- Email: [email protected]
Effect of intraoperative ketorolac on postanesthesia care unit comfort
journal of Fain and Symptom Management
Vol. 9No. 3 Apti I994
f 71
John B. Valdrighi, MD, I&and I-I. Ha~lowell, MD, Rabert G. Loeb, MD, Kendra I-I. Behrman, RN, and Elizabeth A. Disbrow, MA Departntent ofAnesthesiology
Universityof CaQrnia
effective adjunct a’nthe wumagmmt 1994;9:~7f-I 74.
at Davis. Sacramento, California
of postv#wrative
Analgesics, nonsteroidal antiinfllammatg’ drqs, pain, postOperativeanalg&a
Address aunt reqwsts to:John B. Valdrighi, MD, 3227 Via Grande Way, Sacramento, CA 95825, USA,
0 U.S. Gmeer Pain ~e~~~~o~itte~, 1994 Published by Elsevier, New York, New York
§ymptom
Manage
ketorohc, i$ioid.s, mq&hine, postoperative
Intramuscular (IM) ketorolac (30-W mg) has been demonst~t~ to have analgesic potency comparable to IM morphine (12 mg).i-s In those studies, ketorolac was administered in the postoperative period to patients with preexisting pain. However, when IM ketorolac (30 mg) was compared with IM
Acc~ted for pab~j~atjo~~September 23, 1993.
pain. J Fain
morphine (10 mg} given int_raoperatively for the prophylactic treatment of the pain in the postanesthesia care unit (PACU), ketorulac was found to be less effectivee4 The latter study suggests that ketorolac, while a sufftcient analgesic for moderate postoperative pain, is not as effective as morphine in the management of severe pain occurring in the immediate postop erative period. The efficacy of the combination of intraoperative ketorolac and opioid analgesics, however, has not been thoroughly examined. The present study evaluated the effects of intraoperative ketorolac on subsequent patient comfort in the PACU.
Valdrighi et al.
172
Table 1 Descriptive Data
-
Control group mean (SEM)
Ketorolac group
mean (SEM)
Age (Y) Height (cm)
33
(3)
40
(4)
168
(2)
166
(2)
Weight (kg)
67.5 (2.9)
69.6 (3.1)
Female
60% (n = 9)
47% (n = 7)
Surgical duration (min) Outpatient
status
Time from drug administration to PACU admission (min) Intraoperative administration of opioids (fentanyl equivalent
180
(26)
160
(14)
47% (12= 7)
53% (n = 8)
56
(7)
45
(7)
303
(70)
338
(84)
N) SEM, s~lldad
error of he
nwau: and PAW, pmanesthcsia
care unit.
Methods Following approval from the human subject research committee, written informed consend was obtained from 30 patients. Eligible partici-
pants for the study were male or female patients between 18 and 70 yr of age, weighing 50-90 kg, who were undergoing general anesthesia for elective limb or lower abdominal procedures. No patients receiving preoperative analgesics were enrolled. Patients also were excluded for peptic ulcer disease, pregnancy or lactation, drug dependencies, psychiatric illnesses, morphine or aspirinlike drug allergies, and liver, renal, or hematologic disorders. Patients were randomly assigned to one of two groups. Upon surgical closure, one group received IM ketorolac (60 mg, 2 mL), and the other group received normal saline (2 mL, IM). The site of injection was based upon intraoperative access and included either the deltoid or vastus lateralis muscle. Patients, operating room and PACU personnel, and observing researchers were blinded to the treatment administered, Anesthesiologists were instructed to administer a “balanced general anesthetic” including opioids and to assume that the patient would not receive ketorolac upon surgical closure. Regional anesthetic techniques were excluded.
VOL.9 No. 3 April 1994
intraoperatively adminiFor comparison, stered opioids were recorded by generic name and dose, and then were converted to fentanyl equivalents (100 pg fentanyl = 10 mg morphine = 15 pg sufentanil = 750 j.tg alfentimil).” Postoperatively, both groups received morphine as needed for pain (l-3 mg intravenously repeated every 5 min until comfort was attained). Subjects were followed in the PACU until discharge or for a maximum of two hours. Vital signs, Aldrete recovery scores,” visual analog pain scores,7J total opioid dose, time to first opioid dose, and incidence of requiring morphine for pain were recorded. The visual analog pain score was based upon a loo-point (lo-cm) scale with 0 rated as no pain and 100 being the most severe pain. This score was obtained 1 hr after PACU admission. Statistical analysis was performed by analysis of variance (ANOVA) for parametric variables with results expressed as mean value + standard error of the mean @EM). Gender, race, surgical procedure, intraoperative opioids administered, AIdrete recovery scores, and the incidence of PACU administration of morphine were analyzed using a x2 test. Aldrete scores were analyzed by considering the results as either less than 9 or scores of 9 or 10 and then the incidence of each occurrence was examined for the two groups.
