Acta Anaesthesiol Scand 1992: 36: 7 16-721
Comparison of ketorolac and morphine for postoperative pain after major surgery E. M. STOUTEN, S. ARMBRUSTER, R. J. HOUMES, 0. PRAKASH, W. ERDMANN and B. LACHMANN Drpartment of Anesthesiology, Erasmus University, Rotterdam, The Netherlands
This study was designed to determine the relative analgesic efficacy and safety of single intramuscular injections of ketorolac (10 mg or 30 mg) and morphine (10 mg) in patients of either sex with moderate to severe pain after major surgery. In a single-dose, randomised, double-blind study of parallel design, pain was assessed immediately before injection of test medication and at regular intervals for 8 h thereafter. One hundred and seventeen patients (109 undergoing cardiac surgery; 8 lung surgery) were randomized to one of the three treatment groups. Pain intensity was assessed using a 5-point verbal scale before administration of study drugs. Postadministration, at 30 min and hourly for 8 h, pain intensity and pain relief were assessed, again using the 5-point verbal scale. Additionally, as a measure of analgesia, forced expiratory volumr (FEV,) was obtained in all patients. Vital signs including blood pressure, pulse, temperature, respiratory rate and blood gases (Paco,) were recorded prior to and after study medication. Based on hourly pain intensity differences and hourly pain relief observations, ketorolac 10 mg was generally more effective than morphine 10 mg, and ketorolac 30 mg was generally more effective than ketorolac 10 mg. The results of this study show that ketorolac is an effective and safe (with regard to arterial pressure, blood gases and lung function) analgesic for relief of postoperative pain after major surgery in stable patients. No clinically significant adverse effects occurred during the study. One cannot exclude an influence on patients with organ system dysfunction or on parameters not measured in this study. Received 12 January 1991, accepted f o r publication in a reiiised version 5 March 1992
Key words: Ketorolac; morphine; non-steroidal anti-inflammatory drugs; postoperative pain.
Adequate pain relief following surgical procedures remains a major concern for anaesthetists. To date, intermittent i.m. injection of opiates remains, despite all known disadvantages, including respiratory depression, the most common method for postoperative pain relief (1). There is some progress towards the use of non-steroidal, anti-inflammatory drugs (NSAIDs) for postoperative analgesia. One of the newer NSAIDs is ketorolac tromethamine, which is available for parenteral, rectal and oral use. Ketorolac does not produce respiratory depression (2), addiction (3), or psychomotor effects (4,5 ) , and does not inhibit gastrointestinal motility (2). Its analgesic action may, in part, be due to its ability to inhibit prostaglandin synthesis (6-8). This may be an important factor in the treatment of postoperative pain, where prostaglandins are thought to be a modulating factor. This study was designed to evaluate the relative analgesic efficacy, and safety for hemodynamics and the respiratory system as far as measured by the study drugs on parameters including arterial pressure, blood gases and forced expiratory volume and by assessing the elicited and reported adverse events of a single i.m. injection of ketorolac (10 mg or 30 mg) or morphine (10 mg) in patients with moderate, severe or very
severe pain after major surgery (over 90% of patients underwent cardiac surgery).
