The Safety and Analgesic Efficacy of Intranasal Ketorolac in Patients with Postoperative Pain

John E. Moodie, MB, ChB, FRCA, FANZCA* Colin R. Brown, BSc, MBBS, FANZCA* Eileen J. Bisley, BN, G Dip BusS* Hans U. Weber, PhD† Lincoln Bynum, MD‡
BACKGROUND: We evaluated the safety and efficacy of multiple doses of intranasal ketorolac tromethamine (ketorolac) for postoperative pain. METHODS: This was a double-blind, placebo-controlled study in patients undergoing major surgery who were randomized to receive intranasal ketorolac, 10 mg or 30 mg, or placebo every 8 h for 40 h. After surgery, patients with pain intensity of at least 40 on a 100-mm visual analog scale were assessed at 30 min and at 1, 2, 3, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 h after receiving the study drug. Patient-controlled IV morphine provided supplemental analgesia. RESULTS: Among 127 patients enrolled, morphine use during the first 24 h was significantly less in patients receiving 30 mg of ketorolac (37.8 mg) than in the placebo group (56.5 mg) and in the 10-mg ketorolac group (54.3 mg). Over 48 h, the 30-mg ketorolac group used significantly less morphine than the placebo group. Summed pain intensity differences at 4 and 6 h significantly favored the 30-mg ketorolac group over the other groups. The rates of pyrexia and tachycardia were significantly lower in the ketorolac 30-mg group than in the placebo group. Other adverse events were reported with similar frequency in all treatment groups and most were considered unrelated to treatment. CONCLUSION: Thirty milligrams of intranasal ketorolac demonstrated significant analgesic efficacy compared to 10 mg of intranasal ketorolac and placebo.
(Anesth Analg 2008;107:2025–31)

K

etorolac tromethamine (ketorolac) is a racemic, nonsteroidal, antiinflammatory drug (NSAID) with potent analgesic and moderate antiinflammatory activity. It is structurally a member of the pyrrolo-pyrrole group. Ketorolac is available as a water-soluble salt, ketorolac tromethamine (originally marketed as Toradol®, Roche Laboratories). The parenteral formulation is used IM or IV for the treatment of moderate to severe pain. The postoperative analgesic efficacy of ketorolac has been extensively evaluated. Ketorolac has been reported to provide relief from moderate to severe pain in a majority of patients and has similar analgesic efficacy to morphine and meperidine.1 The nasal route of administration is an alternative to parenteral injections. It offers rapid absorption across the nasal mucous membrane and relative ease of administration. Various formulations of ketorolac have undergone preclinical testing to determine their feasibility for use with nasal administration.2– 4 A ketorolac nasal spray
From the *Department of Anaesthesia, Waikato Clinical Research, Waikato Hospital, Hamilton, New Zealand; †Palo Alto, California; and ‡ICON Clinical Research, Redwood City, California. Accepted for publication July 29, 2008. Supported by Roxro Pharma LLC, Menlo Park, California. Address correspondence and reprint requests to: Dr. John E. Moodie, Waikato Clinical Research, Department of Anaesthesia, Health Waikato, Hamilton, New Zealand. Address e-mail to research@wc.net.nz. Copyright © 2008 International Anesthesia Research Society
DOI: 10.1213/ane.0b013e318188b736

formulation could provide an advantageous route for treatment of moderate to severe pain for the postoperative patient who is unable to take oral pain medications or needs more potent analgesia than is provided by oral products, while avoiding the inconvenience of an IV line and the discomfort of IM injections. Preclinical and clinical studies to evaluate local irritation using intranasal ketorolac solutions have indicated the feasibility of this route of administration. Pharmacokinetic evaluation of intranasal ketorolac in a phase 1 trial indicated that the compound was rapidly absorbed with a half-life of 5 to 6 h and a bioavailability of approximately 70% compared to IM administration.5 The data are displayed in Table 1 and Figure 1. The time to maximum plasma concentration for the intranasal formulation (0.75 h) was the same as the IM formulation, but shorter than that reported for oral administration (0.90 h).6 From these results, an intranasal dose of 30 mg was considered appropriate for further development, since the plasma levels from this dose lay between those achieved by IM administration of 15 and 30 mg, which have demonstrated good efficacy. In an effort to show a dose response, a comparator dose of 10 mg was chosen. Ten milligrams is the lowest recommended dose intended for oral administration.7

