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The analgesic efficacy of ketorolac for acute pain
The Journal of Emergency Medicine. Vol 14, No I, pp 67-75, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0736-4679196 $15.00 + .OO
SSDI 0736-4679( 95)02052-7
Pharmacology of Emergency Medicine
THE ANALGESIC
EFFICACY
OF KETOROLAC
Michael S. Catapano,
FOR ACUTE
PAIN
MD
Department of Emergency Medicine, North Shore University Hospital-Cornell University Medical College, Manhasset, New York Reprint Address: Michael S. Catapano, MD, Department of Emergency Medicine, North Shore University HospitalCornell University Medical College, 300 Community Drive, Manhasset, NY 11030
q Abstract-Ketoroiac is a nonsteroidal anti-inflammatory drug, available in both oral and parenteral forms, that possesses significant analgesic potency. Its analgesic efficacy has been studied extensively for the treatment of moderate-to-severe pain in many clinical settings. Although ketorolac possesses significant analgesic potency, it has limited utility as an analgesic for the acute treatment of moderate-to-severe pain in the emergency department. Oral ketorolac has been shown to provide analgesia that is the same or better than aspirin, acetaminophen, and dextropropoxyphene with acetaminophen, and equal analgesia to most other commonly available oral analgesics, including ibuprofen and acetaminophen with codeine. Intramuscular ketorolac provides analgesia equivalent to commonly used doses of meperidine and morphine. However, its utility in acute pain, when rapid relief is necessary, is limited due to a prolonged onset to analgesic action (30-60 min) and a significant number of patients who exhibit little or no response, more than 25% in most studies. The use of intravenous ketorolac has been less well studied. It has analgesic potency but its utility in patients with moderate-to-severe pain is also limited because there is a significant percentage of patients who fail to obtain adequate relief. Ketorolac may be most useful in supplementing parenteral opiates. Cl Keywords-ketorolac;
and ethical foundation for this approach, improved patient satisfaction and clinical outcome, and reduced costs make it imperative that emergency physicians be expert in acute pain management. Unfortunately, pain management surveys performed in many clinical settings, including the Emergency Department, continue to demonstrate that up to half of patients with pain obtain inadequate relief ( 1- 11). These studies have documented many reasons to explain the discrepancy between the goal of optimal pain management and the failure in practice to provide a large proportion of patients with effective pain relief. Certainly, work pressure may prevent nurses and physicians from performing adequate pain assessments on patients, leading to an underestimation of pain. Suboptimal use of available analgesics, such as intramuscular administration of fixed doses of opiates on an “as needed” basis, also leads to inadequate pain relief. Erratic absorption of medication can occur after intramuscular administration, and patients have a wide variation in analgesic requirements. Adverse effects of available agents and exaggerated fear of physical dependency cause a reluctance to administer sufficient doses of opiates. Many physicians do not have rapid and complete relief of pain as their goal of pain management, settling for the lesser goals of “making the patient comfortable” or “taking the edge off the pain,” thus impairing their ability to provide optimum pain relief. The Clinical Practice Guidelines for Acute Pain Management developed by the Agency for Health Care Policy and Research, United States Department of Health and Hu-
analgesia; acute pain
INTRODUCTION Providing effective pain relief is central to the mission of the emergency physician. In addition to the moral
of Emergency Medicine is coordinated by Richard F. C&k, MD, of the University of California, San Diego Medical Center, and the San Diego Regional Poison Center, San Diego, California RECEIVED: 14 December 1994; FINAL SUBMISSION RECEIVED : 19 April 1995; ACCEPTED: 10 May 1995 Pharmacology
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M. S. Catapano
68
man Services, emphasizes these points (12). These guidelines and other educational efforts will assist clinicians in acute pain assessment and management. Educational programs may improve pain management, but clinicians’ efforts at providing effective pain relief are hampered by the adverse effects of currently available drugs. Opiates can cause respiratory depression, hypotension, bowel and bladder dysfunction, and nausea and vomiting, which limit their utility. Nonsteroidal anti-inflammatory drugs (NSAID) and acetaminophen have an analgesic ceiling and have their own set of toxic effects. An ideal analgesic agent for emergency department use would have several characteristics. It would be painless to administer and have a quick onset of action. There would be a low incidence of well-tolerated adverse effects. It would have no analgesic “ceiling” above which increased doses of the drug have no effect. Availability in oral and parenteral forms would be useful, and the cost should be similar to other available analgesics. The drug would have no potential for abuse or dependency. There is currently no drug that meets these criteria. Ketorolac is a nonsteroidal anti-inflammatory drug with significant analgesic properties. It has been used extensively in emergency departments for a variety of painful conditions, frequently as a first-line drug. Printed advertisements promise the analgesic strength of narcotics without the adverse effects of narcotics. This article will examine the pharmacology and clinical trials of ketorolac to define the role of ketorolac for acute pain management in the emergency department.
PHARMACOLOGY Ketorolac is an inhibitor of prostaglandin synthesis and is structurally related to tolmetin and zomepirac ( 1315 ) . It has an adverse effect profile and anti-inflammatory, antipyretic, and analgesic properties similar to other NSAIDs. Ketorolac is available for both oral and parenteral use. Ketorolac possesses moderate anti-inflammatory effects. It is much more potent than phenylbutazone, indomethacin, or naproxen in inhibiting the formation of carrageenan induced paw edema in rats, an animal model of inflammation ( 13,14). Similarly, ketorolac is more potent than indomethacin and naproxen in inhibiting the formation of cotton-pellet induced granulomas and the development of arthritis in an adjuvant induced arthritis model in rats, two other animal models of inflammation (13,14). Ketorolac has significant analgesic properties in animal models of analgesia ( 13,14). It demonstrates substantial potency in animal models of analgesia in which inflammation is the inciting cause. These include inhi-
bition of phenylquinone induced writhing in mice, inhibition of pain provoked by flexing adjuvant inflamed paws in rats, and inhibition of pain provoked by compression of yeast inflamed paws in rats. Ketorolac, unlike opiates, does not reduce the pain threshold in the normal, noninflammed state. Ketorolac inhibits the pain provoked by compression of yeast inflamed paws in rats but has no effect on the pain threshold in non inflamed paws. Ketorolac also has no effect on hot plate induced pain in mice, an animal model of analgesia that measures centrally acting or morphine-like analgesic effects. Morphine is very active in this test. This test indicates that ketorolac has no centrally acting or morphine-like analgesic effects. Ketorolac does not bind to opioid receptors and has low addictive potential (16). More recent studies suggest that ketorolac may have some central analgesic effects unrelated to opioid receptors (17,18). Ketorolac has a pharmacological and toxic effect profile similar to other nonsteroidal anti-inflammatory drugs ( 13). It does not possess corticosteroid activity or stimulate the adrenal gland to release corticosteroids. Ketorolac has moderate potency as an antipyretic (13,19). Gastrointestinal erosive activity occurs in rats given oral ketorolac ( 13 ) . An endoscopic study in humans showed that short-term administration of both parenteral and oral ketorolac results in gastric ulceration (20). Except for the 90 mg intramuscular dose of ketorolac, the degree of ulceration produced by ketorolac was less than that produced by two aspirin tablets (650 mg) . Whether or not a single intramuscular dose of ketorolac results in a significant rate of gastric ulceration is unknown. Ketorolac has no activity on the central nervous system at usual therapeutic doses. No behavioral effects were observed in mice and dogs given ketorolac, except at extremely high dosages. Ketorolac does not potentiate hexobarbital induced sleep in mice, possesses no anticonvulsant activity, and has no effect on electroencephalogram recordings ( 13 ) The effect of ketorolac on hemostasis appears to be minimal (21-24). It has no effect on the prothrombin time and partial thromboplastin time. Like other NSAIDs, ketorolac inhibits platelet aggregation and leads to a modest prolongation of the bleeding time, although still in the normal range. The clinical significance of this finding is uncertain. Ketorolac should probably be used cautiously in patients in whom significant bleeding is a concern. Unlike opiates, ketorolac has no hemodynamic or ventilatory effects (25 -29). Intraoperative and postoperative studies on patients show that ketorolac use results in no change in heart rate, blood pressure, cardiac output, or pulmonary vascular pressure. Opiates, on the other hand, have significant effects on these