PATIENTS AND METHODS Study design This was a single-dose, randomised, double-blind (double-observer) study of parallel design. Written informed consent was received from all patients in the study, which was conducted in accordance with the guidelines of the Declaration of Helsinki and approved by the local Ethical Review Committee of Erasmus University, Rotterdam. One hundred and seventeen patients verbally reporting at least moderate pain up to 48 h after major surgery (1 15 median sternotomies, 2 thoracotomies) were randomly assigned to receive: ketorolac 10 mg, ketorolac 30 mg, or morphine 10 mg. All study drugs were supplied in 1-ml ampoules, identically packaged and labelled in a manner suitable for randomised treatment allocation. To ensure the double-blind design of the study, dispensing and administering of the medications were performed by persons not responsible for patient treatment and data collection (double-observer technique). The identity of the test medications was not known to the persons performing the clinical assessments. Study medications were administered intramuscularly into the lateral thigh (vastus lateralis). The observation period following administration of test medication lasted 8 h. Postoperatively, patients of either sex were kept on ventilatory support until they were considered to be in a stable condition. After extubation, patients experiencing at least moderate pain within 48 h of surgery, who requested analgesic medication and met the trial entry criteria, were entered in the study. Patients had to be stable,
KETOROLAC FOR POSTOPERATIVE PAIN TREATMENT alert and able to communicate verbally with the investigators concerning the presence of their pain postoperatively. Patients were informed that they could withdraw from the study at any time and for any reason. Any patient who experienced inadequate pain relief or recurring pain episodes was given rescue medication and withdrawn from further study. Pain intensity was assessed before administering the study medication. Patients were interviewed concerning both pain intensity and pain relief at 30 min and hourly for 8 h after treatment. Upon completion of the observation period, the overall analgesic response of the test medication was assessed by both the investigator and the patient. Additionally as a measure of analgesia, forced expiratory volume (FEV,) (Vitalograph, Vitalograph Ltd. Buckingham, U K ) was obtained for all patients prior to and at 2 h after administration of study drugs. Safe9 evaluation The vital parameters arterial blood pressure (Dinamap, Critikon, USA), respiratory rate and body temperature were obtained at baseline and periodically following administration of study drugs. I n addition, arterial blood gas measurements (ABL 330, Radiometer, Copenhagen, Denmark) were made at baseline, and 1 and 2 h postadministration. Postoperatively, all patients received additional oxygen via a nasal catheter; therefore only the Paco, measurements were used in the statistical analysis. According to the study procedure, any adverse events verbally reported by the patient, or elicited or observed by the investigator, were rated mild, moderate or severe and fully recorded. Patient selection Patients of either sex recruited for this study had to be aged between 18 and 70 years; be alert and able to communicate with the investigator; and be stable postoperative patients. Based on patient history and pre-operative evaluations, criteria excluding patients from the study included: diabetes, chronic renal failure (serum creatinine 2 110 pmol/l, and/or BUN 28.0 mmol/l), asthma, psychiatric disorders, use of highly protein-bound anticoagulants, patients receiving any concomitant medication within 4 h prior to receiving study medication likely to influence response to analgesia (e.g. sedatives, hypnotics). Eighty-eight males and 29 females (aged 22-68 years) met the admission criteria following major surgery (Table I ). All patients underwent a standardised anaesthesia procedure, including highdose fentanyl (40-50 pg/kg i.v. peroperatively). In accordance with the randomization schedule: 38 patients received ketorolac-I0 mg; 39 received ketorolac 30 mg; and 40 patients received morphine 10 mg. All study medication was given as a single injection into the vastus lateralis. Efficay evaluation Subjective reports obtained by interviews were used as indices of response. Prior to drug administration and at 30 min and hourly for 8 h after drug administration, pain intensity was assessed using a 5point verbal scale (O=no pain, 1 =mild pain, 2=moderate pain, 3 =severe pain, 4 = very severe pain). During each postmedication
Table 1 Number of patients per surgical procedure.