METHODS
The protocol was approved by the Northern Y Ethics Committee for Health Waikato.
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Vol. 107, No. 6, December 2008

which is delivered with a low actuation force and requires minimal training. allergy or significant reaction to opioids. J Clin Pharmacol 2007. subjects had access to morphine sulfate that was administered via patientcontrolled analgesia (PCA) beginning at the time of the first study drug dose. allergic reaction to aspirin or other NSAIDs.00 (1.75 (0. active peptic ulcer disease.76 (1. they received a dose of intranasal ketorolac.25–1. France) that delivered 100 L of aerosolized solution to each nostril.38) 30 mg 2382 (433) 0.50–2. Patients with 2026 Intranasal Ketorolac Relieves Postoperative Pain postoperative signs of discomfort received an IV opioid titrated to comfort. clinically significant abnormality on screening laboratory tests. according to standard clinical practice. ketorolac 30 mg (2 100 L of a 15% solution).75 (0. advanced renal impairment or risk for renal failure due to intravascular volume depletion. subjects received study drug every 8 h through 40 h. pain intensity score of 40 mm on 100-mm visual analog scale (VAS). body weight from 100 to 300 pounds. recent participation in another investigational drug study (within 1 mo).00) 7141 (3466) 5.25–1. reproduced by permission). 10 mg or 30 mg. history of any other clinically significant medical problem that in the opinion of the investigator would interfere with study participation.47:13– 8.50 (0. consisting of the study drug vehicle without ketorolac. the lockout time ANESTHESIA & ANALGESIA .72) 15 mg 916 (2930 0. Plasma ketorolac concentrations by time: intramuscular and intranasal (From McAleer SD.11) 1806 (883) 0.75 (0. willingness to comply with all testing and requirements defined in the protocol. Exclusion criteria included allergy or sensitivity to ketorolac or EDTA. and willingness to complete a posttreatment visit. or placebo vehicle. or placebo. When patients were alert enough to complete the pain assessments and had a pain intensity rating of at least 40 on a 100-mm VAS (with no upper limit). expected postoperative hospitalization of at least 48 h. The study drug was administered by a metered device (Valois Pharm. eligible patients who had undergone major surgery participated in a 2-d treatment period and a follow-up visit. The placebo solution. history of cocaine use. ability to provide written informed consent. and previous participation in this study. The PCA device was set to deliver 1 mg of morphine by each actuation with a lockout time of 6 min. Study Design and Treatment Plan After a screening visit. For pain not relieved by the study drug. Figure 1.00) 3723 (1483) 4. pregnancy or breastfeeding. negative serum pregnancy test.Table 1. Thereafter.25–1.03) 10770 (3886) 4. intended to be inserted in the nostril and aimed slightly laterally for deposition in the area of the nasal turbinates. At the discretion of the investigator. the choice of opioid and the doses administered were at the discretion of the surgeon or anesthesiologist. Mean (SD) Ketorolac Pharmacokinetic Parameters Intranasal Route dose Cmax (ng/mL) Tmax (h)a AUC (ng h/mL) T1/2 (h) a Intramuscular 30 mg 15 mg 1163 (280) 0.80 (1. Polack T. Le Vaudreuil. current upper respiratory tract infection or other respiratory tract condition that could interfere with absorption of nasal spray or with assessment of adverse events (AEs). Eligibility Criteria Inclusion criteria included men or women aged 18 yr or older. Venables E. recent (within 6 mo) gastrointestinal bleeding or perforation.33) Median (range). The device has a premetering chamber that determines the metered dose. use of any intranasal product within 24 h before study entry. a history of peptic ulcer disease or gastrointestinal bleeding (clinically relevant at the discretion of the investigator). The device is disposable with a primeless feature that enhances ease of use. Sheikh MS. Majid O. One hundred twenty-seven subjects were randomly assigned to 1 of the 3 intranasal treatment groups: ketorolac 10 mg (2 100 L of a 5% solution).24 (1.50) 4956 (1921) 5. was identical in appearance to the active drug.