Results The two groups were not significantly different in height, weight, age, gender, race, intraoperatively administered opioids, and surgical procedures (Tables 1 and 2). In the PACU, there were no differences in Aldrete scores or respiratory rates. The control group required opioids more often than the ketorolac group (Figure 1). Additionally, when patients required opioids, Table 2 Operative Site (n)
Upper extremity hwer extremity Laparoscopy Lower abdominal
Control
Ketorolac
group
group
; 3 2
5 7 2 1
VOL.9 No. 3 Apt-2 1994
Ketorolar for PostoperatirlePain
40%
Con?rcd
Ketnrolae
Fig. 1. Patients requiring opioid analgesia in postanesthesia care unit (PACU) (saline control versus ketorolac): incidence of PAW opioid supplementation. Fewer patients in the ketorolac-treated group required postoperative opioid analgesics (P < 0.05).
the control group received the first morphine dose signi6candy earlier than the ketorofac group (1.5 + 4 vs 37 & 7 min, respectively, P< 0.01, Figure 2). When patients who did not require opioid analgesics were added to the analysis by considering the first dosage time to be the end of the observation period (2 hr), there again was a significant difference between control and ketorolac groups in time to first-administered morphine dose: 22 f 8 vs 76 f 11 min, respectively (PC O.OOl). Although the ketorolac group required a lower total dosage of postoperative opioids than did the control group (5.5 * I.9 vs 10.1 f 1.8 morphin~quivalent mg, respec~vely~, this diierence did not reach statistical significance (P = 0.08). Time to PACU discharge also was not different behveen groups (Figure 2). The ketorolac group did, however, report significandy lower pain scores than did the control group at 1 hr [36 f 5.4 and 64 f 5.6, respectively (Figure 3) I.
173
roidal a~tii~~~ammatQ~ therapy has been overlooked. h-r the present study, the effects of adding ketorolac to opioids administered as part of a balanced general anesthetic technique were examined. There were no differences between the two groups in in~operatively administered analgesics other than the administration of ketorolac to the intervention group. The ketorolac group required opioid supplementation less frequently in the PACU. The control group also required opioid analgesia sooner tban did the keeorolac group. The latter finding demonstrates that the intmoperative administration of ketorolac was additive to the analgesic effect of opioids that had been administered as part of a balanced general anesthetic technique. There were no disceruible differences between the groups in the rate of recovery from anesthesia, as demonstrated by Aldrete recovery scores and time to PACU discharge. However, the ketorolac group did have lower visual analogue pain scores and, hence, was more comfor~bIe in the PAW. This is the most interesting finding, because both groups were allowed as much morphine as necessary for the treatment of pain. There are several possible explanations for the finding that a combination of ketorolac with opioids may be more effective than opioids alone. The analgesic properties of these two classes of compounds may be additive, ahowing greater pain control Fig. 2. Times to first opioid suppfementation and postanesthesia care unit (PACU) discharge. The time to the first required opioid dose in the PACU
was greater in the ketorolac group versus the control
group fP< 0.01). The time to discharge from the PACU was not different between groups.
Previous studies have demonstrated that ketorolac is an efficacious analgesic comparable to morphine in the treatment of moderate postoperative pain. t-s Studies of the efficacy of this nonsteroidal antiinflammatory drug in the treatment of severe pain occurring immediately postoperatively, however, have yielded conflicting results4*s The question addressed by these previous studies is whether ketorolac is superior to opioids for the treatment of postop erative pain. By limiting the evaluation to a dete~ination of analgesic efftcacy, the possible efficacy of combined opioid and nonste-
ControlversusKatorolac 120
it F
40 20 0
FirstNarcotic
Vol. 9 No. 3 April I994
Wdrighi et al.
174
1W
ControlversusKetorolac
so
w
erences
1. O’Hara DA, Fragen RJ, Kinzer M, Pemberton D. Ketorolac tromethamine as compared with morphine sulfate for treatment of postoperative pain. Clin Pharmacol Ther 1987;41:556561.