Ketorolac for Acute Pain
hemodynamic parameters. When administered intraoperatively or to human volunteers, ketorolac has no effect on respiratory rate or end-tidal carbon dioxide partial pressure. As expected, opiates cause a decrease in the respiratory rate and an increase in the end-tidal carbon dioxide partial pressure. Intramuscular injections of ketorolac are nonirritating, as shown by histologic and muscle enzyme studies in animals (14). Oral, intramuscular (IM), and intravenous (IV) administration of ketorolac results in similar pharmacokinetic profiles with only a few differences (30-32). Studies in human volunteers show that absorption and bioavailability of ketorolac is complete after oral, intramuscular, and intravenous dosing. Absorption is rapid for all three forms of dosing. As would be expected, the time to reach peak serum concentration (t,,) is shortest after intravenous use, approximately 5 min. The t mmafter oral use, 30-53 min, may be slightly shorter than for intramuscular use, 45-50 min. The peak serum concentration (C,,) after a 10 mg dose is the same for both oral and intramuscular dosing. The C,, following intravenous use is almost three times greater than after oral or intramuscular administration. The serum halflife ranges from 5-6 hours for all three forms of administration. Ketorolac is over 99% bound to plasma proteins. Ketorolac is metabolized in the liver to form inactive glucuronide metabolites ( 13 ) . A small amount of ketorolac is converted to para-hydroxy ketorolac, an inactive metabolite. The primary route of excretion of unchanged ketorolac and its metabolites is by the kidneys. Very small amounts of ketorolac are excreted into breast milk or enter the fetal circulation (33,34). There are significant differences in the pharmacokinetics of ketorolac in the elderly and in patients with kidney disease when compared to normal volunteers (35-38). The elimination of ketorolac is reduced in both of these groups, leading to a longer serum halflife. Dosing intervals should be longer in these patients. As with most NSAIDs, ketorolac should be used cautiously, if at all, in patients with renal impairment or hypoperfusion, because of the risk of renal failure. Patients with hepatic impairment show no alteration in the pharmacokinetics of ketorolac when compared to healthy controls (38,39).
CLINICAL
STUDIES OF ORAL KETOROLAC
Oral ketorolac has been shown to provide analgesia that is equal to the most commonly used oral analgesics. These include ibuprofen, diflunisal, aspirin with codeine, acetaminophen with codeine, dextropropoxy-
69
phene with acetaminophen, and acetaminophen with hydrocodone. Oral ketorolac has been shown to provide the same or better analgesia than acetaminophen and aspirin. Most of these studies, however, were done in patients undergoing operative procedures, using single doses of analgesics; they may not reflect the needs of patients requiring analgesia in the emergency department. Many patients in the emergency department have pain unrelated to surgery and require an analgesic that will be effective with multiple dosing. Despite these provisos, much useful information can be gleaned from these clinical trials. Ketorolac provides the same or more effective pain relief than aspirin. In 120 women with postpartum uterine pain, ketorolac 10 mg was slightly better than aspirin 650 mg and more effective than ketorolac 5 mg (40). In two single-dose studies involving patients with postoperative pain, ketorolac 10 mg and 20 mg and aspirin 650 mg gave equivalent relief (41,42). Ketorolac 20 mg may have been slightly more effective. In a single- and multiple-dose trial involving patients undergoing oral surgery, ketorolac 10 mg was significantly superior to aspirin 650 mg in all measurements of pain relief (43). Patients with chronic pain also favor ketorolac 10 mg over aspirin 650 mg. In a l-year study of patients with chronic pain, there were significantly more treatment failures with aspirin than with ketorolac (44). Adverse effects associated with ketorolac in these studies were mild and no worse than aspirin. Aspirin 650 mg with codeine 60 mg has approximately equivalent analgesic efficacy to ketorolac 10 mg and 20 mg in postoperative patients (41,42). Two studies show that ketorolac provides the same or better pain relief than acetaminophen. Single doses of acetaminophen 500 mg and 1000 mg were compared to ketorolac 5 mg, 10 mg, and 20 mg in postoperative orthopedic patients (45). All treatments were superior to acetarninophen 500 mg and ketorolac 5 mg. Ketorolac 10 mg and 20 mg had better scores than acetaminophen 1000 mg in most measurements of pain relief, however, these differences were not statistically significant. In a single- and multiple-dose study of patients undergoing oral surgery, ketorolac 10 mg and 20 mg had the same analgesic efficacy and were both better than acetaminophen 600 mg (46). Adverse effects in these studies were mild and the same in all treatment groups. Acetaminophen with codeine and ketorolac have similar analgesic efficacy. In patients following oral surgery, gynecological surgery, ambulatory surgery, and with cancer pain, single- and multiple-dose studies of ketorolac 10 mg compared to acetaminophen 6001000 mg with codeine 60 mg show equivalent pain relief (43,47-49). One study in patients with oral surgery showed that ketorolac 10 mg and 20 mg was
M. S. Catapano
70 significantly more effective than acetaminophen 600 mg with codeine 60 mg (46). For the most part, adverse effects were the same, except somnolence and nausea and vomiting were more common in patients treated with acetaminophen and codeine. Oral ketorolac has similar analgesic efficacy to other NSAIDs. In a 5-day clinical trial involving postmeniscectomy patients, ketorolac 10 mg and diflunisal 500 mg, a salicylic acid derivative, gave the same pain relief (50). Ketorolac 10 mg also had the same analgesic efficacy as naproxen sodium 550 mg in postoperative patients and ibuprofen 400 mg in oral surgery patients (46,5 1) . In postoperative patients, ketorolac IO mg was better than a combination of ibuprofen 400 mg and acetaminophen 325 mg (52). Ketorolac also compares favorably with opiates and other opiate combinations. Oral ketorolac 10 mg was found to have the same analgesic efficacy as intramuscular morphine 10 mg in postoperative patients (5 1,53). Morphine had a slight advantage in peak pain relief. Ketorolac 10 mg is superior to dextropropoxyphene 65 mg with acetaminophen 400 mg in postoperative patients, and acetaminophen 1000 mg with hydrocodone 10 mg in patients following oral surgery (52,54). There was more nausea and vomiting in patients receiving acetaminophen with hydrocodone than ketorolac. A short-term clinical trial of ketorolac in cancer patients also showed analgesic efficacy (55). Ketorolac 10 mg appears to have equal efficacy when compared to pentazocine 50 mg, with fewer adverse effects. Oral ketorolac has been shown to provide analgesia that is equal to or better than aspirin, acetaminophen, and dextropropoxyphene with acetaminophen. Aspirin with codeine, acetaminophen with codeine, pentazotine, acetaminophen with hydrocodone, ibuprofen, and dihunisal provide equivalent analgesia to ketorolac. Ketorolac 20 mg provides little, if any, additional analgesic benefit compared to ketorolac 10 mg. Adverse effects are mild and well tolerated. Sedation, nausea, and vomiting occur less frequently with ketorolac than with opiate combinations. Aspirin, acetaminophen, ibuprofen, and acetaminophen with codeine are available for pennies per tablet, while ketorolac 10 mg costs over one dollar per tablet. Oral ketorolac is recommended for acute pain control only and is not intended for chronic pain management.
