Ketorolac (Oradol): A. New Analgesic Or an Old NSAID?

Ketorolac (Trdo)~~ Ale nlei Ketorolac (oradol): A. new analgesic or an old NSAID?

William Spickler, MD, PhD

In the preceding editorial Drs. Robert E. Ariano and produce no adverse effects but significant nar- and Sheryl A. Zelenitsky correctly describe ke- cotic-sparing effects.4'9 torolac (Toradol) as a nonsteroidal anti-inflam- Given orally 10 mg of ketorolac was found to be matory drug (NSAID) that is effective in the short- more effective than or as effective as other common- term management of pain and the only NSAID in ly used oral opioid combinations (e.g., acetamino- Canada available in both a parenteral and an oral phen [600 mg] plus codeine [60 mg]) in the treat- form. ment of mild to moderate pain.5 Ketorolac and other NSAIDs inhibit the synthe- Since ketorolac became available for routine use sis of prostaglandins. Ketorolac is a potent inhibitor in Canada, in April 1991, the clinical trial experience of fatty acid cyclo-oxygenase, the first enzyme in the has been confirmed: the parenteral form of the synthetic pathway from arachidonate to prostagland- drug is particularly useful for managing acute pain ins. The reduction in prostaglandin levels results in postoperatively when a parenteral analgesic is both anti-inflammatory and analgesic effects. needed6"'0-'3 and after dental surgery.5'8 Contin- As Ariano and Zelenitsky point out, there is a uation of the treatment of acute pain with the oral pharmacologic separation of these effects in that form has been effective.14 ketorolac produces a predominantly analgesic effect Physicians should be aware that NSAIDs have rather than an anti-inflammatory one when given their own adverse effects. Ketorolac's product mono- in clinically useful doses. Ketorolac is not known graph2 clearly describes patients who should not be to affect opiate receptors; therefore, its analgesic given any NSAID: those who are allergic to ketoro- effects are solely the result of prostaglandin inhib- lac, those who are allergic to ASA or other NSAIDs ition. Also, there is no evidence of a central, mor- (a cross-sensitivity may be present) and those with phine-like activity.' Ketorolac's product mono- the complete or partial syndrome of nasal polyps, graph2 clearly indicates that it is an NSAID, but angioedema, bronchospastic reactivity (e.g., asthma) the drug is different from other NSAIDs in that or other allergic reactions to NSAIDs. NSAIDs its analgesic property far exceeds its anti-inflamma- should be avoided in patients who are prone to tory one. In animal studies ketorolac produced up peptic ulcers or inflammatory disease of the gastroin- to 800 times the analgesic effect of acetylsalicylic testinal tract. They should be used with great caution acid (ASA).3 in patients with impaired renal function because of The parenteral and oral formulations of ketoro- their known inhibition of prostaglandin synthesis. lac have been studied extensively in randomized, Elderly patients are at an increased risk for serious double-blind clinical trials that involved placebo and adverse effects from all NSAIDs. Epidemiologic active controls.4-7 These trials tested the drug's studies have identified age as a significant risk factor analgesic effect on patients who had undergone for acute hemorrhage of the gastrointestinal tract general, gynecologic and orthopedic surgery. The from NSAIDs.'5 Prudent clinical judgement dictates drug was also tested on patients after acute ambula- caution and the lowest effective dose in treating tory care such as dental surgery.8 In the parenteral elderly people. form 30 mg of ketorolac was found to provide as Ariano and Zelenitsky specify that the incidence much pain relief as 100 mg of meperidine or 12 mg rates of adverse events affecting the central nervous of morphine given intramuscularly; 10 mg of ketoro- system and the gastrointestinal tract are 23% and lac provided the same relief as 50 mg of meperidine 13% respectively in patients given ketorolac paren- or 6 mg of morphine. As well, the parenteral form of terally. However, they fail to mention that these ketorolac could be used concurrently with opioids figures came from two postoperative multiple-dose

Dr. Spickler is vice-president and director ofmedical research, Pacific Sector, Syntex Corporation, Palo Alto, Calif

Reprint requests to: Dr. William Spickler, Division ofDevelopment Research, Syntex Corporation, PO Box 10850, 3401 Hillview Ave., Palo Alto, CA 94303, USA