21. 40. 10-mg. and 30-mg groups. AEs were elicited in response to a nonspecific question about any changes in the subjects’ health status since the previous query. 12. 36. Baseline and Treatment Assessments Subjects were asked to provide a pain intensity rating immediately before receiving the study drug. An intent-to-treat approach was taken to the efficacy analyses. 107. 74. uterine myomectomy.4% in the 10-mg ketorolac group. 3. and 11 (26. The anesthetic technique was similar in all groups.8%.2% in the 30-mg ketorolac group. The same analysis was also applied to 2 secondary variables: 1) total morphine use from the start of dosing through 48 h. subjects were awakened for scheduled evaluations. 5. Acetaminophen (paracetamol) and NSAIDs were not available as rescue medication. other procedures included open fracture reduction and fixation. 32. Perioperative analgesics (defined as medication given pre and intraoperatively as well as postoperatively before study entry) included morphine administered to 45.2%. oophorectomy. in the 10-mg group. spinal fusion. Baseline pain intensity scores by VAS were similar in all treatment groups (Table 2). Pain intensity was measured on a 100-mm VAS with 0 no pain and 100 worst pain possible. 8.and the dose could be increased or decreased according to the requirements of the individual subject. 11 (25. No adjustments were made for multiple comparisons. early discharge (two 30-mg subjects). refusal of the nasal spray (3 subjects each in the 10-mg and 30-mg groups). The total daily morphine dose by PCA was measured.5% in the placebo group. 4. and 48 h after the first study drug dose. At each pain evaluation. and 76. rescue pain medication was available for pain not sufficiently controlled by the study drug and morphine by PCA. December 2008 2027 . the mean age was 53 years. Epidural analgesia was not used in any subject postoperatively. The distribution of surgical categories is shown in Table 3.4% were Caucasian.” The “other” category included refusal to continue the IV line (1 subject in each group).0%) withdrew from the study prematurely.6%) in the 10-mg ketorolac group.2%) in the 30-mg ketorolac group (Table 2). The proportions of subjects discontinuing the study early because of AEs were similar among the three treatment groups. 28. or “lost to follow-up. If requested. at 30 min.” Two categories of reasons for early termination were recorded: AE and “other. 10-mg. The distributions of © 2008 International Anesthesia Research Society Statistical Analyses and Determination of Sample Size All subjects receiving study drug were included in the efficacy and safety analyses. and at 1. Overall. Data on morphine consumption were collected at 8-h intervals. 6. If necessary. Results were compared among groups with the Kruskal–Wallis test. and 2) total morphine use from 24 h after the start of dosing through 48 h. 44. an hourly pain intensity difference (PID) was calculated by subtracting the hourly score from the baseline score.4% of the placebo. arthrodesis.1% were men. local anesthetics. Only one patient. 34. 76. respectively. and prohibited medication (1 subject in each group). osteotomy.3% were Polynesian.7% of the placebo. Patients were instructed to make a mark on the 100-mm line that corresponded to the intensity of pain at rest that they were experiencing at that time. Baseline characteristics were similar in the three treatment groups. 40 subjects per group would provide approximately 80% power to detect a mean reduction of Vol. and 66. There were no early withdrawals due to inadequate analgesia. patient request (one 10-mg subject). and 30-mg groups. mean height was 167 cm. protocol violation. bone graft. Rates of AEs were summarized and tabulated by treatment group. or remifentanil. All subjects received either fentanyl. From the pain intensity values during the first 6 h. All patients underwent general anesthesia. The primary efficacy variable for this study was total morphine use in milligrams by PCA from the start of dosing through 24 h. as appropriate. RESULTS Subject Disposition and Characteristics Of 127 subjects enrolled. and 52.3%) in the placebo group. including the use of general anesthetics. alfentanil. AEs were mapped to preferred terms and system organ classes using the Medical Dictionary for Regulatory Activities. the determination was made that with a standard deviation of 25 mg and a significance level of 5%. 16. and mean weight was 80. 28 subjects (22. and shoulder arthroplasty. 24. and the treatment groups were compared with the Kruskal–Wallis test.1 kg. and neuromuscular blocking drugs. From the results of previous ketorolac studies performed by the authors. The protocol contained no instructions concerning specific questions related to nasal tolerability or opioid toxicity. received rescue opioid medication in addition to PCA morphine and was administered morphine 4 mg and tramadol in a total dose of 250 mg.9%.5%. 60. 6. Subjects requiring rescue medication could be given additional morphine or another opioid. Table 2 also shows that the majority of subjects received all six study drug doses: 90. A summed PID (SPID) was calculated and analyzed at 4 and 6 h by adding the weighted PID scores over those intervals. 16 mg in morphine consumption in the active-treatment groups as compared to the placebo group. including 6 (14. respectively. 33. except for a trend toward older age and larger percentage of men in the placebo group. total knee arthroplasty. Rates of AEs were compared among treatment groups using the 2 test or Fisher’s exact test. 2. Spinal anesthesia was administered to 54. 20. Most procedures were in the categories of total hip arthroplasty and abdominal hysterectomy. No.