80
2. Yee JP, Koshiver JE, Allbon C, Brown CR. Comparison of intramuscular ketorolac tromethamine and morphine sulfate for analgesia of pain after major surgery. Pharmacotherapy 1986;6:253261. Ketorolao
Control
Patient Group
Fig. 3 One hour postoperative visual analogue pain scores. Visual analogue pain scores obtained 1 hr after postanesthesia care unit admission were lower in the ketorolac treated group than in the control group (PC 0.01).
without increasing undesirable side effects. Additionally, ketorolac acts peripherally, independent of central opioid receptors, and hence may act synergistically with opioids to interrupt pain transmission. to Regardless of the mechanism of this interaction, this study demonstrates that the intraoperative administration of ketorolac in conjunction with opioids is an adjunct in the management of postoperative pain.
Acknowledgment This work was funded in part by a grant from Roche Laboratories.
3. Micaela MT, Brogden RN. Ketorolac: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs 1990;39:86199. .k. 4. Power I, Noble DW, Douglas E, Spence AA. Comparison of IM ketorolac trometamol and morphine sulphate for pain relief after cholecystectomy. Br J Anaesth 1990;65:448-455. 5. Wood M, Wood AJ[J.Drugs and anesthesia, Baltimore: Williams and Wilkins, 1990:136. 6. Aldrete JA, Kroulik D. A postanesthetic score. Anesth Analg 1970;49:924-934.
2nd ed. recovery
7. Huskisson EC: Visual analogue scales. In: Melzack R, ed. Pain measurement and assessment. New York: Raven, 1983:33-37. 8. Kuhn S, Cooke K, Collins M, Jones JM, Mucklow JC. Perceptions of pain relief after surgery. BMJ 1990;300:1687-1690. 9. Watcha C, White phine as thesiology
MF, Jones MB, Lagueruela RG, Schweiger PF. Comparison of ketorolac and moradjuvants during pediatric surgery. Anes 1992;76:368-372.
10. Dahl JB, Kehlet H. Non-steroidal anti-inflammatory drugs: rationale for use in severe postoperative pain. BrJ Anaesth 1991;66:703-712.
Vol. 9No. 3 Apti I994
f 71
John B. Valdrighi, MD, I&and I-I. Ha~lowell, MD, Rabert G. Loeb, MD, Kendra I-I. Behrman, RN, and Elizabeth A. Disbrow, MA Departntent ofAnesthesiology
Universityof CaQrnia
effective adjunct a’nthe wumagmmt 1994;9:~7f-I 74.
at Davis. Sacramento, California
of postv#wrative
Analgesics, nonsteroidal antiinfllammatg’ drqs, pain, postOperativeanalg&a
Address aunt reqwsts to:John B. Valdrighi, MD, 3227 Via Grande Way, Sacramento, CA 95825, USA,
0 U.S. Gmeer Pain ~e~~~~o~itte~, 1994 Published by Elsevier, New York, New York
§ymptom
Manage
ketorohc, i$ioid.s, mq&hine, postoperative
Intramuscular (IM) ketorolac (30-W mg) has been demonst~t~ to have analgesic potency comparable to IM morphine (12 mg).i-s In those studies, ketorolac was administered in the postoperative period to patients with preexisting pain. However, when IM ketorolac (30 mg) was compared with IM
Acc~ted for pab~j~atjo~~September 23, 1993.
pain. J Fain
morphine (10 mg} given int_raoperatively for the prophylactic treatment of the pain in the postanesthesia care unit (PACU), ketorulac was found to be less effectivee4 The latter study suggests that ketorolac, while a sufftcient analgesic for moderate postoperative pain, is not as effective as morphine in the management of severe pain occurring in the immediate postop erative period. The efficacy of the combination of intraoperative ketorolac and opioid analgesics, however, has not been thoroughly examined. The present study evaluated the effects of intraoperative ketorolac on subsequent patient comfort in the PACU.
Valdrighi et al.