Coronary bypass Aorticlmitral valve repair Other
Ketorolac 10 mg
Ketorolac 30 mg
Morphine 10 mg
35 2 1
29 7 3
30 6 4
717
observation period, pain relief was assessed using a 5-point verbal scale (0 = n o relief, 1 =little relief, 2 = moderate relief, 3 = much relief, 4 =complete relief). At the end of the study, both the investigator and the patient globally assessed drug efficacy using a 5-point scale ( I = poor, 2 =fair, 3 =good, 4 = very good, and 5 = excellent). To differentiate the analgesic response objectively, patients were requested to participate in an effort-oriented respiratory function test. Forced expiratory volume (FEV,) was obtained for all patients prior to and at 2 h following administration of test medication. A differential response in FEV, would be an indication of greater analgesia since patients with less pain could perform this test better at 2 h than at baseline. Relative analgesic efficacy was measured by several primary efficacy measures: hourly pain intensity differences (PIDs); hourly pain relief (PAR); percent of patients withdrawn from study because of inadequate pain relief or recurring pain intensity; overall investigator and patient assessments; mean summed pain intensity differences (SPID) at 3 h, 6 h and the entire 8 h; and total pain relief score (TOTPAR) at 3 h, 6 h and the entire 8 h. Adverse events Adverse events occurring during the study were recorded from information provided spontaneously by the patient or elicited by the investigator’s questions. The severity of adverse events was rated as mild, moderate or severe. Also evaluated were whether the effect was thought to be related to the test compound and whether the adverse event required premature patient withdrawal from study completion. Statistical methods Initial pain intensity was recorded for comparison between treatment groups and for subsequent analysis of analgesic efficacy. Pain intensity difference (PID) scores were calculated as the difference in pain intensity between the initial pain intensity and the subsequent halfhour or hourly values. Area under the P I D by time curve (SPID), time to first positive PID, termination time, maximum PID during the 8-h study period, hours the pain was less than baseline, and area under the pain relief score by time curve (TOTPAR) were calculated for each patient. The summary efficacy measures analysed included overall investigator and patient ratings, patient determination for inadequate pain relief or recurrence of pain, time to first positive PID, termination time, maximum PID, number of hours during which the pain intensity was less than baseline, SPID (0-3, 0-6, 0-8 h) and TOTPAR (0-3, 0-6, 0-8 h). Baseline pain intensity, sex, age, weight, height, and “time since surgery” were analysed for treatment group differences by the Kruskal-Wallis test or the chi-square test. The efficacy parameters were analysed by the rank-transformed ANOVA, adjusting for baseline pain intensity and sex. The inclusion of sex as a factor is due to its significant imbalance among treatment groups (P=0.05). For the vital signs an ANOVA was done on the raw data for the change from baseline (current minus baseline measurement). ANOVA was also done on the rank-transformed data for respiratory function variables and Paco, changes from baseline. Duncan’s multiple range tests were performed to determine individual treatment group differences. All tests for statistical significance were two-tailed and the data were tested at the 0.05 significance level. In patients withdrawn prematurely from the study, post-termination pain intensity was evaluated as the more severe score between the baseline pain intensity score and the last available pain intensity score, while pain relief scores were evaluated as “no pain relief’.
RESULTS Of the 117 enrolled patients, 1 12 patients received study medication within 24 h of surgery (ketorolac 10
718
E. M. STOUTEN E T AL.
mg N = 38, ketorolac 30 mg N = 36, morphine 10 mg N = 3 8 ) , and only five patients received study medication between 24-48 h of surgery (ketorolac 30 mg N = 3, morphine 10 mg N = 2), all of which gave no statistically significant difference. Concomitant medications (sympaticomimetics or blockers, diuretics, ranitidine, theophylline, captopril, potassium chloride and/or antibiotics) were given to 26,30 and 26 patients in the kctorolac 10 mg, ketorolac 30 mg and morphine 10 mg groups, respectively. The groups were similar with respect to baseline pain intensity, age, weight, height and time since surgery (Table 2). A statistically significant difference was found when comparing sex (88 males, 29 females; P= 0.05). All enrolled patients were included in the safety evaluations. Three patients were excluded from all efficacy evaluations: two patients had received morphine 10 mg and were excluded due to protocol violations; the third patient had received ketorolac 30 mg and was excluded due to noncompatibility of baseline pain intensity. This was the only patient who, prior to the start of the study, experienced very severe pain; all the other patients experienced moderate (82%) or severe (17%) pain. In spite of receiving study drugs and additional rescue medication, the patient had no pain relief (in terms of the evaluation scale) and was therefore excluded from the eficacy evaluations - as specified by the protocol. Similarly, three patients who received ketorolac 10 mg, four who received ketorolac 30 mg and five patients who received morphine 10 mg experienced inadequate pain relief or a recurrent pain episode after study medication. These patients received additional analgesics and were withdrawn prematurely from the study. Concurrent diseases which were present in 24 paTable 2 Baseline characteristics. Ketorolac 10mg
Ketorolac 30mg
Morphine 10mg
(test)
Female/male
4/34
12/26
12/26
(C) ( P = 0 . 0 5 )
Age iyr) s.d.