6) 77 49–115 51.7 (2. VAS visual analog scale.3%) 4 (9.7%) 31 (72.0332).2%) 11 (26.4) 54 (19–80) 42 (33.4) 78 50–117 52.0 Total 50 77 127 Placebo 191.5%) 6 (14.9 and 130.0183) and at 6 h (P 0.8%) 56.6%) 97 (76.1) 47 (22–78) 11 (25.4 (2.8 (2.7 (2. Table 3.0%) 52.0%) 1 (2.1%) 0 10 (23. The times to reach a VAS score of 40 are displayed in Table 4.5.6%) 53.0015.0 440. The differences between the 10-mg ketorolac and the placebo group and between the 2 ketorolac groups were not statistically significant for these time intervals. The difference between the 2 ketorolac groups was also significant (P 0.0 18 24 42 95. Times From End of Surgery to Reach VAS of 40 Time (min) Mean Median Standard error Minimum Maximum Ketorolac Ketorolac 10 mg 30 mg 22 21 43 91.5) 53 (24–80) 13 (31.7%) 167 (1.5%) 2 (4.3 mg in the 10-mg ketorolac group. The durations of the surgical procedures are described in Table 3. 0.6%) 6 (14.5) 50 40–86 Total 127 102 (80.4%) 16 (12.2%) 3 (7. ANESTHESIA & ANALGESIA . Overall treatment effect by 1-way ANOVA P VAS visual analog scale.0 17.0%) 29 (69. 54.4 (1.6) 49 40–90 42 38 (90. respectively) as compared to the placebo group (75.0293).9%) 24 (57.32.8) 83 50–124 52.6.0 (1. A plot of raw VAS scores (mean and standard error of the mean) with time is shown in Figure 3.8%) 167 (1. and 37.8) 166 135–197 80.3%) 167 (0. PI Ketorolac 10 mg 43 32 (74. respectively) (P 0.8 30.14 50.0%) 49.1%) 0 32 (76.6) 167 135–183 79.5) 165 152–197 81.0 Ketorolac 30 mg 169.3) 166 150–188 79.2%) 0 10 (23.6%) 32 (74.0 415.1 and 195. but the difference between the 10-mg ketorolac group and the placebo group was not.0017 and 0.4%) 7 (16.5 117.0013).8 mg in the 30-mg ketorolac group (Table 5).0 20. The mean morphine consumption during the first 24 h was 56.0%) 12 (9.3 135.4%) 1 (0. the SPID values at 4 and 6 h were significantly higher in the ketorolac 30-mg group (120.0 0. Analgesic Response A plot of cumulative morphine doses with time is shown in Figure 2.5) 61 (19–78) 18 (42.7) 48 40–90 pain intensity.9 (1.5) 80 49–124 51.3%) 28 (22.9%) 2 (1.0–180.5) 51 42–81 Ketorolac 30 mg 42 32 (76. Comparing the 2 ketorolac groups also showed significant differences in favor of ketorolac 30 mg for SPID at 4 h (P 0. As shown in Table 5.8 175.0%) 0 34 (81.3%) 167 (1.5 mg in the placebo group.4%) 2 (4. Subject Disposition and Baseline Characteristics Placebo Number of patients Enrolled Received all 6 doses Early withdrawal Due to AE* For “other” reasons Age Mean (SEM) Median (range) Sex Male Female Ethnicity Asian Caucasian Hispanic Polynesian Height (cm) Mean (SEM) Median Range Weight (kg) Mean (SEM) Median Range Baseline PI by VAS Mean (SEM) Median Range AE adverse event.1%) 85 (66.2 (2.1 (1.4%) 11 (25.0–205.0 Range 45.7 (2.8%) 27 (21. The difference between the 30-mg ketorolac group and the placebo group was statistically significant (P 0.1 40.0 Table 4.1%) 8 (19.Table 2.0 Ketorolac 10 mg 154. Surgery Categories and Durations by Treatment Group Placebo Categories Abdominal 10 Orthopedic 32 Total 42 Durations Mean 95.3 (1.13. respectively).00 45. all pairwise comparisons P individual procedures were similar in the different treatment groups.07 35.6%) 5 (11. 2028 Intranasal Ketorolac Relieves Postoperative Pain The mean morphine consumption during the intervals of 24 to 48 h and 0 to 48 h was significantly less in the 30-mg ketorolac group than in the placebo group (Table 5).0 (1.5 15.0 435.0–195.

