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The effect of ketorolac on recovery after outpatient gynecologic laparoscopy
CURRENT THERAPEUTIC RESEARCH” VOL. 57, NO. 8, AUGUST
1996
THEEFFECTOFKETOROLACONRECOVERYAFTER OUTPATIENT GYNECOLOGIC LAPAROSCOPY IAN H. SAMPSON, Department
of Anesthesiology,
IVAN DIMICH, AND ADIBA SHAMS1
Mount
Sinai
School of Medicine,
New York, New
York
ABSTRACT
Opioids, although effective postoperative analgesics, are associated with undesirable side effects. To determine whether nonopioid medication would reduce the amount required for postoperative analgesia, the efficacy of ketorolac, an injectable nonsteroidal anti-inflammatory drug, was studied in ambulatory patients undergoing gynecologic laparoscopy. Patients were randomized to a treatment group (n = 49) or control group (n = 50), then studied using a prospective double-masked design. Intraoperatively, the ketorolac treatment group received a 60-mg intramuscular injection of ketorolac; the control group received an injection of placebo (0.9% sodium chloride). Anesthetic management, postoperative pain, and the management of nausea were standardized in the two groups. Postoperative pain was treated with incremental doses of fentany125 pg intravenously. Nausea and vomiting were treated with droperidol or prochlorperazine. Pain and nausea assessments were done every 30 minutes in the postanesthesia care unit (PACU), at discharge, and at 24 hours after discharge. Postoperatively, for the first hour in the PACU, visual analog scale pain scores, as well as verbal pain scores, were statistically significantly lower in the ketorolac treatment group. Similarly, the severity of pain was twofold less in the ketorolac treatment group than in the control group. Less fentanyl was required in the ketorolac group (26 f 20 pg, mean + SD) compared with the control group (56 + 32 pg, mean + SD). However, there were no significant differences between the two groups with respect to postoperative sedation or nausea, although the incidence of vomiting requiring treatment was higher in the control group. There was high overall satisfaction of patients in both groups. In conclusion, intraoperative administration of ketorolac resulted in fewer patients awakening in pain and in a decreased need for opioid analgesic in the postoperative period. Ketorolac is an effective alternative to opioids for the control of postoperative pain in patients undergoing gynecologic laparoscopy. INTRODUCTION
An increasing
number
of gynecologic
laparoscopic
procedures
are now per-
Address correspondence to: Ivan Dimich, MD, Mount Sinai Medical Center, 1 Gustave L. T,evy Place, Dept. of Anesthesiology/Box 1010, New York, NY 10029-6574. Received for publication on April 15,1996.Printed in the U.S.A. Reproduction in whole or part is not permitted.
606
0011-393x/96/$3.50
I. H. SAMPSON
ET AL.
formed on an ambulatory basis, with the patients discharged from the surgical facility only a few hours after the procedure. The most common complications following laparoscopy are pain, nausea, and vomiting. Inadequate postoperative analgesia and prolonged vomiting can delay discharge or result in unanticipated admission to the hospital. Ketorolac tromethamine* (hereafter referred to as ketorolac), a nonsteroidal anti-inflammatory drug (NSAID), has been reported to afford postoperative analgesia comparable to the potent opioids but without their troublesome side effects (ie, drowsiness, respiratory depression, nausea, or vomiting).1-4 The objective of the current study was to determine whether a single intramuscular dose of ketorolac, given in the operating room 30 minutes before the end of surgery, would prevent pain and decrease the incidence of nausea and vomiting in the postanesthesia care unit (PACU). We performed a randomized, double-masked, placebo-controlled study including female patients undergoing gynecologic laparoscopy with general anesthesia. Intravenous fentanyl was used postoperatively as the comparable analgesic. PATIENTSANDMETHODS
With approval from the institutional human ethics committee, informed consent was obtained from 100 American Society of Anesthesiologists’ (ASA) physical status I and II patients undergoing elective gynecologic laparoscopy as outpatients. Exclusion criteria included (1) known allergy or contraindication to any NSAIDs (aspirin) or any opioids; (2) known bleeding, diathesis, or active peptic ulcer disease; and (3) advanced liver or kidney disease. Patients were randomized by a computer-generated list to receive either ketorolac (treatment group) or placebo (control group) during surgery. Preoperatively no sedatives or prophylactic antiemetics were given. The anesthetic technique was standardized for all patients and consisted of fentanyl 2 kg/kg intravenously (IV) and propofol 2 to 3 mg/kg IV for induction of anesthesia, followed by succinylcholine to facilitate tracheal intubation. Anesthesia was maintained with 67% nitrous oxide in oxygen and isoflurane (1% to 1.2%). Vecuronium was administered for maintenance of muscle relaxation, and additional narcotics were avoided. Patients in the treatment group received intramuscular ketorolac 60 mg (2 mL) in the deltoid region approximately 30 minutes before completion of surgery and patients in the control group received placebo (2 mL 0.9% sodium chloride) instead of ketorolac. The anesthesiologist did * Trademark: ToradoP G&he Laboratories, Nutley, New Jersey). 607
