Selected Subjects CATEGORY

YOUNG

ELDERLY

RENAL IMPAIRMENT

HEPATIC IMPAIRMENT

Subjects (n) Mean age (y)

8 30 2.99

I3 72.1 2.52

10 57 2.57

7 51 2.62

0.75 4.45 I 1.3

0.97 6.95* 15.3

0.83 9.62* 25.1*

0.61 5.43* 12.7

0.44

0.32*

0.27*

0.48

5

5

6

7

Cmax

(jJ.g/mL) t..., (h) ~~(h)

AUC (jJ.g/mL•h) Cl (mL!min/kg) Reference

*Statistically significant difference (p:s0.05) versus young subjects. AUC =area under the plasma concentration-time curve; Cl =plasma clearance; C,.., = maximum plasma concentration; t~ = plasma elimination half-life; tm•• =time required to reach maximum plasma concentration.

about 1125 the activity of ketorolac in in vitro platelet aggregation tests. 10 Table l shows the results of studies on the effects of age, renal impairment, and hepatic impairment on the elimination of ketorolac. These studies reported a significant increase in plasma half-life and a decrease in total plasma clearance in the elderly 5 and renally impaired6 subjects compared with young volunteers. Although there was a statistically significant increase in plasma half-life among hepatically impaired subjects, it was not clinically significant. 7 The degree of renal or hepatic impairment among subjects was not specified and the renally and hepatically impaired subjects were older than normal young subjects.

Clinical Studies Five published studies on the efficacy of ketorolac clearly state that the intramuscular route of administration was used. Three additional studies of intramuscular ketorolac are described in abstract form. The efficacy of intramuscular injections of ketorolac has been investigated for the management of moderate to severe pain following major or oral surgery and for patients with renal colic or cancer (Table 2). The studies evaluated the analgesic effects of a single injection for 6-12 hours or until another analgesic was needed. The studies were double-blind, parallel-group designs using similar methods for measuring drug efficacy, including patient assessment of pain intensity by visual analog scales and evaluation of pain intensity, pain relief, and global impressions of therapy by verbal respo.nse scales. For example, pain intensity may be rated as none, mild, moderate, or severe. The scores were compared with baseline values and were graphed using the areas under the curves as measures of summed pain intensity difference and total pain relief. Ketorolac doses of 5-90 mg were more effective than placebou and comparable or superior to morphine,l3·14 meperidine,LS-18 and pentazocine19 in providing pain relief. Ketorolac has a rapid onset of effect similar to morphine but it has a longer duration of action. The analgesic effect peaks about one to two hours after administration. The mean duration of analgesia in patients receiving ketorolac following major surgery was approximately five to eight hours when judged according to

DICP, The Annals of Pharmacotherapy • 1990 November, Volume 24 • 1099

time of withdrawal from studies because of inadequate pain relief. In some studies, a ceiling analgesic effect occurred despite increasing dosage, and it was only in patients with severe pain that the effects of varying doses were differentiated. Multiple-dose studies of intramuscular ketorolac have been conducted but not yet published. In one study of postoperative pain in 452 patients, most of whom had undergone major surgery, patients received either ketorolac 30 mg or morphine 6 or 12 mg every two to three hours for up to five days or 20 doses (average 5 or 6 doses). The analgesic efficacy of ketorolac was similar to that of morphine 12 mg and better than morphine 6 mg. 20 Ketorolac may be used in combination with morphine therapy. Gillies et al. showed that ketorolac has a morphinesparing effect. Fifty-seven patients who underwent upper abdominal surgery received 24-hour intramuscular infusions ofketorolac 1.5 or 3.0 mglh or NaCl 0.9% as well as intravenous morphine through a patient-controlled analgesia system. Patients receiving ketorolac required almost one-third less morphine than did those receiving placebo. They had significantly lower pain scores with both doses at 4-6 hours (p

Ketorolac: a parenteral nonsteroidal antiinflammatory drug.

Ketorolac tromethamine is a pyrrolo-pyrrole nonsteroidal antiinflammatory drug (NSAID) with potent analgesic effects when administered intramuscularly...
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