CLINICAL
STUDIES OF INTRAMUSCULAR KETOROLAC
Much of the early enthusiasm for the use of ketorolac as an analgesic resulted from several studies that compared various doses of intramuscular ketorolac with intramuscular opiates. Ketorolac was found to be as
effective, or better, than opiates. Clinical trials using intramuscular medications for severe pain, however, have been criticized ( 12). The absorption of intramuscular medications can be erratic and, frequently, is not rapid enough to provide prompt analgesia. The more appropriate standard for prompt relief of acute, severe pain is intravenous boluses of opiates, titrated to the individual needs of the patients. Ketorolac has shown analgesic potency comparable to morphine in single-dose clinical trials involving postoperative patients. Intramuscular ketorolac 10 mg, 30 mg, and 90 mg and morphine 6 mg and 12 mg were compared in two studies. One study showed that ketorolac 90 mg was superior to morphine 12 mg. Ketorolac 10 mg and 30 mg and morphine 12 mg had equivalent efficacy (56). In the second study, ketorolac 30 mg and 90 mg were similar to morphine 12 mg for peak relief but had a substantially longer duration of action (57). It is important to note that in both of these studies, many patients in all treatment groups withdrew because of inadequate pain relief. Furthermore, significant pain relief did not occur until 30-60 min after the injection. The slow onset of intramuscular analgesics is further demonstrated by a study that determined the time of onset of analgesia for intramuscular ketorolac 30 mg and morphine 10 mg (58). Less than one-half of the patients achieved a 50% reduction in their pain by 1 hour. The incidence of nausea and vomiting was about the same for ketorolac- and morphine-treated patients. Ketorolac and morphine have also shown equivalent analgesic efficacy in multiple-dose trials in postoperative patients. Several studies have compared ketorolac 30 mg IM to morphine lo-12 mg IM (59-62). Both ketorolac and morphine were found to be effective analgesics for short-term use. However. patients receiving ketorolac tended to more frequently request rescue analgesia than did patients in the morphine groups. As in the previous set of studies, many patients did not receive adequate relief with either ketorolac or morphine, suggesting that intramuscular use of fixed doses of analgesics on an “as needed” basis is a suboptimal method of relieving moderate-to-severe pain. Ketorolac has more analgesic efficacy than commonly used doses of meperidine when used in postoperative patients. Two brief reports showed ketorolac 30 mg and 90 mg IM to be at least equal, and frequently more effective than meperidine 50 mg and 100 mg IM (63,64). These findings were confirmed in two other reports. In postoperative patients and in patients undergoing oral surgery, ketorolac 30 mg and 90 mg IM gave equal or better peak pain relief than did meperidine 100 mg IM (65,66). As would be expected from the pharmocokinetics of the two drugs, the duration of pain relief was much longer with ketorolac than with
Ketorolac for Acute Pain
meperidine. In women following cesarean section, ketorolac 30 mg IM and meperidine 75 mg IM provided the same relief ( 67). Neither medication provided optimal pain relief, as demonstrated by the high rate of withdrawal from these studies because of lack of efficacy. There was slightly less nausea and vomiting in the ketorolac-treated patients. There is one published report comparing ketorolac with pentazocine in postoperative patients (68). Ketorolac 30 mg IM provided adequate pain relief for most patients and was consistently better than pentazocine 30 mg IM. Pentazocine was associated with inadequate relief in many patients and was generally not different from placebo. Intramuscular ketorolac may be useful in decreasing opiate requirements in patients with moderate-to-severe pain. Intravenous opiates are very effective in relieving pain, but their efficacy and associated patient satisfaction is limited by adverse effects, such as nausea and vomiting, respiratory depression, and sedation. In several. brief reports, the “opioid sparing” effect of ketorolac was minimal (69-7 1) . However, multipledose studies using ketorolac 30 mg IM given every 6 hours and continuous infusions demonstrate the use of ketorolac can reduce morphine requirements by up to 67% (72-77). Unfortunately, no significant associated reduction in typical opiate side effects was observed, bringing into question the necessity of decreasing the amount of opiates administered. The analgesic efficacy of intramuscular ketorolac for acutely painful conditions not associated with surgery has been less extensively studied. Mixed results have been observed in patients with cancer-related pain, acute migraine, sickle cell vaso-occlusive crisis, acute gouty arthritis, renal colic, and a variety of acutely painful conditions. Three doses of ketorolac, 10 mg, 30 mg, and 90 mg, were compared to placebo in patients with nonspecified cancer-related pain (78). All three ketorolac groups reported better pain relief than placebo, but were not significantly different from each other. About onequarter of the ketorolac-treated patients did not receive sufficient relief and withdrew from the study. There appears to be limited analgesic efficacy of ketorolac in patients with acute headache and migraine. An uncontrolled study reported significant pain relief in headache patients given ketorolac 60 mg (79). However, controlled clinical trials suggest that ketorolac has limited benefit. In three separate studies, ketorolac 60 mg IM was compared to dihydroergotamine one mg IV with metoclopramide (80)) meperidine 100 mg with hydroxyzine 50 IM (8 I), and meperidine 75 IM (82). Ketorolac was no better, and usually worse, than the other treatment groups in providing relief. From 40 to 70% of the ketorolac patients still had
71
moderate-to-severe pain and required rescue medication. The short study period (1 hour) in these trials may have caused an underestimation of ketorolac’s effects, since its usual onset to peak analgesia is l-2 hours. An uncontrolled, unblinded study of self-administered ketorolac 60 IM in headache patients showed that 64% reported good relief (83). As in the other studies, a substantial number of patients had little or no pain relief. Anecdotal reports of ketorolac’s utility in sickle cell vaso-occlusive crisis have not been supported in a small, controlled study (84). Patients with sickle cell vaso-occlusive crisis were given IV meperidine 50 mg and IV promethazine 12.5 mg to start (85). They then received either ketorolac 60 mg IM or saline placebo and were followed for 4 hours. Patients were able to receive IV meperidine 25-50 mg every 30 min, as needed, if pain persisted. Pain relief was the same in the ketorolac and placebo groups, as was the total amount of meperidine administered. Ketorolac has analgesic efficacy in the treatment of renal colic. Ketorolac 10 mg, 90 mg, or meperidine 100 mg were given to patients with renal colic (86). Ketorolac 90 mg provided superior relief to the other treatment groups. Ketorolac 10 mg and meperidine 100 mg provided equivalent relief but were associated with a 40% rate of inadequate analgesia. This study is of limited value since neither of the two ketorolac doses are commonly used for the treatment of acute pain. Ketorolac has analgesic efficacy in many other painful conditions that are commonly seen in the emergency department. An uncontrolled study in nine patients with acute gouty arthritis reported that all patients had significant relief (87). An uncontrolled study of 445 emergency department patients with a variety of painful conditions treated with ketorolac 60 mg IM showed that a majority of patients had some pain relief, although the amount of pain relief was not specified (88). In a controlled clinical trial of emergency department patients with a variety of painful conditions, ketorolac 60 mg IM and meperidine 100 mg IM provided the same pain relief (89). Intramuscular ketorolac provides analgesia equivalent to commonly used doses of meperidine and morphine. However, its utility in the management of moderate-to-severe pain in the emergency department, when rapid relief is necessary, is very limited due to a prolonged onset to analgesic action (30-60 min) and a significant number of patients who exhibit little or no response, more than 25% in most studies. Patients with less than moderate-to-severe pain will most likely receive adequate relief from oral analgesics and would not require parenteral analgesics. Ketorolac 90 mg may have a slight advantage over the 30 mg dose, but at a cost of increased gastric ulceration. There are no
M. S. Catapano
i2
published data that suggest that ketorolac 60 mg is superior to 30 mg. A dose of 0.5 mg/kg appears to be effective in children. Ketorolac may be associated with slightly less nausea and vomiting than opiates.