KETOROLAC
AFTER
GYNJXOLOGIC
LAPAROSCOPY
not know which of these medications he or she was injecting. At the end of surgery, muscle relaxation was reversed with glycopyrrolate and neostigmine. In the PACU, the presence of pain and nausea was assessed at 30minute intervals by a research nurse who was unaware of which medication had been given. Symptoms persisting on two successive evaluations were treated according to a standardized fentanyl or antiemetic protocol. If the patient developed pain and requested analgesia, she was treated with an incremental dose of 25-pg fentanyl IV. The requirement for fentanyl and any antiemetics was recorded. Postoperative pain was assessed using a self-rating visual analog scale (VAS) ranging from 0 to 10 where 0 = no pain and 10 = worst possible pain.5 Pain intensity was also assessed using a verbal pain score (VPS) ranging from 0 to 4 where 0 = no pain, 1 = mild pain, 2 = discomforting pain, 3 = distressing pain, and 4 = severe pain.576Pain scores were obtained on arrival in the PACU (time O), and at 30-minute intervals until discharge and then 24 hours later. Nausea and vomiting were assessed every 30 minutes using a scale ranging from 0 to 3 where 0 = no nausea, 1 = mild nausea, 2 = moderate nausea requiring treatment, and 3 = severe vomiting requiring treatment. Nausea and vomiting were treated with droperidol* 0.3 mg IV or prochlorperazinet 10 mg in standard PACU doses. The time of administration and doses of drugs given in the PACU were recorded. Postoperative drowsiness was evaluated using the following score from 1 to 5, where 1 = asleep and does not respond to any stimulus, 2 = asleep but responds to tactile stimuli, 3 = asleep but responds to verbal stimuli, 4 = awake but drowsy, and 5 = completely awake. The time taken for the patient to meet recovery and discharge criteria was recorded. This included the ability to tolerate oral liquids, ambulate with assistance, and ambulate without assistance. Time of discharge from the PACU and readiness to leave the hospital were recorded. Before discharge, patients were asked to make a subjective overall assessment of the pain relief achieved and an overall rating of the efficacy of the drugs. Overall rating scores were 0 = none, 1 = fair, 2 = good, 3 = very good, and 4 = excellent. A prescription for a conventional oral analgesic, chosen by the patient’s surgeon, was provided and given to the patient before discharge. During the 24-hour postoperative period, patients were asked to record in a diary the degree of any pain and amount of analgesic taken. Follow-up phone calls were made by a research nurse 24 hours after discharge from the hospital. * Trademark: t Trademark:
Inapsine@’ (Janssen Pharmaceutics Inc., Titusville, New Jersey). Compazine@ (SmithKline Beecham Pharmaceuticals, Philadelphia,
608
Pennsylvania).
I. H. SAMPSON
ET AL
Statistical Analysis Data are expressed as mean + SD. Continuous variables were analyzed by using an analysis of variance with the Bonferroni correction applied for multiple comparison between groups. Descriptive variables were analyzed using the chi-square test with P < 0.05 considered statistically significant. RESULTS
Demographic data are presented in Table 1. The two groups were comparable with respect to age, body weight, ASA physical status, duration of laparoscopic procedure, and duration of anesthetic. The most common laparoscopic procedures were lysis of pelvic adhesions, ablation of endometriosis, ovarian cystectomy, and diagnostic laparoscopy. One patient was excluded from the study because of surgical complications. Data from 99 patients were analyzed (ketorolac group, n = 49; control group, n = 50). On arrival in the PACU, similar mean drowsiness scores were recorded in both groups (ketorolac, 3.7; control, 3.5). However, during the first and second hour of PACU stay, the ketorolac group was less drowsy and reported higher scores than the control group (first-hour mean scores: ketorolac, 4.2; control, 3.4). At the time of discharge from the PACU, both groups had high mean scores (ketorolac, 4.9; control, 4.8). In the PACU, VAS pain scores (Figure 1) were lower at all measurement intervals in the ketorolac group than in the control group. The difference was statistically significant at 0, 30-, and 60-minute measurements (P< 0.05). At discharge from the PACU and at the 24-hour followup, VAS scores were similar in both groups. The severity and intensity of pain (VPS; Figure 2) was twofold higher in the control group than in the ketorolac group; this difference was statistically significant at 0, 30-, and 60-minute measurement times (P< 0.05). Postoperative requirements for parenteral analgesia and antiemetics
Table I. Demographic mean 2 SD.
data of trial patients.