The difference between the ketorolac 30-mg group and the placebo group was statistically significant (P 0.8 (5.0182 0.5%).2) n 38 89. Analgesic Responses by Treatment Group—Mean (SEM) Placebo Morphine use (mg) 0–24 h Morphine use (mg) 24–48 h Morphine use (mg) 0–48 h 4-h SPID 6-h SPID 56.5) n 43 Ketorolac 30 mg 37. indicating that the efficacy differences were similar in the abdominal and orthopedic surgery types.0%) and the ketorolac © 2008 International Anesthesia Research Society 2029 .6% in the placebo group.4) n 42 Ketorolac 10 mg 54.3 (5. Tachycardia was less frequent in the ketorolac 30-mg group (19. both occurring in 50.1) n 42 P* 0. seven 10-mg subjects (3.0088).3%) than in the placebo group (61. surgery type.0013 0. Table 5.2% in the 30-mg ketorolac group (Table 6)). Pyrexia was less frequent in the ketorolac 30-mg group (33.6 (14.9 (10.0015 * Kruskal–Wallis test for difference between ketorolac 30 mg and placebo. Raw visual analog scale (VAS) scores by time.4) n 39 75.5 (12.9%) or the ketorolac 10-mg group (55.1) n 42 130. 100% in the 10-mg ketorolac group.6 (4. The most common AEs were pyrexia and nausea. Cumulative patient-controlled analgesia (PCA) morphine use by time.8) n 41 32.6 (10. December 2008 moderate.11 (5.Figure 2.3) n 42 195.3) n 35 61.3 (6. and four 30-mg subjects (2. Safety AEs were frequently reported in all treatment groups (97. SPID summed pain intensity difference.7 (11.0060 0.8) n 39 87.7) n 38 78.5 (4. Most AEs were either mild or Vol. and their interaction in the model showed no statistical significance.9 (9.4) n 41 28. Severe AEs were reported by one placebo subject (0.1 (9.0017 0.1%). 6.4 (10.5) n 43 154.1%). Figure 3.0) n 41 23.8 (15. and 95.8) n 35 120.4% overall. 107.8%). No. Analyses of morphine consumption and 6-h SPID by 2-way ANOVA with treatment group.