MAY 15, 1993 CAN MED ASSOC J 1993; 148 (10) 1693 studies of ketorolac and morphine given intramuscu- tising and promotional materials. Such information larly.7"6 In the group of patients given morphine the helps physicians make rational and considered thera- incidence rates of adverse events were 44% and 28% peutic decisions. respectively, roughly twice as high as the rates for I agree with Ariano and Zelenitsky that paren- ketorolac. teral ketorolac therapy may be indicated in patients In discussing the cost of ketorolac versus narcot- who have a contraindication to narcotic analgesics. ics Ariano and Zelenitsky do not consider the true However, whether all such patients should first be cost of postoperative pain management. The direct given an oral or rectal form of NSAIDs is debatable. cost of parenteral narcotic therapy to the pharmacist To my knowledge the parenteral form of ketorolac is is very low. However, it has been demonstrated that the only NSAID indicated for the short-term man- in comparison with patients given narcotics those agement of moderate to severe pain; for patients given ketorolac can consume liquids and food by undergoing major abdominal, orthopedic or gyneco- mouth and can walk sooner, require less nursing logic surgery a parenterally administered NSAID time and leave the hospital sooner.14 In one random- offers an important treatment option. ized controlled trial of parenteral and oral ketorolac In conclusion, ketorolac is an effective analgesic therapy versus parenteral therapy with meperidine in the management of acute pain. It is a member of followed by oral therapy with acetaminophen plus the group of drugs that inhibit prostaglandin synthe- codeine (Syntex: unpublished observations) the net sis and is uniquely available in both a parenteral and saving with ketorolac was $74.71 (Cdn) per patient, an oral form. It has been shown to have an efficacy primarily owing to an earlier release from hospital. comparable to that of narcotics in the treatment of One study that compared parenteral ketorolac many painful conditions and is cost effective when therapy with parenteral meperidine and morphine total care costs are considered. An effective analgesic therapy examined personnel costs in five US hos- that can be given parenterally and orally and does pitals.'7 The potential saving with the use of a not have narcotic side effects is an important add- noncontrolled analgesic such as ketorolac ranged ition to the treatment options available for the from 13¢ to 36¢ (US) per dose; the weighted average management of acute pain. was 23¢ (US) per dose. This could translate into a significant saving, given that the five hospitals dis- References pensed 191 000 parenteral doses of narcotic analgesics in 1986.'7 The reductions in the length of 1. Rooks WH, Maloney PJ, Shott LD et al: The analgesic and anti-inflammatory profile of ketorolac and its tromethamine hospital stay and the amount of care have been salt. Drugs Exp Clin Res 1985; 11: 479-492 shown to result in a significant saving to the health 2. Product Monograph: Toradol (Ketorolac Tromethamine), 10 care system. This does not consider the cost to mg Tablets; Toradol IM (Ketorolac Tromethamine Injection), society of addiction from the misuse of narcotic 10 mg/mL, 15 mg/mL or 30 mg/mL Intramuscular Injection. Analgesic Agent, Syntex Inc, Mississauga, Ont, 1992: 1 analgesics. 3. Rooks WH, Tomolonis AJ, Maloney PJ et al: The analgesic With regard to the oral formulation Ariano and and anti-inflammatory profile of RS-37619. Agents Actions Zelenitsky chose to compare the costs of ketorolac 1982; 12: 684-690 and several drugs that are used primarily as anti- 4. Burns JW, Aitken HA, Bullingham RES et al: Double-blind comparison of the morphine sparing effect of continuous and inflammatory agents rather than analgesics. It might intermittent i.m. administration of ketorolac. Br J Anaesth have been more appropriate to compare ketorolac 1991; 67: 235-238 with drugs such as floctafenine and mefenamic acid, 5. Forbes JA, Butterworth GA, Burchfield WH et al: Evaluation whose prices and indications are comparable to of ketorolac, aspirin, and an acetaminophen-codeine com- bination in postoperative oral surgery pain. Pharmacotherapy those of ketorolac. 1990; 10 (6, pt 2): 77S-93S The authors correctly point out that the adver- 6. Stanski DR, Cherry C, Bradley R et al: Efficacy and safety of tising of ketorolac has focused on its comparison single doses of intramuscular ketorolac tromethamine com- with narcotics. Indeed, some of Syntex's clinical pared with meperidine for postoperative pain. Ibid: 40S-44S 7. Brown CR, Mazzulla JP, Mok MS et al: Comparison of repeat trials tested whether ketorolac could be used instead doses of intramuscular ketorolac tromethamine and morphine of narcotics, especially in the short-term manage- sulfate for analgesia after major surgery. Ibid: 45S-50S ment of acute pain. The facts in the advertisement 8. Fricke JR, Angelocci D, Fox K et al: Comparison of the stand. Whether physicians make therapeutic de- efficacy and safety of ketorolac and meperidine in the relief of dental pain. J Clin Pharmacol 1992; 32: 376-384 cisions based solely on what they read in advertise- 9. Gillies GWA, Kenny GNC, Bullingham RES et al: The ments is moot. I believe that before prescribing new morphine sparing effect of ketorolac tromethamine. Anaesthe- medicines most physicians refer to the official pre- sia 1987; 42: 727-731 scribing information, which is found in the Compen- 10. Yee JP, Koshiver JE, Allbon C et al: Comparison of intramuscular ketorolac tromethamine and morphine sulfate for dium of Pharmaceuticals and Specialties (Canadian analgesia of pain after major surgery. Pharmacotherapy 1986; Pharmaceutical Association, Ottawa), the product 6: 253-261 monograph and material that accompanies all adver- 11. O'Hara DA, Fragen RJ, Kinzer M et al: Ketorolac trometha-