CLINICAL
STUDIES OF INTRAVENOUS KETOROLAC
When used as a single agent, intravenous ketorolac has analgesic efficacy but provides inadequate pain relief for many patients with moderate-to-severe pain. Two similar studies in patients with postoperative pain compared intravenous ketorolac 10 mg and 30 mg with morphine 2 mg and 4 mg (90,9 1) . A second dose was given 15 min later, if needed. The morphine 2 mg group experienced less pain relief than the other three treatment groups. Ketorolac 10 mg, 30 mg, and morphine 4 mg provided equal analgesia. Most patients withdrew from the studies because of inadequate pain relief. Ketorolac 30 mg compared favorably with fentanyl 50 pg in postoperative patients, but a significant withdrawal rate due to ineffective analgesia was observed in this study as well (48). A study done in children undergoing surgery found ketorolac to be slightly less effective than morphine (92). Morphine had a quicker onset of analgesia. More patients in the ketorolac group required rescue analgesia. There is ample evidence that concomitant use of ketorolac and an opiate will result in less opiate used. Brief reports have shown that intravenous ketorolac can reduce the amount of morphine, meperidine, and sufentanil used in postoperative patients (93,94). Compared to placebo, intravenous ketorolac can also reduce the amount of morphine or meperidine required in postoperative patients, both adults and children, using patient controlled analgesia systems (25,95-97). Patients in the ketorolac group reported significantly better pain scores. For the most part, the decrease in opiate requirements did not translate into fewer adverse effects, although there was slightly less sedation and nausea and vomiting in the ketorolac-treated groups. There are few published data supporting the use of intravenous ketorolac for acutely painful conditions commonly seen in the emergency department. Significant analgesic efficacy was seen in an uncontrolled, unblinded study of intravenous ketorolac in the treatment of renal colic (98). These results need to be confirmed in a controlled, blinded trial. The analgesic efficacy of a continuous intravenous infusion of ketorolac was compared to placebo in 21 patients with sickle cell vaso-occlusive crisis (99). Analgesia was supplemented with meperidine 100 mg IM, as needed. Patients in the ketorolac group used 33% less meperidine than did the placebo group and reported better pain
relief. There was no significant difference in adverse effects between the groups. Intravenous ketorolac has recently been approved by the Food and Drug Administration. It has analgesic potency, but its utility as a single analgesic agent in patients with moderate-to-severe pain is limited because there is a significant percentage of patients who fail to obtain adequate relief. Pharmacologic data indicate that intravenous ketorolac would have a rapid onset of analgesia, however. there are no published data to support this contention. Intravenous ketorolac may be most useful in supplementing parenteral opiates. It is clear that concomitant use of ketorolac will decrease the amount of opiates required in patients with moderate-to-severe pain and provide better pain relief than with opiates alone. Unfortunately, the reduction in opiate requirements associated with ketorolac use has not been consistently accompanied by a reduction in the typical adverse effects of opiates. Parenteral ketorolac ($6.50 for 30 tng) costs about IO- 15 times as tnuch as equivalent analgesic doses of tneperidine ($.42 for 100 mg) and morphine ($.52 for 10 mg).
CONCLUSIONS The scientific evidence that demonstrates the analgesic efficacy of ketorolac for use in the emergency department is inconclusive. Many of the studies were done in patients undergoing operative procedures, using single doses of analgesics, and may not reflect the needs of patients requiring analgesia in the emergency depart ment. The clinical trials of intramuscular and intravenous ketorolac and opiates used suboptimal doses of opiates, thus potentially underestimating the analgesic efficacy of opiates. Most of the studies involving ketorolac were performed or supported by the manufacturer. This practice may lead to bias including underreporting of negative results ( 100). Despite these limitations. several conclusions can be made about the emergency department use of ketorolac. Ketorolac has significant analgesic potency and is a safe and useful agent for the acute treatment of mod erate-to-severe pain in the emergency department, however, it does not meet the criteria for an ideal analgesic agent. In fact, ketorolac provides few advantages over currently available analgesics and has several disadvantages. The most important disadvantage of ketorolac is that there is an analgesic “ceiling.” Doses above 30 mg for parenteral ketorolac and 10 mg for oral ketorolac provide little additional analgesic benefit and are associated with more adverse effects. Like other NSAIDs, ketorolac is associated with adverse effects not seen with opiates. Ketorolac must be used with caution in the elderly and in patients with renal
Ketorolac for Acute Pain
73
impairment or hypoperfusion because of the risk of precipitating renal failure. Gastric ulceration may occur even with short-term use. Overall, the adverse effects of ketorolac are mild and well tolerated. There is some evidence that suggests that ketorolac causes less sedation. nausea, and vomiting than opiates. Ketorolac may be useful in patients unable to tolerate opiates or in those patients in whom respiratory depression or sedation is a concern. Oral ketorolac has been shown to provide analgesia that is equal to or better than aspirin, acetaminophen, and dextropropoxyphene with acetaminophen, but provides no analgesic advantage compared to other commonly used analgesics including ibuprofen and acetaminophen with codeine. The high cost of ketorolac compared to other oral analgesics, a factor of lo-15 times as expensive, argues against routine use of ketorolac. The recommended dose of oral ketorolac is 10 mg every 6 hours. In patients with moderate-to-severe pain, when rapid relief is necessary. both intramuscular ketorolac and intramuscular opiates have limited utility due to their prolonged onset to analgesic action (30-60 min) and a significant number of patients who exhibit little
or no response (about 25% ) Intravenous analgesia is more appropriate in this setting. In patients with lessthan-severe pain, intramuscular ketorolac may be no more effective than oral ibuprofen ( 101). The role of oral analgesics in emergency department patients with mild-to-moderate pain should be investigated further. The recommended dose of intramuscular ketorolac is 15-30 mg every 6 hours. Intravenous ketorolac, as a single agent, also has limited utility in patients with moderate-to-severe pain because a significant percentage of patients fail to obtain adequate relief. Intravenous ketorolac may be most useful in supplementing parenteral opiates, It is clear that concomitant use of ketorolac and opiates will decrease the amount of opiates required in patients with moderate-to-severe pain and provide better pain relief than with opiates alone. Unfortunately, the reduction in opiate requirements associated with ketorolac use has not been consistently accompanied by a reduction in the typical adverse effects of opiates. The use of ketorolac in this situation also warrants further investigation. The recommended dose of intravenous ketorolac is 15-30 mg every 6 hours.