Unless noted otherwise,
Ketomlac (II = 49)
Variable Age(Y)
Body weight (kg) ASA phystcal status (l/II) Duration of laparoscopic procedure (min) Duration of anesthetic (min) ASA = American Society of Anesthesiologists. 609
values are given as
Contml (n = 50)
KETOROLACAFTERGYNECOLOGlCLAPARO6COPY
10 9
-o-0
%,.I ....\ *
Ketorolac Control
,........
*
P < 0.05
.‘.. *
‘b ...... ‘... “s--....,,, ‘....,,
0 :
1
I
I
I
1
0
30
60
90
120
J
I
150
24
hours
Time in the PACU after Operation (min) Figure 1. Visual analog scores (mean + SD). Scores were based on a scale of 0 to 10 where 0 = no pain and 10 = worst possible pain. *P < 0.05. PACU = postanesthesia care unit.
are summarized in Table II. A significantly higher percentage of the patients in the control group complained of pain in the PACU (74%) than in the ketorolac group (37%). In the PACU, less total analgesic (fentanyl) medication was required for the ketorolac group (26 + 20 pg) than in the control group (56 ? 32 kg). Time to first analgesic request in the control group was 14.5 minutes versus 45.5 minutes in ketorolac group. 35
3.0
-
?! 8 m
Ketorolac
--O-
* P
0
Control
*
;;
00
!
I
I
I
I
0
30
60
90
I
120
1
150
24
hours
Time in the PACU after Operation (min) Figure 2. Verbal pain scores (mean k SD). Scores were based on a scale of 0 to 4 where 0 = no pain, 1 = mild pain, 2 = discomforting pain, 3 = distressing pain, and 4 = severe pain. *P < 0.05. PACU = postanesthesia care unit. 610
I. H. SAMPSONET AL
Table II. Postorxrative side effects: Bwuirements
for parenteral analgesics and antiemetics.
Ketomlac (n = 49) No. of patients requiring fentanyl in PAW (“ID) Mean time to first analgesic requested (min) Fentanyl dose (pq)t No. of patients with nausea in PACU (% No. of patients requiring antiemetics in bACU (%) Time to PACU discharge (min)t
1w&
Control (n = 50) 37J$)*
26 * 20 135 2 20
!ACU = ostanesthesia care unit. P c O.g5 versus ketorolac group. t Mean ? SD. Nausea and vomiting were reported more often by patients in the control group, although the difference did not reach statistical significance (Table II). However, 42% of the patients in the control group required multiple antiemetic therapy compared with 29% in the ketorolac group (P < 0.05). The time for each of the various recovery milestones was not significantly different between the groups. The average discharge time from the PACU for both groups was similar (ketorolac, 135 2 20 minutes; control, 145 * 25 minutes). The patients’ mean overall rating scores of the study favored ketorolac but not to a statistically significant degree (ketorolac, 3.4; placebo, 2.8). At 24 hours, pain scores and the incidence of nausea and vomiting were similarly low in both groups. One of the weaknesses of this study was that it did not include monitors for common NSAID side effects (eg, bleeding, especially gastrointestinal, or decreased renal output). DISCUSSION AND CONCLUSION
A variety of analgesic techniques have been used to manage postoperative pain after gynecologic laparoscopy. Current postoperative pain management relies strongly on the use of opioid analgesics, which have significant side effects.’ In an attempt to improve the recovery in ambulatory surgery, research has been directed toward the new nonopioid analgesics. Ketorolac is an NSAID that has been reported to be as effective as opioids in the treatment of postoperative pain. Availability in both the oral and parenteral forms makes ketorolac unique among NSAIDs.le4 Ketorolac provides analgesia by inhibiting prostaglandin and by decreasing peripheral nerve sensitivity.’ Varrasi et ala studied the analgesic efficacy and safety of perioperative ketorolac in patients undergoing cholecystectomy and concluded that ketorolac reduced postoperative pain and did not interfere with hemostasis or renal function. Furthermore, Murray et al9 reported that 611
KETOROLACAFTERGYNECOLOGICLAPAROSCOPY
ketorolac, in contrast to alfentanil, did not induce any cardiorespiratory depression. However, in recent reports, there is conflicting evidence about ketorolac’s efficacy in reducing postoperative pain or vomiting after outpatient surgery. lo-l2 Differences in operations (abdominal vs orthopedic), type of anesthesia, intraoperative narcotic use, patient age, and the timing of ketorolac administration are some possible reasons for inconsistent findings. In our study, we included only patients undergoing gynecologic laparoscopy. The ages of patients were similar, anesthesia was standardized, and opioids were used intraoperatively in minimal doses. We gave 60 mg of ketorolac intramuscularly 30 minutes before the end of surgery because studies on the bioavailability of ketorolac have established that a maximum serum level occurs approximately 45 minutes after intramuscular administration.’ The most significant finding in our study was that patients receiving ketorolac intraoperatively had lower pain scores during the first 2 hours in the PACU. On arrival to the PACU, patients in the control group experienced at least brief episodes of pain before fentanyl was administered. The difference in the time to first request for analgesia was statistically significant: 45.5 minutes in the ketorolac group versus 14.5 minutes in the control group. Also significant was the difference in total analgesic consumption in the PACU (26 ? 20 pg for the ketorolac group versus 56 2 32 kg for the control group). These findings indicate that intraoperative administration of ketorolac may offer an efficient alternative to opioids. However, in our study ketorolac did not completely eliminate postoperative pain. Thirty-seven percent of patients still requested fentanyl supplementation for adequate pain relief. Vasques et alI3 recommend that intravenous ketorolac should also be given postoperatively instead of fentanyl to control postoperative pain. In the past, most investigators have focused on the prophylactic benefits of only one drug, including ketorolac. However, recently, data have been published on the use of multimodal analgesics for laparoscopic procedures. Michololiakou et all4 showed that regimens combining ketorolac, opioid (meperidine), and local anesthesia (bupivacaine) provided almost complete pain relief in the immediate postoperative period after laparoscopic cholecystectomy. The argument for the use of a combination of analgesics is that drugs acting by different mechanisms result in additive and synergistic analgesic effects.15 In conclusion, intraoperative administration of ketorolac resulted in fewer patients awakening in pain and in a decreased need for opioid analgesia in the PACU compared with the placebo control group. Although there were no differences between the two groups in terms of recovery events and discharge, ketorolac appears to offer improved patient comfort in the immediate postoperative period after gynecologic laparoscopy. 612
1. H. SAMPSON
ET AL
Acknowledgments This study was supported by a grant from Roche Laboratories, a division of Hoffmann-La Roche Inc., Nutley, New Jersey. The authors would like to express their appreciation to our research nurses, Colette Bradford, Marietta DePerio, and Philip Kahn, for their help in the postoperative evaluation of these patients. References: 1. Dahl S, Kehlet H. Non-steroidal anti-inflammatory drugs: Rational use in severe postoperative pain. Br J Amesth. 1991;66:703-712. 2. Wong H, Carpenter R, Kopacz D, Fragen R. A randomized, double-blind evaluation of ketorolac tromethamine for postoperative analgesics in ambulatory surgery. Anesthesiology. 1993;78:6-14. 3. Greenberg C, Levine M, Brown A. Ketorolac is an effective analgesic for outpatient laparoscopy and shoulder arthroscopy. Anesthesiology. 1992;77. Abstract 21. 4. Reinhart D, Klein K, Cole T, et al. Combination transdermal fentanyl and ketorolac for postoperative analgesia. Anesthesiology. 1992;77. Abstract 31. 5. Huskinson F. Measurement of pain. Lancet. 1974;2:1127-1131. 6. Seymour R. An evaluation of length and end phase of visual analogue scales in dental pain. Pain. 1985;21:177-183. 7. Lowenstein E, Philbin D. Narcotic anesthesia in the eighties. Anesthesiology. 1981;55:95-97. 8. Varrasi G, Panella L, Piroli I, Maringoli F. The effects of perioperative ketorolac infusion on postoperative pain and endocrine metabolic response. Anesth A&g. 1995;78:514519. 9. Murray A, Brocuway M, Kenny G. Comparison of the cardiorespiratory effects of ketorolac and alfentanil during propofol anesthesia. Br J Anaesth. 1989;63:601-603. 10. Green C, Sujitk R, Pandit K. No fentanyl sparing effect of intraoperative IV ketorolac after laparoscopic tubal ligation. Anesthesiology. 1992;77. Abstract 7. 11. Higgins M, Givogre J, Marco P, et al. Recovery from outpatient laparoscopic tubal ligation is not improved by preoperative administration of ketorolac or ibuprofen. Anesth Annlg. 1994;79:278-280. 12. Lin G, Ding Y, Feinstein R. Laparoscopic cholecystectomy: Effect of ketorolac on postoperative pain and ventilatory function. Anesthesiology. 1992;77. Abstract 32. 13. Vasques J, Sukhan R, Pappas A. Propofol for ambulatory gynecological laparoscopy. Does omission of intraoperative opioid alter postoperative emetic sequela and recovery? Anesthesiology. 1995;83. Abstract 15. 14. Michololiakou C, Chung F, Shasura S. Preoperative multimodal analgesia facilitates recovery after ambulatory laparoscopic cholecystectomy. Anesth An&g. 1996;82:44-51. 15. Keats A, Telford Y, Kurosu Y. Potentiation of meperidine by promethazine. Anesthesiology. 1961;22:34.