55.7 6.5
55.2 11.2
54.1 12.1
( K ) (NS)
Weight (kg) s.d.
78 I1
73
76 9
( K ) (NS)
11
Height (cm) s.d.
175 7
I72 9
I74 10
(K) (NS)
Time since surgery (h) 0-24 h 38 >24 h 0
35 3
37 I
(K) (NS) ( K ) (NS)
Baseline pain (no. of patients) Moderate 30 Severe 8
33 5
31 7
(C) (NS) (C) (NS)
(C) =Chi-square test, (K) = Kruskal-Wallis test, (NS)=not significant.
KBTOROLAC 10 mg -+- KBTOROLAC 30 mg -t MORPHINE 10 mg +
a 2 c,
E
-
0 " " " " " " " " 0 1 2 3 4 5
6
'
7
8
Time (h) Fig. I . Changes in pain intensity values (mean s.e.mean) over time (for significant difference between the groups, see Results section).
tients were (according to the protocol) considered to have no effect on the safety and efficacy assessments of the study drugs. Concomitant medication necessary for the welfare of these patients was continued, as required, throughout the study period.
Efficacy Pain intensity. All three test medications were rapid in onset of action, and pain intensity differences indicated equal effectiveness at 0.5 and 1 h following administration of test medication (Fig. 1). Statistically significant differences between treatments were observed at 2, 3, 4, and 5 h postadministration. Although ketorolac 30 mg was usually more effective than ketorolac 10 mg, the difference was not statistically significant. Both of these test medications were statistically superior to morphine at these observation times (P=O.O5). At 6, 7 and 8 h postadministration, ketorolac 30 mg and ketorolac 10 mg were still more effective than morphine 10 mg; however, the differences at these later observation periods were not statistically significant. At 8 h ketorolac 30 mg again showed a statistically significant efficacy (P
Comparison of ketorolac and morphine for postoperative pain after major surgery E. M. STOUTEN, S. ARMBRUSTER, R. J. HOUMES, 0. PRAKASH, W. ERDMANN and B. LACHMANN Drpartment of Anesthesiology, Erasmus University, Rotterdam, The Netherlands
This study was designed to determine the relative analgesic efficacy and safety of single intramuscular injections of ketorolac (10 mg or 30 mg) and morphine (10 mg) in patients of either sex with moderate to severe pain after major surgery. In a single-dose, randomised, double-blind study of parallel design, pain was assessed immediately before injection of test medication and at regular intervals for 8 h thereafter. One hundred and seventeen patients (109 undergoing cardiac surgery; 8 lung surgery) were randomized to one of the three treatment groups. Pain intensity was assessed using a 5-point verbal scale before administration of study drugs. Postadministration, at 30 min and hourly for 8 h, pain intensity and pain relief were assessed, again using the 5-point verbal scale. Additionally, as a measure of analgesia, forced expiratory volumr (FEV,) was obtained in all patients. Vital signs including blood pressure, pulse, temperature, respiratory rate and blood gases (Paco,) were recorded prior to and after study medication. Based on hourly pain intensity differences and hourly pain relief observations, ketorolac 10 mg was generally more effective than morphine 10 mg, and ketorolac 30 mg was generally more effective than ketorolac 10 mg. The results of this study show that ketorolac is an effective and safe (with regard to arterial pressure, blood gases and lung function) analgesic for relief of postoperative pain after major surgery in stable patients. No clinically significant adverse effects occurred during the study. One cannot exclude an influence on patients with organ system dysfunction or on parameters not measured in this study. Received 12 January 1991, accepted f o r publication in a reiiised version 5 March 1992
Key words: Ketorolac; morphine; non-steroidal anti-inflammatory drugs; postoperative pain.