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75 83. Turkewitz LJ, Casaly JS, Dawson GA, et al. Self-administration of parenteral ketorolac tromethamine for head pain. Headache. 1992;32:452-4. 84. Pollack CV, Sanders DY, Severance HW. Emergency department analgesia without narcotics for adults with acute sickle cell pain crisis: case reports and review of crisis management. J Emerg Med. 1991;9:445-52. 85. Wright SW, Norris RL, Mitchell TR. Ketorolac for sickle cell vaso-occlusive crisis pain in the emergency department: lack of a narcotic-sparing effect. Ann Emerg Med. 1992;21:9258. 86. 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. 87. Shrestha M, Chiu MJ, Martin RL, Cush JJ, Wainscott MS. Treatment of acute gouty arthritis with intramuscular ketorolac tromethamine. Am J Emerg Med. 1994; 12:454-5. 88. Bartfield JM, Kern AM, Raccio-Robak N, Snyder HS, Baevsky RH. Ketorolac tromethamine use in a university-based emergency department. Acad Emerg Med. 1994; 1:532-S. 89. Koenig I&, Hodgson L, Kozak R, Jordan K, Sexton TR, Leiken AM. Ketorolac vs meperidine for the management of pain in the emergency department. Acad Emerg Med. 1994; I:5449. 90. Peirce RJ, Fragen RJ, Pemberton DM. Intravenous ketorolac tromethamine versus morphine sulfate in the treatment of immediate postoperative pain. Pharmacotherapy. 1990: 10: 11 lS115s. 91. Brown CR, Moodie JE, Wild VM, Bynum LJ. Comparison of intravenous ketorolac tromethamine and morphine sulfate in the treatment of postoperative pain. Pharmacotherapy. 1990;10:116S-121s. 92. Maunuksela EL, Kokke H, Bullingham RES. Comparison of intravenous ketorolac with morphine for postoperative pain in children. Clin Pharmacol Ther. 1992;52:436-43. 93. Wheatley RG, Blackbum A, Stevens J, Madej TH, Hunter D. Analgesic effects of intravenous ketorolac in lower abdominal surgery. Anesthesiology. 1992;77:A818. 94. Bellamy CD, Chovan J, Brose EL, Gunzenhauser L. Ketorolac superior to sufentanil, giving longer pain relief with less nausea and less recovery time after laparoscopy. Anesthesiology. 1991;75:A29. 95. Parker RK, Holtmann B, Smith I, White PF. Use of ketorolac after lower abdominal surgery. Effect on analgesic requirement and surgical outcome. Anesthesiology. 1994;80:6- 12. 96. Ready LB, Brown CR, Stahlgren LH, et al. Evaluation of intravenous ketorolac administered by bolus or infusion for treatment of postoperative pain. Anesthesiology. 1994; 80: 1277- 1286. 97. Vetter TR, Heiner EJ. Intravenous ketorolac an an adjuvant to pediatric patient-controlled analgesia with morphine. J Clin Anesth. 1994;6:110-113. 98. Larsen LS, Miller A, Allegra JR. The use of intravenous ketorolac for the treatment of renal colic in the emergency department, Am J Emerg Med. 1993; 11:197-9. 99. Perlin E, Finke H, Castro 0, et al. Enhancement of pain control with ketorolac tromethamine in patients with sickle cell vasoocclusive crisis. Am J Hematol. 1994;46:43-7. 100. Lexchin J. Interactions between physicians and the pharmaceutical industry: what does the literature say? Can Med Assoc J. 1993; 149:1401-7. 101. Wright JM, Price SD, Watson WA. NSAID use and efficacy in the emergency department: single doses of oral ibuprofen versus intramuscular ketorolac. Ann Pharmacother. 1994: 28:309- 12.
SSDI 0736-4679( 95)02052-7
Pharmacology of Emergency Medicine
THE ANALGESIC
EFFICACY
OF KETOROLAC
Michael S. Catapano,
FOR ACUTE
PAIN
MD
Department of Emergency Medicine, North Shore University Hospital-Cornell University Medical College, Manhasset, New York Reprint Address: Michael S. Catapano, MD, Department of Emergency Medicine, North Shore University HospitalCornell University Medical College, 300 Community Drive, Manhasset, NY 11030
q Abstract-Ketoroiac is a nonsteroidal anti-inflammatory drug, available in both oral and parenteral forms, that possesses significant analgesic potency. Its analgesic efficacy has been studied extensively for the treatment of moderate-to-severe pain in many clinical settings. Although ketorolac possesses significant analgesic potency, it has limited utility as an analgesic for the acute treatment of moderate-to-severe pain in the emergency department. Oral ketorolac has been shown to provide analgesia that is the same or better than aspirin, acetaminophen, and dextropropoxyphene with acetaminophen, and equal analgesia to most other commonly available oral analgesics, including ibuprofen and acetaminophen with codeine. Intramuscular ketorolac provides analgesia equivalent to commonly used doses of meperidine and morphine. However, its utility in acute pain, when rapid relief is necessary, is limited due to a prolonged onset to analgesic action (30-60 min) and a significant number of patients who exhibit little or no response, more than 25% in most studies. The use of intravenous ketorolac has been less well studied. It has analgesic potency but its utility in patients with moderate-to-severe pain is also limited because there is a significant percentage of patients who fail to obtain adequate relief. Ketorolac may be most useful in supplementing parenteral opiates. Cl Keywords-ketorolac;
and ethical foundation for this approach, improved patient satisfaction and clinical outcome, and reduced costs make it imperative that emergency physicians be expert in acute pain management. Unfortunately, pain management surveys performed in many clinical settings, including the Emergency Department, continue to demonstrate that up to half of patients with pain obtain inadequate relief ( 1- 11). These studies have documented many reasons to explain the discrepancy between the goal of optimal pain management and the failure in practice to provide a large proportion of patients with effective pain relief. Certainly, work pressure may prevent nurses and physicians from performing adequate pain assessments on patients, leading to an underestimation of pain. Suboptimal use of available analgesics, such as intramuscular administration of fixed doses of opiates on an “as needed” basis, also leads to inadequate pain relief. Erratic absorption of medication can occur after intramuscular administration, and patients have a wide variation in analgesic requirements. Adverse effects of available agents and exaggerated fear of physical dependency cause a reluctance to administer sufficient doses of opiates. Many physicians do not have rapid and complete relief of pain as their goal of pain management, settling for the lesser goals of “making the patient comfortable” or “taking the edge off the pain,” thus impairing their ability to provide optimum pain relief. The Clinical Practice Guidelines for Acute Pain Management developed by the Agency for Health Care Policy and Research, United States Department of Health and Hu-
analgesia; acute pain
INTRODUCTION Providing effective pain relief is central to the mission of the emergency physician. In addition to the moral
of Emergency Medicine is coordinated by Richard F. C&k, MD, of the University of California, San Diego Medical Center, and the San Diego Regional Poison Center, San Diego, California RECEIVED: 14 December 1994; FINAL SUBMISSION RECEIVED : 19 April 1995; ACCEPTED: 10 May 1995 Pharmacology
67
M. S. Catapano
68
man Services, emphasizes these points (12). These guidelines and other educational efforts will assist clinicians in acute pain assessment and management. Educational programs may improve pain management, but clinicians’ efforts at providing effective pain relief are hampered by the adverse effects of currently available drugs. Opiates can cause respiratory depression, hypotension, bowel and bladder dysfunction, and nausea and vomiting, which limit their utility. Nonsteroidal anti-inflammatory drugs (NSAID) and acetaminophen have an analgesic ceiling and have their own set of toxic effects. An ideal analgesic agent for emergency department use would have several characteristics. It would be painless to administer and have a quick onset of action. There would be a low incidence of well-tolerated adverse effects. It would have no analgesic “ceiling” above which increased doses of the drug have no effect. Availability in oral and parenteral forms would be useful, and the cost should be similar to other available analgesics. The drug would have no potential for abuse or dependency. There is currently no drug that meets these criteria. Ketorolac is a nonsteroidal anti-inflammatory drug with significant analgesic properties. It has been used extensively in emergency departments for a variety of painful conditions, frequently as a first-line drug. Printed advertisements promise the analgesic strength of narcotics without the adverse effects of narcotics. This article will examine the pharmacology and clinical trials of ketorolac to define the role of ketorolac for acute pain management in the emergency department.