613
1996
THEEFFECTOFKETOROLACONRECOVERYAFTER OUTPATIENT GYNECOLOGIC LAPAROSCOPY IAN H. SAMPSON, Department
of Anesthesiology,
IVAN DIMICH, AND ADIBA SHAMS1
Mount
Sinai
School of Medicine,
New York, New
York
ABSTRACT
Opioids, although effective postoperative analgesics, are associated with undesirable side effects. To determine whether nonopioid medication would reduce the amount required for postoperative analgesia, the efficacy of ketorolac, an injectable nonsteroidal anti-inflammatory drug, was studied in ambulatory patients undergoing gynecologic laparoscopy. Patients were randomized to a treatment group (n = 49) or control group (n = 50), then studied using a prospective double-masked design. Intraoperatively, the ketorolac treatment group received a 60-mg intramuscular injection of ketorolac; the control group received an injection of placebo (0.9% sodium chloride). Anesthetic management, postoperative pain, and the management of nausea were standardized in the two groups. Postoperative pain was treated with incremental doses of fentany125 pg intravenously. Nausea and vomiting were treated with droperidol or prochlorperazine. Pain and nausea assessments were done every 30 minutes in the postanesthesia care unit (PACU), at discharge, and at 24 hours after discharge. Postoperatively, for the first hour in the PACU, visual analog scale pain scores, as well as verbal pain scores, were statistically significantly lower in the ketorolac treatment group. Similarly, the severity of pain was twofold less in the ketorolac treatment group than in the control group. Less fentanyl was required in the ketorolac group (26 f 20 pg, mean + SD) compared with the control group (56 + 32 pg, mean + SD). However, there were no significant differences between the two groups with respect to postoperative sedation or nausea, although the incidence of vomiting requiring treatment was higher in the control group. There was high overall satisfaction of patients in both groups. In conclusion, intraoperative administration of ketorolac resulted in fewer patients awakening in pain and in a decreased need for opioid analgesic in the postoperative period. Ketorolac is an effective alternative to opioids for the control of postoperative pain in patients undergoing gynecologic laparoscopy. INTRODUCTION
An increasing
number
of gynecologic
laparoscopic
procedures
are now per-
Address correspondence to: Ivan Dimich, MD, Mount Sinai Medical Center, 1 Gustave L. T,evy Place, Dept. of Anesthesiology/Box 1010, New York, NY 10029-6574. Received for publication on April 15,1996.Printed in the U.S.A. Reproduction in whole or part is not permitted.
606
0011-393x/96/$3.50
I. H. SAMPSON
ET AL.
formed on an ambulatory basis, with the patients discharged from the surgical facility only a few hours after the procedure. The most common complications following laparoscopy are pain, nausea, and vomiting. Inadequate postoperative analgesia and prolonged vomiting can delay discharge or result in unanticipated admission to the hospital. Ketorolac tromethamine* (hereafter referred to as ketorolac), a nonsteroidal anti-inflammatory drug (NSAID), has been reported to afford postoperative analgesia comparable to the potent opioids but without their troublesome side effects (ie, drowsiness, respiratory depression, nausea, or vomiting).1-4 The objective of the current study was to determine whether a single intramuscular dose of ketorolac, given in the operating room 30 minutes before the end of surgery, would prevent pain and decrease the incidence of nausea and vomiting in the postanesthesia care unit (PACU). We performed a randomized, double-masked, placebo-controlled study including female patients undergoing gynecologic laparoscopy with general anesthesia. Intravenous fentanyl was used postoperatively as the comparable analgesic. PATIENTSANDMETHODS
With approval from the institutional human ethics committee, informed consent was obtained from 100 American Society of Anesthesiologists’ (ASA) physical status I and II patients undergoing elective gynecologic laparoscopy as outpatients. Exclusion criteria included (1) known allergy or contraindication to any NSAIDs (aspirin) or any opioids; (2) known bleeding, diathesis, or active peptic ulcer disease; and (3) advanced liver or kidney disease. Patients were randomized by a computer-generated list to receive either ketorolac (treatment group) or placebo (control group) during surgery. Preoperatively no sedatives or prophylactic antiemetics were given. The anesthetic technique was standardized for all patients and consisted of fentanyl 2 kg/kg intravenously (IV) and propofol 2 to 3 mg/kg IV for induction of anesthesia, followed by succinylcholine to facilitate tracheal intubation. Anesthesia was maintained with 67% nitrous oxide in oxygen and isoflurane (1% to 1.2%). Vecuronium was administered for maintenance of muscle relaxation, and additional narcotics were avoided. Patients in the treatment group received intramuscular ketorolac 60 mg (2 mL) in the deltoid region approximately 30 minutes before completion of surgery and patients in the control group received placebo (2 mL 0.9% sodium chloride) instead of ketorolac. The anesthesiologist did * Trademark: ToradoP G&he Laboratories, Nutley, New Jersey). 607