Adequate pain relief following surgical procedures remains a major concern for anaesthetists. To date, intermittent i.m. injection of opiates remains, despite all known disadvantages, including respiratory depression, the most common method for postoperative pain relief (1). There is some progress towards the use of non-steroidal, anti-inflammatory drugs (NSAIDs) for postoperative analgesia. One of the newer NSAIDs is ketorolac tromethamine, which is available for parenteral, rectal and oral use. Ketorolac does not produce respiratory depression (2), addiction (3), or psychomotor effects (4,5 ) , and does not inhibit gastrointestinal motility (2). Its analgesic action may, in part, be due to its ability to inhibit prostaglandin synthesis (6-8). This may be an important factor in the treatment of postoperative pain, where prostaglandins are thought to be a modulating factor. This study was designed to evaluate the relative analgesic efficacy, and safety for hemodynamics and the respiratory system as far as measured by the study drugs on parameters including arterial pressure, blood gases and forced expiratory volume and by assessing the elicited and reported adverse events of a single i.m. injection of ketorolac (10 mg or 30 mg) or morphine (10 mg) in patients with moderate, severe or very
severe pain after major surgery (over 90% of patients underwent cardiac surgery).
PATIENTS AND METHODS Study design This was a single-dose, randomised, double-blind (double-observer) study of parallel design. Written informed consent was received from all patients in the study, which was conducted in accordance with the guidelines of the Declaration of Helsinki and approved by the local Ethical Review Committee of Erasmus University, Rotterdam. One hundred and seventeen patients verbally reporting at least moderate pain up to 48 h after major surgery (1 15 median sternotomies, 2 thoracotomies) were randomly assigned to receive: ketorolac 10 mg, ketorolac 30 mg, or morphine 10 mg. All study drugs were supplied in 1-ml ampoules, identically packaged and labelled in a manner suitable for randomised treatment allocation. To ensure the double-blind design of the study, dispensing and administering of the medications were performed by persons not responsible for patient treatment and data collection (double-observer technique). The identity of the test medications was not known to the persons performing the clinical assessments. Study medications were administered intramuscularly into the lateral thigh (vastus lateralis). The observation period following administration of test medication lasted 8 h. Postoperatively, patients of either sex were kept on ventilatory support until they were considered to be in a stable condition. After extubation, patients experiencing at least moderate pain within 48 h of surgery, who requested analgesic medication and met the trial entry criteria, were entered in the study. Patients had to be stable,
KETOROLAC FOR POSTOPERATIVE PAIN TREATMENT alert and able to communicate verbally with the investigators concerning the presence of their pain postoperatively. Patients were informed that they could withdraw from the study at any time and for any reason. Any patient who experienced inadequate pain relief or recurring pain episodes was given rescue medication and withdrawn from further study. Pain intensity was assessed before administering the study medication. Patients were interviewed concerning both pain intensity and pain relief at 30 min and hourly for 8 h after treatment. Upon completion of the observation period, the overall analgesic response of the test medication was assessed by both the investigator and the patient. Additionally as a measure of analgesia, forced expiratory volume (FEV,) (Vitalograph, Vitalograph Ltd. Buckingham, U K ) was obtained for all patients prior to and at 2 h after administration of study drugs. Safe9 evaluation The vital parameters arterial blood pressure (Dinamap, Critikon, USA), respiratory rate and body temperature were obtained at baseline and periodically following administration of study drugs. I n addition, arterial blood gas measurements (ABL 330, Radiometer, Copenhagen, Denmark) were made at baseline, and 1 and 2 h postadministration. Postoperatively, all patients received additional oxygen via a nasal catheter; therefore only the Paco, measurements were used in the statistical analysis. According to the study procedure, any adverse events verbally reported by the patient, or elicited or observed by the investigator, were rated mild, moderate or severe and fully recorded. Patient selection Patients of either sex recruited for this study had to be aged between 18 and 70 years; be alert and able to communicate with the investigator; and be stable postoperative patients. Based on patient history and pre-operative evaluations, criteria excluding patients from the study included: diabetes, chronic renal failure (serum creatinine 2 110 pmol/l, and/or BUN 28.0 mmol/l), asthma, psychiatric disorders, use of highly protein-bound anticoagulants, patients receiving any concomitant medication within 4 h prior to receiving study medication likely to influence response to analgesia (e.g. sedatives, hypnotics). Eighty-eight males and 29 females (aged 22-68 years) met the admission criteria following major surgery (Table I ). All patients underwent a standardised anaesthesia procedure, including highdose fentanyl (40-50 pg/kg i.v. peroperatively). In accordance with the randomization schedule: 38 patients received ketorolac-I0 mg; 39 received ketorolac 30 mg; and 40 patients received morphine 10 mg. All study medication was given as a single injection into the vastus lateralis. Efficay evaluation Subjective reports obtained by interviews were used as indices of response. Prior to drug administration and at 30 min and hourly for 8 h after drug administration, pain intensity was assessed using a 5point verbal scale (O=no pain, 1 =mild pain, 2=moderate pain, 3 =severe pain, 4 = very severe pain). During each postmedication
Table 1 Number of patients per surgical procedure.