PHARMACOLOGY Ketorolac is an inhibitor of prostaglandin synthesis and is structurally related to tolmetin and zomepirac ( 1315 ) . It has an adverse effect profile and anti-inflammatory, antipyretic, and analgesic properties similar to other NSAIDs. Ketorolac is available for both oral and parenteral use. Ketorolac possesses moderate anti-inflammatory effects. It is much more potent than phenylbutazone, indomethacin, or naproxen in inhibiting the formation of carrageenan induced paw edema in rats, an animal model of inflammation ( 13,14). Similarly, ketorolac is more potent than indomethacin and naproxen in inhibiting the formation of cotton-pellet induced granulomas and the development of arthritis in an adjuvant induced arthritis model in rats, two other animal models of inflammation (13,14). Ketorolac has significant analgesic properties in animal models of analgesia ( 13,14). It demonstrates substantial potency in animal models of analgesia in which inflammation is the inciting cause. These include inhi-
bition of phenylquinone induced writhing in mice, inhibition of pain provoked by flexing adjuvant inflamed paws in rats, and inhibition of pain provoked by compression of yeast inflamed paws in rats. Ketorolac, unlike opiates, does not reduce the pain threshold in the normal, noninflammed state. Ketorolac inhibits the pain provoked by compression of yeast inflamed paws in rats but has no effect on the pain threshold in non inflamed paws. Ketorolac also has no effect on hot plate induced pain in mice, an animal model of analgesia that measures centrally acting or morphine-like analgesic effects. Morphine is very active in this test. This test indicates that ketorolac has no centrally acting or morphine-like analgesic effects. Ketorolac does not bind to opioid receptors and has low addictive potential (16). More recent studies suggest that ketorolac may have some central analgesic effects unrelated to opioid receptors (17,18). Ketorolac has a pharmacological and toxic effect profile similar to other nonsteroidal anti-inflammatory drugs ( 13). It does not possess corticosteroid activity or stimulate the adrenal gland to release corticosteroids. Ketorolac has moderate potency as an antipyretic (13,19). Gastrointestinal erosive activity occurs in rats given oral ketorolac ( 13 ) . An endoscopic study in humans showed that short-term administration of both parenteral and oral ketorolac results in gastric ulceration (20). Except for the 90 mg intramuscular dose of ketorolac, the degree of ulceration produced by ketorolac was less than that produced by two aspirin tablets (650 mg) . Whether or not a single intramuscular dose of ketorolac results in a significant rate of gastric ulceration is unknown. Ketorolac has no activity on the central nervous system at usual therapeutic doses. No behavioral effects were observed in mice and dogs given ketorolac, except at extremely high dosages. Ketorolac does not potentiate hexobarbital induced sleep in mice, possesses no anticonvulsant activity, and has no effect on electroencephalogram recordings ( 13 ) The effect of ketorolac on hemostasis appears to be minimal (21-24). It has no effect on the prothrombin time and partial thromboplastin time. Like other NSAIDs, ketorolac inhibits platelet aggregation and leads to a modest prolongation of the bleeding time, although still in the normal range. The clinical significance of this finding is uncertain. Ketorolac should probably be used cautiously in patients in whom significant bleeding is a concern. Unlike opiates, ketorolac has no hemodynamic or ventilatory effects (25 -29). Intraoperative and postoperative studies on patients show that ketorolac use results in no change in heart rate, blood pressure, cardiac output, or pulmonary vascular pressure. Opiates, on the other hand, have significant effects on these
Ketorolac for Acute Pain
hemodynamic parameters. When administered intraoperatively or to human volunteers, ketorolac has no effect on respiratory rate or end-tidal carbon dioxide partial pressure. As expected, opiates cause a decrease in the respiratory rate and an increase in the end-tidal carbon dioxide partial pressure. Intramuscular injections of ketorolac are nonirritating, as shown by histologic and muscle enzyme studies in animals (14). Oral, intramuscular (IM), and intravenous (IV) administration of ketorolac results in similar pharmacokinetic profiles with only a few differences (30-32). Studies in human volunteers show that absorption and bioavailability of ketorolac is complete after oral, intramuscular, and intravenous dosing. Absorption is rapid for all three forms of dosing. As would be expected, the time to reach peak serum concentration (t,,) is shortest after intravenous use, approximately 5 min. The t mmafter oral use, 30-53 min, may be slightly shorter than for intramuscular use, 45-50 min. The peak serum concentration (C,,) after a 10 mg dose is the same for both oral and intramuscular dosing. The C,, following intravenous use is almost three times greater than after oral or intramuscular administration. The serum halflife ranges from 5-6 hours for all three forms of administration. Ketorolac is over 99% bound to plasma proteins. Ketorolac is metabolized in the liver to form inactive glucuronide metabolites ( 13 ) . A small amount of ketorolac is converted to para-hydroxy ketorolac, an inactive metabolite. The primary route of excretion of unchanged ketorolac and its metabolites is by the kidneys. Very small amounts of ketorolac are excreted into breast milk or enter the fetal circulation (33,34). There are significant differences in the pharmacokinetics of ketorolac in the elderly and in patients with kidney disease when compared to normal volunteers (35-38). The elimination of ketorolac is reduced in both of these groups, leading to a longer serum halflife. Dosing intervals should be longer in these patients. As with most NSAIDs, ketorolac should be used cautiously, if at all, in patients with renal impairment or hypoperfusion, because of the risk of renal failure. Patients with hepatic impairment show no alteration in the pharmacokinetics of ketorolac when compared to healthy controls (38,39).
CLINICAL
STUDIES OF ORAL KETOROLAC
Oral ketorolac has been shown to provide analgesia that is equal to the most commonly used oral analgesics. These include ibuprofen, diflunisal, aspirin with codeine, acetaminophen with codeine, dextropropoxy-
69
phene with acetaminophen, and acetaminophen with hydrocodone. Oral ketorolac has been shown to provide the same or better analgesia than acetaminophen and aspirin. Most of these studies, however, were done in patients undergoing operative procedures, using single doses of analgesics; they may not reflect the needs of patients requiring analgesia in the emergency department. Many patients in the emergency department have pain unrelated to surgery and require an analgesic that will be effective with multiple dosing. Despite these provisos, much useful information can be gleaned from these clinical trials. Ketorolac provides the same or more effective pain relief than aspirin. In 120 women with postpartum uterine pain, ketorolac 10 mg was slightly better than aspirin 650 mg and more effective than ketorolac 5 mg (40). In two single-dose studies involving patients with postoperative pain, ketorolac 10 mg and 20 mg and aspirin 650 mg gave equivalent relief (41,42). Ketorolac 20 mg may have been slightly more effective. In a single- and multiple-dose trial involving patients undergoing oral surgery, ketorolac 10 mg was significantly superior to aspirin 650 mg in all measurements of pain relief (43). Patients with chronic pain also favor ketorolac 10 mg over aspirin 650 mg. In a l-year study of patients with chronic pain, there were significantly more treatment failures with aspirin than with ketorolac (44). Adverse effects associated with ketorolac in these studies were mild and no worse than aspirin. Aspirin 650 mg with codeine 60 mg has approximately equivalent analgesic efficacy to ketorolac 10 mg and 20 mg in postoperative patients (41,42). Two studies show that ketorolac provides the same or better pain relief than acetaminophen. Single doses of acetaminophen 500 mg and 1000 mg were compared to ketorolac 5 mg, 10 mg, and 20 mg in postoperative orthopedic patients (45). All treatments were superior to acetarninophen 500 mg and ketorolac 5 mg. Ketorolac 10 mg and 20 mg had better scores than acetaminophen 1000 mg in most measurements of pain relief, however, these differences were not statistically significant. In a single- and multiple-dose study of patients undergoing oral surgery, ketorolac 10 mg and 20 mg had the same analgesic efficacy and were both better than acetaminophen 600 mg (46). Adverse effects in these studies were mild and the same in all treatment groups. Acetaminophen with codeine and ketorolac have similar analgesic efficacy. In patients following oral surgery, gynecological surgery, ambulatory surgery, and with cancer pain, single- and multiple-dose studies of ketorolac 10 mg compared to acetaminophen 6001000 mg with codeine 60 mg show equivalent pain relief (43,47-49). One study in patients with oral surgery showed that ketorolac 10 mg and 20 mg was
M. S. Catapano
70 significantly more effective than acetaminophen 600 mg with codeine 60 mg (46). For the most part, adverse effects were the same, except somnolence and nausea and vomiting were more common in patients treated with acetaminophen and codeine. Oral ketorolac has similar analgesic efficacy to other NSAIDs. In a 5-day clinical trial involving postmeniscectomy patients, ketorolac 10 mg and diflunisal 500 mg, a salicylic acid derivative, gave the same pain relief (50). Ketorolac 10 mg also had the same analgesic efficacy as naproxen sodium 550 mg in postoperative patients and ibuprofen 400 mg in oral surgery patients (46,5 1) . In postoperative patients, ketorolac IO mg was better than a combination of ibuprofen 400 mg and acetaminophen 325 mg (52). Ketorolac also compares favorably with opiates and other opiate combinations. Oral ketorolac 10 mg was found to have the same analgesic efficacy as intramuscular morphine 10 mg in postoperative patients (5 1,53). Morphine had a slight advantage in peak pain relief. Ketorolac 10 mg is superior to dextropropoxyphene 65 mg with acetaminophen 400 mg in postoperative patients, and acetaminophen 1000 mg with hydrocodone 10 mg in patients following oral surgery (52,54). There was more nausea and vomiting in patients receiving acetaminophen with hydrocodone than ketorolac. A short-term clinical trial of ketorolac in cancer patients also showed analgesic efficacy (55). Ketorolac 10 mg appears to have equal efficacy when compared to pentazocine 50 mg, with fewer adverse effects. Oral ketorolac has been shown to provide analgesia that is equal to or better than aspirin, acetaminophen, and dextropropoxyphene with acetaminophen. Aspirin with codeine, acetaminophen with codeine, pentazotine, acetaminophen with hydrocodone, ibuprofen, and dihunisal provide equivalent analgesia to ketorolac. Ketorolac 20 mg provides little, if any, additional analgesic benefit compared to ketorolac 10 mg. Adverse effects are mild and well tolerated. Sedation, nausea, and vomiting occur less frequently with ketorolac than with opiate combinations. Aspirin, acetaminophen, ibuprofen, and acetaminophen with codeine are available for pennies per tablet, while ketorolac 10 mg costs over one dollar per tablet. Oral ketorolac is recommended for acute pain control only and is not intended for chronic pain management.