KETOROLAC
AFTER
GYNJXOLOGIC
LAPAROSCOPY
not know which of these medications he or she was injecting. At the end of surgery, muscle relaxation was reversed with glycopyrrolate and neostigmine. In the PACU, the presence of pain and nausea was assessed at 30minute intervals by a research nurse who was unaware of which medication had been given. Symptoms persisting on two successive evaluations were treated according to a standardized fentanyl or antiemetic protocol. If the patient developed pain and requested analgesia, she was treated with an incremental dose of 25-pg fentanyl IV. The requirement for fentanyl and any antiemetics was recorded. Postoperative pain was assessed using a self-rating visual analog scale (VAS) ranging from 0 to 10 where 0 = no pain and 10 = worst possible pain.5 Pain intensity was also assessed using a verbal pain score (VPS) ranging from 0 to 4 where 0 = no pain, 1 = mild pain, 2 = discomforting pain, 3 = distressing pain, and 4 = severe pain.576Pain scores were obtained on arrival in the PACU (time O), and at 30-minute intervals until discharge and then 24 hours later. Nausea and vomiting were assessed every 30 minutes using a scale ranging from 0 to 3 where 0 = no nausea, 1 = mild nausea, 2 = moderate nausea requiring treatment, and 3 = severe vomiting requiring treatment. Nausea and vomiting were treated with droperidol* 0.3 mg IV or prochlorperazinet 10 mg in standard PACU doses. The time of administration and doses of drugs given in the PACU were recorded. Postoperative drowsiness was evaluated using the following score from 1 to 5, where 1 = asleep and does not respond to any stimulus, 2 = asleep but responds to tactile stimuli, 3 = asleep but responds to verbal stimuli, 4 = awake but drowsy, and 5 = completely awake. The time taken for the patient to meet recovery and discharge criteria was recorded. This included the ability to tolerate oral liquids, ambulate with assistance, and ambulate without assistance. Time of discharge from the PACU and readiness to leave the hospital were recorded. Before discharge, patients were asked to make a subjective overall assessment of the pain relief achieved and an overall rating of the efficacy of the drugs. Overall rating scores were 0 = none, 1 = fair, 2 = good, 3 = very good, and 4 = excellent. A prescription for a conventional oral analgesic, chosen by the patient’s surgeon, was provided and given to the patient before discharge. During the 24-hour postoperative period, patients were asked to record in a diary the degree of any pain and amount of analgesic taken. Follow-up phone calls were made by a research nurse 24 hours after discharge from the hospital. * Trademark: t Trademark:
Inapsine@’ (Janssen Pharmaceutics Inc., Titusville, New Jersey). Compazine@ (SmithKline Beecham Pharmaceuticals, Philadelphia,
608
Pennsylvania).
I. H. SAMPSON
ET AL
Statistical Analysis Data are expressed as mean + SD. Continuous variables were analyzed by using an analysis of variance with the Bonferroni correction applied for multiple comparison between groups. Descriptive variables were analyzed using the chi-square test with P < 0.05 considered statistically significant. RESULTS
Demographic data are presented in Table 1. The two groups were comparable with respect to age, body weight, ASA physical status, duration of laparoscopic procedure, and duration of anesthetic. The most common laparoscopic procedures were lysis of pelvic adhesions, ablation of endometriosis, ovarian cystectomy, and diagnostic laparoscopy. One patient was excluded from the study because of surgical complications. Data from 99 patients were analyzed (ketorolac group, n = 49; control group, n = 50). On arrival in the PACU, similar mean drowsiness scores were recorded in both groups (ketorolac, 3.7; control, 3.5). However, during the first and second hour of PACU stay, the ketorolac group was less drowsy and reported higher scores than the control group (first-hour mean scores: ketorolac, 4.2; control, 3.4). At the time of discharge from the PACU, both groups had high mean scores (ketorolac, 4.9; control, 4.8). In the PACU, VAS pain scores (Figure 1) were lower at all measurement intervals in the ketorolac group than in the control group. The difference was statistically significant at 0, 30-, and 60-minute measurements (P< 0.05). At discharge from the PACU and at the 24-hour followup, VAS scores were similar in both groups. The severity and intensity of pain (VPS; Figure 2) was twofold higher in the control group than in the ketorolac group; this difference was statistically significant at 0, 30-, and 60-minute measurement times (P< 0.05). Postoperative requirements for parenteral analgesia and antiemetics
Table I. Demographic mean 2 SD.
data of trial patients.