172
Table 1 Descriptive Data
-
Control group mean (SEM)
Ketorolac group
mean (SEM)
Age (Y) Height (cm)
33
(3)
40
(4)
168
(2)
166
(2)
Weight (kg)
67.5 (2.9)
69.6 (3.1)
Female
60% (n = 9)
47% (n = 7)
Surgical duration (min) Outpatient
status
Time from drug administration to PACU admission (min) Intraoperative administration of opioids (fentanyl equivalent
180
(26)
160
(14)
47% (12= 7)
53% (n = 8)
56
(7)
45
(7)
303
(70)
338
(84)
N) SEM, s~lldad
error of he
nwau: and PAW, pmanesthcsia
care unit.
Methods Following approval from the human subject research committee, written informed consend was obtained from 30 patients. Eligible partici-
pants for the study were male or female patients between 18 and 70 yr of age, weighing 50-90 kg, who were undergoing general anesthesia for elective limb or lower abdominal procedures. No patients receiving preoperative analgesics were enrolled. Patients also were excluded for peptic ulcer disease, pregnancy or lactation, drug dependencies, psychiatric illnesses, morphine or aspirinlike drug allergies, and liver, renal, or hematologic disorders. Patients were randomly assigned to one of two groups. Upon surgical closure, one group received IM ketorolac (60 mg, 2 mL), and the other group received normal saline (2 mL, IM). The site of injection was based upon intraoperative access and included either the deltoid or vastus lateralis muscle. Patients, operating room and PACU personnel, and observing researchers were blinded to the treatment administered, Anesthesiologists were instructed to administer a “balanced general anesthetic” including opioids and to assume that the patient would not receive ketorolac upon surgical closure. Regional anesthetic techniques were excluded.
VOL.9 No. 3 April 1994
intraoperatively adminiFor comparison, stered opioids were recorded by generic name and dose, and then were converted to fentanyl equivalents (100 pg fentanyl = 10 mg morphine = 15 pg sufentanil = 750 j.tg alfentimil).” Postoperatively, both groups received morphine as needed for pain (l-3 mg intravenously repeated every 5 min until comfort was attained). Subjects were followed in the PACU until discharge or for a maximum of two hours. Vital signs, Aldrete recovery scores,” visual analog pain scores,7J total opioid dose, time to first opioid dose, and incidence of requiring morphine for pain were recorded. The visual analog pain score was based upon a loo-point (lo-cm) scale with 0 rated as no pain and 100 being the most severe pain. This score was obtained 1 hr after PACU admission. Statistical analysis was performed by analysis of variance (ANOVA) for parametric variables with results expressed as mean value + standard error of the mean @EM). Gender, race, surgical procedure, intraoperative opioids administered, AIdrete recovery scores, and the incidence of PACU administration of morphine were analyzed using a x2 test. Aldrete scores were analyzed by considering the results as either less than 9 or scores of 9 or 10 and then the incidence of each occurrence was examined for the two groups.
Results The two groups were not significantly different in height, weight, age, gender, race, intraoperatively administered opioids, and surgical procedures (Tables 1 and 2). In the PACU, there were no differences in Aldrete scores or respiratory rates. The control group required opioids more often than the ketorolac group (Figure 1). Additionally, when patients required opioids, Table 2 Operative Site (n)
Upper extremity hwer extremity Laparoscopy Lower abdominal
Control
Ketorolac
group
group
; 3 2
5 7 2 1
VOL.9 No. 3 Apt-2 1994
Ketorolar for PostoperatirlePain
40%
Con?rcd
Ketnrolae
Fig. 1. Patients requiring opioid analgesia in postanesthesia care unit (PACU) (saline control versus ketorolac): incidence of PAW opioid supplementation. Fewer patients in the ketorolac-treated group required postoperative opioid analgesics (P < 0.05).
the control group received the first morphine dose signi6candy earlier than the ketorofac group (1.5 + 4 vs 37 & 7 min, respectively, P< 0.01, Figure 2). When patients who did not require opioid analgesics were added to the analysis by considering the first dosage time to be the end of the observation period (2 hr), there again was a significant difference between control and ketorolac groups in time to first-administered morphine dose: 22 f 8 vs 76 f 11 min, respectively (PC O.OOl). Although the ketorolac group required a lower total dosage of postoperative opioids than did the control group (5.5 * I.9 vs 10.1 f 1.8 morphin~quivalent mg, respec~vely~, this diierence did not reach statistical significance (P = 0.08). Time to PACU discharge also was not different behveen groups (Figure 2). The ketorolac group did, however, report significandy lower pain scores than did the control group at 1 hr [36 f 5.4 and 64 f 5.6, respectively (Figure 3) I.