CLINICAL
STUDIES OF INTRAMUSCULAR KETOROLAC
Much of the early enthusiasm for the use of ketorolac as an analgesic resulted from several studies that compared various doses of intramuscular ketorolac with intramuscular opiates. Ketorolac was found to be as
effective, or better, than opiates. Clinical trials using intramuscular medications for severe pain, however, have been criticized ( 12). The absorption of intramuscular medications can be erratic and, frequently, is not rapid enough to provide prompt analgesia. The more appropriate standard for prompt relief of acute, severe pain is intravenous boluses of opiates, titrated to the individual needs of the patients. Ketorolac has shown analgesic potency comparable to morphine in single-dose clinical trials involving postoperative patients. Intramuscular ketorolac 10 mg, 30 mg, and 90 mg and morphine 6 mg and 12 mg were compared in two studies. One study showed that ketorolac 90 mg was superior to morphine 12 mg. Ketorolac 10 mg and 30 mg and morphine 12 mg had equivalent efficacy (56). In the second study, ketorolac 30 mg and 90 mg were similar to morphine 12 mg for peak relief but had a substantially longer duration of action (57). It is important to note that in both of these studies, many patients in all treatment groups withdrew because of inadequate pain relief. Furthermore, significant pain relief did not occur until 30-60 min after the injection. The slow onset of intramuscular analgesics is further demonstrated by a study that determined the time of onset of analgesia for intramuscular ketorolac 30 mg and morphine 10 mg (58). Less than one-half of the patients achieved a 50% reduction in their pain by 1 hour. The incidence of nausea and vomiting was about the same for ketorolac- and morphine-treated patients. Ketorolac and morphine have also shown equivalent analgesic efficacy in multiple-dose trials in postoperative patients. Several studies have compared ketorolac 30 mg IM to morphine lo-12 mg IM (59-62). Both ketorolac and morphine were found to be effective analgesics for short-term use. However. patients receiving ketorolac tended to more frequently request rescue analgesia than did patients in the morphine groups. As in the previous set of studies, many patients did not receive adequate relief with either ketorolac or morphine, suggesting that intramuscular use of fixed doses of analgesics on an “as needed” basis is a suboptimal method of relieving moderate-to-severe pain. Ketorolac has more analgesic efficacy than commonly used doses of meperidine when used in postoperative patients. Two brief reports showed ketorolac 30 mg and 90 mg IM to be at least equal, and frequently more effective than meperidine 50 mg and 100 mg IM (63,64). These findings were confirmed in two other reports. In postoperative patients and in patients undergoing oral surgery, ketorolac 30 mg and 90 mg IM gave equal or better peak pain relief than did meperidine 100 mg IM (65,66). As would be expected from the pharmocokinetics of the two drugs, the duration of pain relief was much longer with ketorolac than with
Ketorolac for Acute Pain
meperidine. In women following cesarean section, ketorolac 30 mg IM and meperidine 75 mg IM provided the same relief ( 67). Neither medication provided optimal pain relief, as demonstrated by the high rate of withdrawal from these studies because of lack of efficacy. There was slightly less nausea and vomiting in the ketorolac-treated patients. There is one published report comparing ketorolac with pentazocine in postoperative patients (68). Ketorolac 30 mg IM provided adequate pain relief for most patients and was consistently better than pentazocine 30 mg IM. Pentazocine was associated with inadequate relief in many patients and was generally not different from placebo. Intramuscular ketorolac may be useful in decreasing opiate requirements in patients with moderate-to-severe pain. Intravenous opiates are very effective in relieving pain, but their efficacy and associated patient satisfaction is limited by adverse effects, such as nausea and vomiting, respiratory depression, and sedation. In several. brief reports, the “opioid sparing” effect of ketorolac was minimal (69-7 1) . However, multipledose studies using ketorolac 30 mg IM given every 6 hours and continuous infusions demonstrate the use of ketorolac can reduce morphine requirements by up to 67% (72-77). Unfortunately, no significant associated reduction in typical opiate side effects was observed, bringing into question the necessity of decreasing the amount of opiates administered. The analgesic efficacy of intramuscular ketorolac for acutely painful conditions not associated with surgery has been less extensively studied. Mixed results have been observed in patients with cancer-related pain, acute migraine, sickle cell vaso-occlusive crisis, acute gouty arthritis, renal colic, and a variety of acutely painful conditions. Three doses of ketorolac, 10 mg, 30 mg, and 90 mg, were compared to placebo in patients with nonspecified cancer-related pain (78). All three ketorolac groups reported better pain relief than placebo, but were not significantly different from each other. About onequarter of the ketorolac-treated patients did not receive sufficient relief and withdrew from the study. There appears to be limited analgesic efficacy of ketorolac in patients with acute headache and migraine. An uncontrolled study reported significant pain relief in headache patients given ketorolac 60 mg (79). However, controlled clinical trials suggest that ketorolac has limited benefit. In three separate studies, ketorolac 60 mg IM was compared to dihydroergotamine one mg IV with metoclopramide (80)) meperidine 100 mg with hydroxyzine 50 IM (8 I), and meperidine 75 IM (82). Ketorolac was no better, and usually worse, than the other treatment groups in providing relief. From 40 to 70% of the ketorolac patients still had
71
moderate-to-severe pain and required rescue medication. The short study period (1 hour) in these trials may have caused an underestimation of ketorolac’s effects, since its usual onset to peak analgesia is l-2 hours. An uncontrolled, unblinded study of self-administered ketorolac 60 IM in headache patients showed that 64% reported good relief (83). As in the other studies, a substantial number of patients had little or no pain relief. Anecdotal reports of ketorolac’s utility in sickle cell vaso-occlusive crisis have not been supported in a small, controlled study (84). Patients with sickle cell vaso-occlusive crisis were given IV meperidine 50 mg and IV promethazine 12.5 mg to start (85). They then received either ketorolac 60 mg IM or saline placebo and were followed for 4 hours. Patients were able to receive IV meperidine 25-50 mg every 30 min, as needed, if pain persisted. Pain relief was the same in the ketorolac and placebo groups, as was the total amount of meperidine administered. Ketorolac has analgesic efficacy in the treatment of renal colic. Ketorolac 10 mg, 90 mg, or meperidine 100 mg were given to patients with renal colic (86). Ketorolac 90 mg provided superior relief to the other treatment groups. Ketorolac 10 mg and meperidine 100 mg provided equivalent relief but were associated with a 40% rate of inadequate analgesia. This study is of limited value since neither of the two ketorolac doses are commonly used for the treatment of acute pain. Ketorolac has analgesic efficacy in many other painful conditions that are commonly seen in the emergency department. An uncontrolled study in nine patients with acute gouty arthritis reported that all patients had significant relief (87). An uncontrolled study of 445 emergency department patients with a variety of painful conditions treated with ketorolac 60 mg IM showed that a majority of patients had some pain relief, although the amount of pain relief was not specified (88). In a controlled clinical trial of emergency department patients with a variety of painful conditions, ketorolac 60 mg IM and meperidine 100 mg IM provided the same pain relief (89). Intramuscular ketorolac provides analgesia equivalent to commonly used doses of meperidine and morphine. However, its utility in the management of moderate-to-severe pain in the emergency department, when rapid relief is necessary, is very limited due to a prolonged onset to analgesic action (30-60 min) and a significant number of patients who exhibit little or no response, more than 25% in most studies. Patients with less than moderate-to-severe pain will most likely receive adequate relief from oral analgesics and would not require parenteral analgesics. Ketorolac 90 mg may have a slight advantage over the 30 mg dose, but at a cost of increased gastric ulceration. There are no
M. S. Catapano
i2
published data that suggest that ketorolac 60 mg is superior to 30 mg. A dose of 0.5 mg/kg appears to be effective in children. Ketorolac may be associated with slightly less nausea and vomiting than opiates.