Unless noted otherwise,
Ketomlac (II = 49)
Variable Age(Y)
Body weight (kg) ASA phystcal status (l/II) Duration of laparoscopic procedure (min) Duration of anesthetic (min) ASA = American Society of Anesthesiologists. 609
values are given as
Contml (n = 50)
KETOROLACAFTERGYNECOLOGlCLAPARO6COPY
10 9
-o-0
%,.I ....\ *
Ketorolac Control
,........
*
P < 0.05
.‘.. *
‘b ...... ‘... “s--....,,, ‘....,,
0 :
1
I
I
I
1
0
30
60
90
120
J
I
150
24
hours
Time in the PACU after Operation (min) Figure 1. Visual analog scores (mean + SD). Scores were based on a scale of 0 to 10 where 0 = no pain and 10 = worst possible pain. *P < 0.05. PACU = postanesthesia care unit.
are summarized in Table II. A significantly higher percentage of the patients in the control group complained of pain in the PACU (74%) than in the ketorolac group (37%). In the PACU, less total analgesic (fentanyl) medication was required for the ketorolac group (26 + 20 pg) than in the control group (56 ? 32 kg). Time to first analgesic request in the control group was 14.5 minutes versus 45.5 minutes in ketorolac group. 35
3.0
-
?! 8 m
Ketorolac
--O-
* P
0
Control
*
;;
00
!
I
I
I
I
0
30
60
90
I
120
1
150
24
hours
Time in the PACU after Operation (min) Figure 2. Verbal pain scores (mean k SD). Scores were based on a scale of 0 to 4 where 0 = no pain, 1 = mild pain, 2 = discomforting pain, 3 = distressing pain, and 4 = severe pain. *P < 0.05. PACU = postanesthesia care unit. 610
I. H. SAMPSONET AL
Table II. Postorxrative side effects: Bwuirements
for parenteral analgesics and antiemetics.
Ketomlac (n = 49) No. of patients requiring fentanyl in PAW (“ID) Mean time to first analgesic requested (min) Fentanyl dose (pq)t No. of patients with nausea in PACU (% No. of patients requiring antiemetics in bACU (%) Time to PACU discharge (min)t
1w&
Control (n = 50) 37J$)*
26 * 20 135 2 20
!ACU = ostanesthesia care unit. P c O.g5 versus ketorolac group. t Mean ? SD. Nausea and vomiting were reported more often by patients in the control group, although the difference did not reach statistical significance (Table II). However, 42% of the patients in the control group required multiple antiemetic therapy compared with 29% in the ketorolac group (P < 0.05). The time for each of the various recovery milestones was not significantly different between the groups. The average discharge time from the PACU for both groups was similar (ketorolac, 135 2 20 minutes; control, 145 * 25 minutes). The patients’ mean overall rating scores of the study favored ketorolac but not to a statistically significant degree (ketorolac, 3.4; placebo, 2.8). At 24 hours, pain scores and the incidence of nausea and vomiting were similarly low in both groups. One of the weaknesses of this study was that it did not include monitors for common NSAID side effects (eg, bleeding, especially gastrointestinal, or decreased renal output). DISCUSSION AND CONCLUSION
A variety of analgesic techniques have been used to manage postoperative pain after gynecologic laparoscopy. Current postoperative pain management relies strongly on the use of opioid analgesics, which have significant side effects.’ In an attempt to improve the recovery in ambulatory surgery, research has been directed toward the new nonopioid analgesics. Ketorolac is an NSAID that has been reported to be as effective as opioids in the treatment of postoperative pain. Availability in both the oral and parenteral forms makes ketorolac unique among NSAIDs.le4 Ketorolac provides analgesia by inhibiting prostaglandin and by decreasing peripheral nerve sensitivity.’ Varrasi et ala studied the analgesic efficacy and safety of perioperative ketorolac in patients undergoing cholecystectomy and concluded that ketorolac reduced postoperative pain and did not interfere with hemostasis or renal function. Furthermore, Murray et al9 reported that 611
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ketorolac, in contrast to alfentanil, did not induce any cardiorespiratory depression. However, in recent reports, there is conflicting evidence about ketorolac’s efficacy in reducing postoperative pain or vomiting after outpatient surgery. lo-l2 Differences in operations (abdominal vs orthopedic), type of anesthesia, intraoperative narcotic use, patient age, and the timing of ketorolac administration are some possible reasons for inconsistent findings. In our study, we included only patients undergoing gynecologic laparoscopy. The ages of patients were similar, anesthesia was standardized, and opioids were used intraoperatively in minimal doses. We gave 60 mg of ketorolac intramuscularly 30 minutes before the end of surgery because studies on the bioavailability of ketorolac have established that a maximum serum level occurs approximately 45 minutes after intramuscular administration.’ The most significant finding in our study was that patients receiving ketorolac intraoperatively had lower pain scores during the first 2 hours in the PACU. On arrival to the PACU, patients in the control group experienced at least brief episodes of pain before fentanyl was administered. The difference in the time to first request for analgesia was statistically significant: 45.5 minutes in the ketorolac group versus 14.5 minutes in the control group. Also significant was the difference in total analgesic consumption in the PACU (26 ? 20 pg for the ketorolac group versus 56 2 32 kg for the control group). These findings indicate that intraoperative administration of ketorolac may offer an efficient alternative to opioids. However, in our study ketorolac did not completely eliminate postoperative pain. Thirty-seven percent of patients still requested fentanyl supplementation for adequate pain relief. Vasques et alI3 recommend that intravenous ketorolac should also be given postoperatively instead of fentanyl to control postoperative pain. In the past, most investigators have focused on the prophylactic benefits of only one drug, including ketorolac. However, recently, data have been published on the use of multimodal analgesics for laparoscopic procedures. Michololiakou et all4 showed that regimens combining ketorolac, opioid (meperidine), and local anesthesia (bupivacaine) provided almost complete pain relief in the immediate postoperative period after laparoscopic cholecystectomy. The argument for the use of a combination of analgesics is that drugs acting by different mechanisms result in additive and synergistic analgesic effects.15 In conclusion, intraoperative administration of ketorolac resulted in fewer patients awakening in pain and in a decreased need for opioid analgesia in the PACU compared with the placebo control group. Although there were no differences between the two groups in terms of recovery events and discharge, ketorolac appears to offer improved patient comfort in the immediate postoperative period after gynecologic laparoscopy. 612
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Acknowledgments This study was supported by a grant from Roche Laboratories, a division of Hoffmann-La Roche Inc., Nutley, New Jersey. The authors would like to express their appreciation to our research nurses, Colette Bradford, Marietta DePerio, and Philip Kahn, for their help in the postoperative evaluation of these patients. References: 1. Dahl S, Kehlet H. Non-steroidal anti-inflammatory drugs: Rational use in severe postoperative pain. Br J Amesth. 1991;66:703-712. 2. Wong H, Carpenter R, Kopacz D, Fragen R. A randomized, double-blind evaluation of ketorolac tromethamine for postoperative analgesics in ambulatory surgery. Anesthesiology. 1993;78:6-14. 3. Greenberg C, Levine M, Brown A. Ketorolac is an effective analgesic for outpatient laparoscopy and shoulder arthroscopy. Anesthesiology. 1992;77. Abstract 21. 4. Reinhart D, Klein K, Cole T, et al. Combination transdermal fentanyl and ketorolac for postoperative analgesia. Anesthesiology. 1992;77. Abstract 31. 5. Huskinson F. Measurement of pain. Lancet. 1974;2:1127-1131. 6. Seymour R. An evaluation of length and end phase of visual analogue scales in dental pain. Pain. 1985;21:177-183. 7. Lowenstein E, Philbin D. Narcotic anesthesia in the eighties. Anesthesiology. 1981;55:95-97. 8. Varrasi G, Panella L, Piroli I, Maringoli F. The effects of perioperative ketorolac infusion on postoperative pain and endocrine metabolic response. Anesth A&g. 1995;78:514519. 9. Murray A, Brocuway M, Kenny G. Comparison of the cardiorespiratory effects of ketorolac and alfentanil during propofol anesthesia. Br J Anaesth. 1989;63:601-603. 10. Green C, Sujitk R, Pandit K. No fentanyl sparing effect of intraoperative IV ketorolac after laparoscopic tubal ligation. Anesthesiology. 1992;77. Abstract 7. 11. Higgins M, Givogre J, Marco P, et al. Recovery from outpatient laparoscopic tubal ligation is not improved by preoperative administration of ketorolac or ibuprofen. Anesth Annlg. 1994;79:278-280. 12. Lin G, Ding Y, Feinstein R. Laparoscopic cholecystectomy: Effect of ketorolac on postoperative pain and ventilatory function. Anesthesiology. 1992;77. Abstract 32. 13. Vasques J, Sukhan R, Pappas A. Propofol for ambulatory gynecological laparoscopy. Does omission of intraoperative opioid alter postoperative emetic sequela and recovery? Anesthesiology. 1995;83. Abstract 15. 14. Michololiakou C, Chung F, Shasura S. Preoperative multimodal analgesia facilitates recovery after ambulatory laparoscopic cholecystectomy. Anesth An&g. 1996;82:44-51. 15. Keats A, Telford Y, Kurosu Y. Potentiation of meperidine by promethazine. Anesthesiology. 1961;22:34.
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