Coronary bypass Aorticlmitral valve repair Other
Ketorolac 10 mg
Ketorolac 30 mg
Morphine 10 mg
35 2 1
29 7 3
30 6 4
717
observation period, pain relief was assessed using a 5-point verbal scale (0 = n o relief, 1 =little relief, 2 = moderate relief, 3 = much relief, 4 =complete relief). At the end of the study, both the investigator and the patient globally assessed drug efficacy using a 5-point scale ( I = poor, 2 =fair, 3 =good, 4 = very good, and 5 = excellent). To differentiate the analgesic response objectively, patients were requested to participate in an effort-oriented respiratory function test. Forced expiratory volume (FEV,) was obtained for all patients prior to and at 2 h following administration of test medication. A differential response in FEV, would be an indication of greater analgesia since patients with less pain could perform this test better at 2 h than at baseline. Relative analgesic efficacy was measured by several primary efficacy measures: hourly pain intensity differences (PIDs); hourly pain relief (PAR); percent of patients withdrawn from study because of inadequate pain relief or recurring pain intensity; overall investigator and patient assessments; mean summed pain intensity differences (SPID) at 3 h, 6 h and the entire 8 h; and total pain relief score (TOTPAR) at 3 h, 6 h and the entire 8 h. Adverse events Adverse events occurring during the study were recorded from information provided spontaneously by the patient or elicited by the investigator’s questions. The severity of adverse events was rated as mild, moderate or severe. Also evaluated were whether the effect was thought to be related to the test compound and whether the adverse event required premature patient withdrawal from study completion. Statistical methods Initial pain intensity was recorded for comparison between treatment groups and for subsequent analysis of analgesic efficacy. Pain intensity difference (PID) scores were calculated as the difference in pain intensity between the initial pain intensity and the subsequent halfhour or hourly values. Area under the P I D by time curve (SPID), time to first positive PID, termination time, maximum PID during the 8-h study period, hours the pain was less than baseline, and area under the pain relief score by time curve (TOTPAR) were calculated for each patient. The summary efficacy measures analysed included overall investigator and patient ratings, patient determination for inadequate pain relief or recurrence of pain, time to first positive PID, termination time, maximum PID, number of hours during which the pain intensity was less than baseline, SPID (0-3, 0-6, 0-8 h) and TOTPAR (0-3, 0-6, 0-8 h). Baseline pain intensity, sex, age, weight, height, and “time since surgery” were analysed for treatment group differences by the Kruskal-Wallis test or the chi-square test. The efficacy parameters were analysed by the rank-transformed ANOVA, adjusting for baseline pain intensity and sex. The inclusion of sex as a factor is due to its significant imbalance among treatment groups (P=0.05). For the vital signs an ANOVA was done on the raw data for the change from baseline (current minus baseline measurement). ANOVA was also done on the rank-transformed data for respiratory function variables and Paco, changes from baseline. Duncan’s multiple range tests were performed to determine individual treatment group differences. All tests for statistical significance were two-tailed and the data were tested at the 0.05 significance level. In patients withdrawn prematurely from the study, post-termination pain intensity was evaluated as the more severe score between the baseline pain intensity score and the last available pain intensity score, while pain relief scores were evaluated as “no pain relief’.