CLINICAL
STUDIES OF INTRAVENOUS KETOROLAC
When used as a single agent, intravenous ketorolac has analgesic efficacy but provides inadequate pain relief for many patients with moderate-to-severe pain. Two similar studies in patients with postoperative pain compared intravenous ketorolac 10 mg and 30 mg with morphine 2 mg and 4 mg (90,9 1) . A second dose was given 15 min later, if needed. The morphine 2 mg group experienced less pain relief than the other three treatment groups. Ketorolac 10 mg, 30 mg, and morphine 4 mg provided equal analgesia. Most patients withdrew from the studies because of inadequate pain relief. Ketorolac 30 mg compared favorably with fentanyl 50 pg in postoperative patients, but a significant withdrawal rate due to ineffective analgesia was observed in this study as well (48). A study done in children undergoing surgery found ketorolac to be slightly less effective than morphine (92). Morphine had a quicker onset of analgesia. More patients in the ketorolac group required rescue analgesia. There is ample evidence that concomitant use of ketorolac and an opiate will result in less opiate used. Brief reports have shown that intravenous ketorolac can reduce the amount of morphine, meperidine, and sufentanil used in postoperative patients (93,94). Compared to placebo, intravenous ketorolac can also reduce the amount of morphine or meperidine required in postoperative patients, both adults and children, using patient controlled analgesia systems (25,95-97). Patients in the ketorolac group reported significantly better pain scores. For the most part, the decrease in opiate requirements did not translate into fewer adverse effects, although there was slightly less sedation and nausea and vomiting in the ketorolac-treated groups. There are few published data supporting the use of intravenous ketorolac for acutely painful conditions commonly seen in the emergency department. Significant analgesic efficacy was seen in an uncontrolled, unblinded study of intravenous ketorolac in the treatment of renal colic (98). These results need to be confirmed in a controlled, blinded trial. The analgesic efficacy of a continuous intravenous infusion of ketorolac was compared to placebo in 21 patients with sickle cell vaso-occlusive crisis (99). Analgesia was supplemented with meperidine 100 mg IM, as needed. Patients in the ketorolac group used 33% less meperidine than did the placebo group and reported better pain
relief. There was no significant difference in adverse effects between the groups. Intravenous ketorolac has recently been approved by the Food and Drug Administration. It has analgesic potency, but its utility as a single analgesic agent in patients with moderate-to-severe pain is limited because there is a significant percentage of patients who fail to obtain adequate relief. Pharmacologic data indicate that intravenous ketorolac would have a rapid onset of analgesia, however. there are no published data to support this contention. Intravenous ketorolac may be most useful in supplementing parenteral opiates. It is clear that concomitant use of ketorolac will decrease the amount of opiates required in patients with moderate-to-severe pain and provide better pain relief than with opiates alone. Unfortunately, the reduction in opiate requirements associated with ketorolac use has not been consistently accompanied by a reduction in the typical adverse effects of opiates. Parenteral ketorolac ($6.50 for 30 tng) costs about IO- 15 times as tnuch as equivalent analgesic doses of tneperidine ($.42 for 100 mg) and morphine ($.52 for 10 mg).
CONCLUSIONS The scientific evidence that demonstrates the analgesic efficacy of ketorolac for use in the emergency department is inconclusive. Many of the studies were done in patients undergoing operative procedures, using single doses of analgesics, and may not reflect the needs of patients requiring analgesia in the emergency depart ment. The clinical trials of intramuscular and intravenous ketorolac and opiates used suboptimal doses of opiates, thus potentially underestimating the analgesic efficacy of opiates. Most of the studies involving ketorolac were performed or supported by the manufacturer. This practice may lead to bias including underreporting of negative results ( 100). Despite these limitations. several conclusions can be made about the emergency department use of ketorolac. Ketorolac has significant analgesic potency and is a safe and useful agent for the acute treatment of mod erate-to-severe pain in the emergency department, however, it does not meet the criteria for an ideal analgesic agent. In fact, ketorolac provides few advantages over currently available analgesics and has several disadvantages. The most important disadvantage of ketorolac is that there is an analgesic “ceiling.” Doses above 30 mg for parenteral ketorolac and 10 mg for oral ketorolac provide little additional analgesic benefit and are associated with more adverse effects. Like other NSAIDs, ketorolac is associated with adverse effects not seen with opiates. Ketorolac must be used with caution in the elderly and in patients with renal
Ketorolac for Acute Pain
73
impairment or hypoperfusion because of the risk of precipitating renal failure. Gastric ulceration may occur even with short-term use. Overall, the adverse effects of ketorolac are mild and well tolerated. There is some evidence that suggests that ketorolac causes less sedation. nausea, and vomiting than opiates. Ketorolac may be useful in patients unable to tolerate opiates or in those patients in whom respiratory depression or sedation is a concern. Oral ketorolac has been shown to provide analgesia that is equal to or better than aspirin, acetaminophen, and dextropropoxyphene with acetaminophen, but provides no analgesic advantage compared to other commonly used analgesics including ibuprofen and acetaminophen with codeine. The high cost of ketorolac compared to other oral analgesics, a factor of lo-15 times as expensive, argues against routine use of ketorolac. The recommended dose of oral ketorolac is 10 mg every 6 hours. In patients with moderate-to-severe pain, when rapid relief is necessary. both intramuscular ketorolac and intramuscular opiates have limited utility due to their prolonged onset to analgesic action (30-60 min) and a significant number of patients who exhibit little
or no response (about 25% ) Intravenous analgesia is more appropriate in this setting. In patients with lessthan-severe pain, intramuscular ketorolac may be no more effective than oral ibuprofen ( 101). The role of oral analgesics in emergency department patients with mild-to-moderate pain should be investigated further. The recommended dose of intramuscular ketorolac is 15-30 mg every 6 hours. Intravenous ketorolac, as a single agent, also has limited utility in patients with moderate-to-severe pain because a significant percentage of patients fail to obtain adequate relief. Intravenous ketorolac may be most useful in supplementing parenteral opiates, It is clear that concomitant use of ketorolac and opiates will decrease the amount of opiates required in patients with moderate-to-severe pain and provide better pain relief than with opiates alone. Unfortunately, the reduction in opiate requirements associated with ketorolac use has not been consistently accompanied by a reduction in the typical adverse effects of opiates. The use of ketorolac in this situation also warrants further investigation. The recommended dose of intravenous ketorolac is 15-30 mg every 6 hours.
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