173
roidal a~tii~~~ammatQ~ therapy has been overlooked. h-r the present study, the effects of adding ketorolac to opioids administered as part of a balanced general anesthetic technique were examined. There were no differences between the two groups in in~operatively administered analgesics other than the administration of ketorolac to the intervention group. The ketorolac group required opioid supplementation less frequently in the PACU. The control group also required opioid analgesia sooner tban did the keeorolac group. The latter finding demonstrates that the intmoperative administration of ketorolac was additive to the analgesic effect of opioids that had been administered as part of a balanced general anesthetic technique. There were no disceruible differences between the groups in the rate of recovery from anesthesia, as demonstrated by Aldrete recovery scores and time to PACU discharge. However, the ketorolac group did have lower visual analogue pain scores and, hence, was more comfor~bIe in the PAW. This is the most interesting finding, because both groups were allowed as much morphine as necessary for the treatment of pain. There are several possible explanations for the finding that a combination of ketorolac with opioids may be more effective than opioids alone. The analgesic properties of these two classes of compounds may be additive, ahowing greater pain control Fig. 2. Times to first opioid suppfementation and postanesthesia care unit (PACU) discharge. The time to the first required opioid dose in the PACU
was greater in the ketorolac group versus the control
group fP< 0.01). The time to discharge from the PACU was not different between groups.
Previous studies have demonstrated that ketorolac is an efficacious analgesic comparable to morphine in the treatment of moderate postoperative pain. t-s Studies of the efficacy of this nonsteroidal antiinflammatory drug in the treatment of severe pain occurring immediately postoperatively, however, have yielded conflicting results4*s The question addressed by these previous studies is whether ketorolac is superior to opioids for the treatment of postop erative pain. By limiting the evaluation to a dete~ination of analgesic efftcacy, the possible efficacy of combined opioid and nonste-
ControlversusKatorolac 120
it F
40 20 0
FirstNarcotic
Vol. 9 No. 3 April I994
Wdrighi et al.
174
1W
ControlversusKetorolac
so
w
erences
1. O’Hara DA, Fragen RJ, Kinzer M, Pemberton D. Ketorolac tromethamine as compared with morphine sulfate for treatment of postoperative pain. Clin Pharmacol Ther 1987;41:556561.
80
2. Yee JP, Koshiver JE, Allbon C, Brown CR. Comparison of intramuscular ketorolac tromethamine and morphine sulfate for analgesia of pain after major surgery. Pharmacotherapy 1986;6:253261. Ketorolao
Control
Patient Group
Fig. 3 One hour postoperative visual analogue pain scores. Visual analogue pain scores obtained 1 hr after postanesthesia care unit admission were lower in the ketorolac treated group than in the control group (PC 0.01).
without increasing undesirable side effects. Additionally, ketorolac acts peripherally, independent of central opioid receptors, and hence may act synergistically with opioids to interrupt pain transmission. to Regardless of the mechanism of this interaction, this study demonstrates that the intraoperative administration of ketorolac in conjunction with opioids is an adjunct in the management of postoperative pain.
Acknowledgment This work was funded in part by a grant from Roche Laboratories.
3. Micaela MT, Brogden RN. Ketorolac: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs 1990;39:86199. .k. 4. Power I, Noble DW, Douglas E, Spence AA. Comparison of IM ketorolac trometamol and morphine sulphate for pain relief after cholecystectomy. Br J Anaesth 1990;65:448-455. 5. Wood M, Wood AJ[J.Drugs and anesthesia, Baltimore: Williams and Wilkins, 1990:136. 6. Aldrete JA, Kroulik D. A postanesthetic score. Anesth Analg 1970;49:924-934.
2nd ed. recovery
7. Huskisson EC: Visual analogue scales. In: Melzack R, ed. Pain measurement and assessment. New York: Raven, 1983:33-37. 8. Kuhn S, Cooke K, Collins M, Jones JM, Mucklow JC. Perceptions of pain relief after surgery. BMJ 1990;300:1687-1690. 9. Watcha C, White phine as thesiology
MF, Jones MB, Lagueruela RG, Schweiger PF. Comparison of ketorolac and moradjuvants during pediatric surgery. Anes 1992;76:368-372.
10. Dahl JB, Kehlet H. Non-steroidal anti-inflammatory drugs: rationale for use in severe postoperative pain. BrJ Anaesth 1991;66:703-712.