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ANALGESIA

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, and Lincoln Bynum, MD

From the *Department of Anaesthesia, Waikato Clinical Research, Waikato Hospital, Hamilton, New Zealand; Palo Alto, California; and ICON Clinical Research, Redwood City, 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{at}wc.net.nz.

Abstract

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.

Ketorolac 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 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

View larger version (11K): [in this window] [in a new window]   Figure 1. Plasma ketorolac concentrations by time: intramuscular and intranasal (From McAleer SD, Majid O, Venables E, Polack T, Sheikh MS. J Clin Pharmacol 2007;47:13–8, reproduced by permission).

METHODS

The protocol was approved by the Northern Y Ethics Committee for Health Waikato.

Eligibility Criteria
Inclusion criteria included men or women aged 18 yr or older, body weight from 100 to 300 pounds, negative serum pregnancy test, ability to provide written informed consent, pain intensity score of 40 mm on 100-mm visual analog scale (VAS), expected postoperative hospitalization of at least 48 h, willingness to comply with all testing and requirements defined in the protocol, and willingness to complete a posttreatment visit. Exclusion criteria included allergy or sensitivity to ketorolac or EDTA, allergic reaction to aspirin or other NSAIDs, 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), use of any intranasal product within 24 h before study entry, clinically significant abnormality on screening laboratory tests, history of cocaine use, active peptic ulcer disease, recent (within 6 mo) gastrointestinal bleeding or perforation, a history of peptic ulcer disease or gastrointestinal bleeding (clinically relevant at the discretion of the investigator), advanced renal impairment or risk for renal failure due to intravascular volume depletion, history of any other clinically significant medical problem that in the opinion of the investigator would interfere with study participation, recent participation in another investigational drug study (within 1 mo), allergy or significant reaction to opioids, pregnancy or breastfeeding, and previous participation in this study.

Study Design and Treatment Plan
After a screening visit, eligible patients who had undergone major surgery participated in a 2-d treatment period and a follow-up visit. Patients with postoperative signs of discomfort received an IV opioid titrated to comfort; the choice of opioid and the doses administered were at the discretion of the surgeon or anesthesiologist, according to standard clinical practice. 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), they received a dose of intranasal ketorolac, 10 mg or 30 mg, or placebo. Thereafter, subjects received study drug every 8 h through 40 h. For pain not relieved by the study drug, subjects had access to morphine sulfate that was administered via patient-controlled analgesia (PCA) beginning at the time of the first study drug dose.

One hundred twenty-seven subjects were randomly assigned to 1 of the 3 intranasal treatment groups: ketorolac 10 mg (2 x 100 µL of a 5% solution), ketorolac 30 mg (2 x 100 µL of a 15% solution), or placebo vehicle. The study drug was administered by a metered device (Valois Pharm, Le Vaudreuil, France) that delivered 100 µL of aerosolized solution to each nostril, intended to be inserted in the nostril and aimed slightly laterally for deposition in the area of the nasal turbinates. The device is disposable with a primeless feature that enhances ease of use. The device has a premetering chamber that determines the metered dose, which is delivered with a low actuation force and requires minimal training. The placebo solution, consisting of the study drug vehicle without ketorolac, was identical in appearance to the active drug.

The PCA device was set to deliver 1 mg of morphine by each actuation with a lockout time of 6 min. At the discretion of the investigator, the lockout time and the dose could be increased or decreased according to the requirements of the individual subject.

Baseline and Treatment Assessments
Subjects were asked to provide a pain intensity rating immediately before receiving the study drug, 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 the first study drug dose. Pain intensity was measured on a 100-mm VAS with 0 = no pain and 100 = worst pain possible. 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. If necessary, subjects were awakened for scheduled evaluations.

The total daily morphine dose by PCA was measured. If requested, rescue pain medication was available for pain not sufficiently controlled by the study drug and morphine by PCA. Subjects requiring rescue medication could be given additional morphine or another opioid. Acetaminophen (paracetamol) and NSAIDs were not available as rescue medication.

At each pain evaluation, AEs were elicited in response to a nonspecific question about any changes in the subjects’ health status since the previous query. The protocol contained no instructions concerning specific questions related to nasal tolerability or opioid toxicity.

Statistical Analyses and Determination of Sample Size
All subjects receiving study drug were included in the efficacy and safety analyses. An intent-to-treat approach was taken to the efficacy analyses. No adjustments were made for multiple comparisons.

The primary efficacy variable for this study was total morphine use in milligrams by PCA from the start of dosing through 24 h. Data on morphine consumption were collected at 8-h intervals, and the treatment groups were compared with the Kruskal–Wallis test.

The same analysis was also applied to 2 secondary variables: 1) total morphine use from the start of dosing through 48 h, and 2) total morphine use from 24 h after the start of dosing through 48 h.

From the pain intensity values during the first 6 h, an hourly pain intensity difference (PID) was calculated by subtracting the hourly score from the baseline score. A summed PID (SPID) was calculated and analyzed at 4 and 6 h by adding the weighted PID scores over those intervals. Results were compared among groups with the Kruskal–Wallis test.