1694 CAN MED ASSOCJ 1993; 148 (10) LE 15 MAI 1993 mine as compared with morphine sulfate for treatment of Congress, American College of Surgeons, New Orleans, Oct postoperative pain. Clin Pharmacol Ther 1987; 41: 556-561 11-16, 1992: 510-512 12. Estenne B, Julien M, Charleuz H et al: Comparison of 15. Buchanan WW, Bellamy N: NSAIDs: clinical efficacy and ketorolac, pentazocine, and placebo in treating postoperative toxicity. Inflammopharmacol 1991; 1: 1 1 5- 133 pain. Curr Ther Res 1988; 43: 1178-1183 16. Spindler JS, Mehlisch D, Brown C: Intramuscular ketorolac and morphine in the treatment of moderate to severe pain 13. Andujar EG: Analgesia with ketorolac (Toradol) or pentazo- after major surgery. Pharmacotherapy 1990; 10 (6, pt 2): 51S- cine (Fortral) in patients with post-traumatic orthopaedic 58S pain. Clin Trials J 1990; 27: 211-218 17. Koffer H, Hildebrand JR III, Connell ML: Potential for 14. Tommeraasen M, Mehlisch D, Otterson W et al: A double- nonnarcotic analgesics to save personnel costs associated with blind study of the impact of postoperative analgesics on controlling injectable morphine and meperidine. Am J Hosp health care utilization. In Surgical Forum: 78th Clinical Pharm 1990; 47: 1084-1088

Conferences Jerusalem, Israel continuedfrom page 1681 Ortra Ltd., 2 Kaufman St., PO Box 50432, Tel Aviv 61500, Israel; tel 011-972-3-664825, fax 011-972-3- June 16-18, 1993: 26th Annual Meeting of the Society for 660952 Epidemiologic Research Keystone, Colo. June 23-24, 1993: IMAC '93 - 3rd International Dr. Richard Hamman, Department of Preventive Conference on Image Management and Communication Medicine and Biometrics, UCHSC, PO Box 425, (followed by CAR '93 - Computer Assisted Radiology) Denver, CO 80262; tel (303) 270-6863, Berlin, Germany fax (303) 270-3183 Official language: English IMAC '93, Professor Heinz U. Lemke, Institut fur June 16-19, 1993: 28th Meeting of the Canadian Congress Technische Informatik, Technische Universitat, of Neurological Sciences Sekr. CG FR 3-3, Franklinstrasse 28/29, W- 1000, Toronto Berlin 10, Germany Permanent Secretariat, Canadian Congress of Neurological Sciences, Ste. 810, 906-12 Ave. SW, Calgary, AB June 24-26, 1993: CAR '93 - Computer Assisted T2R 1K7; tel (403) 229-9544, tel (403) 229-1661 Radiology (preceded by IMAC '93 - International Conference on Image Management and June 16-20, 1993: 6th International Symposium of Facial Communication) Plastic and Reconstructive Surgery (sponsored by the Berlin, Germany American Academy of Facial Plastic and Reconstructive Official language: English Surgery) CAR '93, Professor Heinz U. Lemke, Institut fur, San Francisco Technische Informatik, Technische Universitat, Cindy Butler, symposium coordinator; tel (202) 265-4704, Sekr. CG FR 3-3, Franklinstrasse 28/29, W- 1000, fax (202) 265-4714 Berlin 10, Germany

June 20-24, 1993: Canadian Association of Radiologists June 24-26, 1993: Pediatric Emergency Therapeutics 56th Annual Scientific Meeting (PET) and Pediatric Advanced Life Support (PALS) Quebec Course (followed by the Canadian Paediatric Society Suzanne Charette, executive director, Canadian 70th Annual Meeting) Association of Radiologists, 510-5101 Buchan St., Vancouver Montreal, PQ H4P 2R9; tel (514) 738-3111, Canadian Paediatric Society, 401 Smyth Rd., Ottawa, ON fax (514) 738-5199 K1H 8L1; tel (613) 737-2728, fax (613) 737-2794 June 25-27, 1993: Lung Association 93rd Annual Meeting Du 20 au 24 juin 1993: L'Association canadienne des Halifax radiologistes 56e reunion scientifique annuelle Lung Association, National Office, 508-1900 City Park Quebec Dr., Blair Business Park, Gloucester, ON K1J 1A3; Suzanne Charette, directeur executif, L'Association tel (613) 747-6776, fax (613) 747-7430 canadienne des radiologistes, 510-5101, rue Buchan, Montreal, QC H4P 2R9; tel (514) 738-3111, June 26-27, 1993: Pediatric Advanced Life Support fax (514) 738-5199 Calgary Shelley Gerelus, Cardio-Pulmonary Resuscitation June 20-25, 1993: International Adolescent Health Week Program, Mount Royal College, 4825 Richard Rd. SW, in Israel - 2nd International Conference on Youth and Calgary, AB T3E 6K6; tel (403) 240-6090, Disability, 2nd European Forum on Adolescent Health fax (403) 240-6729 and Symposium on "Quality of Life, Youth and Disability" continued on page 1702

MAY 15, 1993 CAN MED ASSOC J 1993; 148 (10) 1695