RESULTS Of the 117 enrolled patients, 1 12 patients received study medication within 24 h of surgery (ketorolac 10
718
E. M. STOUTEN E T AL.
mg N = 38, ketorolac 30 mg N = 36, morphine 10 mg N = 3 8 ) , and only five patients received study medication between 24-48 h of surgery (ketorolac 30 mg N = 3, morphine 10 mg N = 2), all of which gave no statistically significant difference. Concomitant medications (sympaticomimetics or blockers, diuretics, ranitidine, theophylline, captopril, potassium chloride and/or antibiotics) were given to 26,30 and 26 patients in the kctorolac 10 mg, ketorolac 30 mg and morphine 10 mg groups, respectively. The groups were similar with respect to baseline pain intensity, age, weight, height and time since surgery (Table 2). A statistically significant difference was found when comparing sex (88 males, 29 females; P= 0.05). All enrolled patients were included in the safety evaluations. Three patients were excluded from all efficacy evaluations: two patients had received morphine 10 mg and were excluded due to protocol violations; the third patient had received ketorolac 30 mg and was excluded due to noncompatibility of baseline pain intensity. This was the only patient who, prior to the start of the study, experienced very severe pain; all the other patients experienced moderate (82%) or severe (17%) pain. In spite of receiving study drugs and additional rescue medication, the patient had no pain relief (in terms of the evaluation scale) and was therefore excluded from the eficacy evaluations - as specified by the protocol. Similarly, three patients who received ketorolac 10 mg, four who received ketorolac 30 mg and five patients who received morphine 10 mg experienced inadequate pain relief or a recurrent pain episode after study medication. These patients received additional analgesics and were withdrawn prematurely from the study. Concurrent diseases which were present in 24 paTable 2 Baseline characteristics. Ketorolac 10mg
Ketorolac 30mg
Morphine 10mg
(test)
Female/male
4/34
12/26
12/26
(C) ( P = 0 . 0 5 )
Age iyr) s.d.
55.7 6.5
55.2 11.2
54.1 12.1
( K ) (NS)
Weight (kg) s.d.
78 I1
73
76 9
( K ) (NS)
11
Height (cm) s.d.
175 7
I72 9
I74 10
(K) (NS)
Time since surgery (h) 0-24 h 38 >24 h 0
35 3
37 I
(K) (NS) ( K ) (NS)
Baseline pain (no. of patients) Moderate 30 Severe 8
33 5
31 7
(C) (NS) (C) (NS)
(C) =Chi-square test, (K) = Kruskal-Wallis test, (NS)=not significant.
KBTOROLAC 10 mg -+- KBTOROLAC 30 mg -t MORPHINE 10 mg +
a 2 c,
E
-
0 " " " " " " " " 0 1 2 3 4 5
6
'
7
8
Time (h) Fig. I . Changes in pain intensity values (mean s.e.mean) over time (for significant difference between the groups, see Results section).
tients were (according to the protocol) considered to have no effect on the safety and efficacy assessments of the study drugs. Concomitant medication necessary for the welfare of these patients was continued, as required, throughout the study period.
Efficacy Pain intensity. All three test medications were rapid in onset of action, and pain intensity differences indicated equal effectiveness at 0.5 and 1 h following administration of test medication (Fig. 1). Statistically significant differences between treatments were observed at 2, 3, 4, and 5 h postadministration. Although ketorolac 30 mg was usually more effective than ketorolac 10 mg, the difference was not statistically significant. Both of these test medications were statistically superior to morphine at these observation times (P=O.O5). At 6, 7 and 8 h postadministration, ketorolac 30 mg and ketorolac 10 mg were still more effective than morphine 10 mg; however, the differences at these later observation periods were not statistically significant. At 8 h ketorolac 30 mg again showed a statistically significant efficacy (P