0790).7%) and the 10-mg group (14. Ketorolac administered as an intranasal aerosol appears to provide analgesic efficacy similar to other methods of parenteral administration. The fact that the high-dose ketorolac group had a lower rate of pyrexia is probably due to the antipyretic effect associated with all NSAIDs.3%) 19 (45. as reflected in SPID scores at 4 and 6 h.3%) 18 (14.4%) 64 (50. All these events were rated mild or moderate in intensity.6%) 26 (61.9%) 20 (47.7%) 1 (2.2%) 12 (28.5%) 6 (14.5%) 10 (23. The AEs observed were typical of the postoperative period.9%) 4 (9.1636).8%) and the ketorolac 10-mg group (18.9%) 6 (14. somnolence. and seven 30-mg subjects (16.2%) 11 (26. Previous studies have shown significantly decreased opioid side effects.11. statistical significance (P 0.6%) 14 (33. even 2030 Intranasal Ketorolac Relieves Postoperative Pain though the subjects in the 30-mg ketorolac group used less morphine.2%) 9 (21.3%) than in the placebo group (40. Reduction in pain severity.6%) 33 (26. The difference was not statistically significant (P 0. and hypotension. Ketorolac 10 mg 43 43 (100.9%) 12 (27.6%) 8 (18.9%) 15 (34.3%). the rate of nasal irritation must be part of the benefit–risk ratio in the context of the physical distress and inconvenience of alternative routes of administration such as IM and IV injection.Table 6. Nasal events that mapped to the term “nasal passage irritation” were reported by five placebo subjects (11. fluid retention. Events that mapped to “epistaxis” were reported by one placebo subject (2. but did not achieve.10 –13 The fact that nausea and vomiting were not significantly reduced in the ketorolac group is probably explained by the presence of multiple factors other than opioids that may cause these symptoms.9%) and the ketorolac 10-mg group (20.e. Hypotension tended to be less frequent in the ketorolac 30-mg group (7.3%) 8 (18. AEs typically associated with NSAID use (i.4%).5%) than in the placebo group (23.4%) 8 (19. including somnolence.0901). was significantly greater in the 30-mg ketorolac group than in both other treatment groups. statistical significance (P 0. hematemesis.9%).9%) 7 (16.0%) 9 (20. The difference between the ketorolac 30-mg group and the placebo group approached.16.3%) 7 (16. six 10-mg subjects (14.6%) 64 (50. and three 30-mg subjects (7.. This effect has been demonstrated in controlled clinical trials with ketorolac.9%) 5 (11. For intranasal ketorolac.5%).1%).18 –20 formulations. Pruritus tended to be less frequent in the ketorolac 30-mg group (9. they experienced superior pain relief. but did not achieve.0%) than in the placebo group (11. probably reflect the lower morphine consumption in that group.0%) 24 (55.8%) 22 (17.4%) 37 (29.1%) 12 (27.9%).7%).9 The trends toward lower rates of pruritus. Most Common Adverse Events by MedDRA System Organ Class and Preferred Term Placebo Number of patients Number of patients reporting adverse events Pyrexia Nausea Anemia Vomiting Headache Tachycardia Constipation Pruritus Dizziness Nasal passage irritation Somnolence Hypotension MedDRA Medical Dictionary for Regulatory Activities.4%) 3 (7.6%). such as anesthetic medications and intraperitoneal manipulation.8%) 25 (58.6%) 9 (21.3%) 11 (26.0317).3%) Ketorolac 30 mg 42 40 (95. one 10-mg subject (2.3%) 10-mg group (16.9%).1%) 35 (27. and a significantly lower rate of tachycardia in the ketorolac 30-mg group.2%) 29 (22. the difference between the ketorolac 30-mg group and the placebo group approached.4%) than in the placebo group (11. The safety analyses showed that the 30-mg ketorolac group had a side effect profile similar to that observed in the placebo group.1%) than in the placebo group (14. Thus.0%) 11 (26. in ketorolac recipients.1%) Total 127 124 (97. Nasal irritation was reported by more subjects in the 30-mg group (16.8%) 13 (10.3%).6%) 7 (16.2%) 14 (33.2%) 42 41 (97.21 The results of this study indicate that intranasal administration of ketorolac is an effective way of ANESTHESIA & ANALGESIA .0%). dyspepsia.12. DISCUSSION The analgesic efficacy of intranasal ketorolac in 30 mg doses was evident in the significantly reduced morphine consumption compared with the 10-mg ketorolac group and the placebo group. The current results confirm the combination of superior analgesic efficacy plus opioid sparing that has been described previously.2%) 4 (9.2%) 15 (11. abdominal pain. The reporting of this symptom by placebo recipients reflects the common occurrence of mucosal irritation with any nasal product.9%) 5 (11.8. Tachycardia was rated mild in all cases and required no specific therapy.2%) 18 (14. including IM13–17 and IV9.8%) 5 (11. The difference between the ketorolac 30-mg group and the placebo group was statistically significant (P 0.4%) 17 (40.8%) 10 (23. Somnolence tended to be less frequent in the ketorolac 30-mg group (2.3%) 6 (14. and oliguria) were all reported by three or fewer subjects in any group.0%) 32 (25.

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