AEs were mapped to preferred terms and system organ classes using the Medical Dictionary for Regulatory Activities. Rates of AEs were summarized and tabulated by treatment group. Rates of AEs were compared among treatment groups using the ² test or Fisher’s exact test, as appropriate.

From the results of previous ketorolac studies performed by the authors, the determination was made that with a standard deviation of 25 mg and a significance level of 5%, 40 subjects per group would provide approximately 80% power to detect a mean reduction of 16 mg in morphine consumption in the active-treatment groups as compared to the placebo group.

RESULTS

Subject Disposition and Characteristics
Of 127 subjects enrolled, 28 subjects (22.0%) withdrew from the study prematurely, including 6 (14.3%) in the placebo group, 11 (25.6%) in the 10-mg ketorolac group, and 11 (26.2%) in the 30-mg ketorolac group (Table 2). There were no early withdrawals due to inadequate analgesia, protocol violation, or "lost to follow-up." Two categories of reasons for early termination were recorded: AE and "other." The "other" category included refusal to continue the IV line (1 subject in each group), early discharge (two 30-mg subjects), refusal of the nasal spray (3 subjects each in the 10-mg and 30-mg groups), patient request (one 10-mg subject), and prohibited medication (1 subject in each group). The proportions of subjects discontinuing the study early because of AEs were similar among the three treatment groups.

Table 2 also shows that the majority of subjects received all six study drug doses: 90.5% in the placebo group, 74.4% in the 10-mg ketorolac group, and 76.2% in the 30-mg ketorolac group.

Baseline characteristics were similar in the three treatment groups, except for a trend toward older age and larger percentage of men in the placebo group. Overall, the mean age was 53 years, 33.1% were men, 76.4% were Caucasian, 21.3% were Polynesian, mean height was 167 cm, and mean weight was 80.1 kg. Baseline pain intensity scores by VAS were similar in all treatment groups (Table 2).

All patients underwent general anesthesia. Perioperative analgesics (defined as medication given pre and intraoperatively as well as postoperatively before study entry) included morphine administered to 45.2%, 60.5%, and 66.7% of the placebo, 10-mg, and 30-mg groups, respectively. All subjects received either fentanyl, alfentanil, or remifentanil. The anesthetic technique was similar in all groups, including the use of general anesthetics, local anesthetics, and neuromuscular blocking drugs. Spinal anesthesia was administered to 54.8%, 34.9%, and 52.4% of the placebo, 10-mg, and 30-mg groups, respectively. Epidural analgesia was not used in any subject postoperatively.

Only one patient, in the 10-mg group, received rescue opioid medication in addition to PCA morphine and was administered morphine 4 mg and tramadol in a total dose of 250 mg.

The distribution of surgical categories is shown in Table 3. Most procedures were in the categories of total hip arthroplasty and abdominal hysterectomy; other procedures included open fracture reduction and fixation, total knee arthroplasty, oophorectomy, arthrodesis, uterine myomectomy, spinal fusion, osteotomy, bone graft, and shoulder arthroplasty. The distributions of individual procedures were similar in the different treatment groups.

The durations of the surgical procedures are described in Table 3. The times to reach a VAS score of 40 are displayed in Table 4.

Analgesic Response
A plot of cumulative morphine doses with time is shown in Figure 2. The mean morphine consumption during the first 24 h was 56.5 mg in the placebo group, 54.3 mg in the 10-mg ketorolac group, and 37.8 mg in the 30-mg ketorolac group (Table 5). The difference between the 30-mg ketorolac group and the placebo group was statistically significant (P = 0.0013). The difference between the 2 ketorolac groups was also significant (P = 0.0332), but the difference between the 10-mg ketorolac group and the placebo group was not.

View larger version (8K): [in this window] [in a new window]   Figure 2. Cumulative patient-controlled analgesia (PCA) morphine use by time.

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). 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.

A plot of raw VAS scores (mean and standard error of the mean) with time is shown in Figure 3. As shown in Table 5, the SPID values at 4 and 6 h were significantly higher in the ketorolac 30-mg group (120.1 and 195.5, respectively) as compared to the placebo group (75.9 and 130.6, respectively) (P = 0.0017 and 0.0015, respectively). Comparing the 2 ketorolac groups also showed significant differences in favor of ketorolac 30 mg for SPID at 4 h (P = 0.0183) and at 6 h (P = 0.0293).

View larger version (12K): [in this window] [in a new window]   Figure 3. Raw visual analog scale (VAS) scores by time.

Analyses of morphine consumption and 6-h SPID by 2-way ANOVA with treatment group, surgery type, and their interaction in the model showed no statistical significance, indicating that the efficacy differences were similar in the abdominal and orthopedic surgery types.

Safety
AEs were frequently reported in all treatment groups (97.6% in the placebo group, 100% in the 10-mg ketorolac group, and 95.2% in the 30-mg ketorolac group (Table 6)). Most AEs were either mild or moderate. Severe AEs were reported by one placebo subject (0.5%), seven 10-mg subjects (3.1%), and four 30-mg subjects (2.1%).

The most common AEs were pyrexia and nausea, both occurring in 50.4% overall. Pyrexia was less frequent in the ketorolac 30-mg group (33.3%) than in the placebo group (61.9%) or the ketorolac 10-mg group (55.8%). The difference between the ketorolac 30-mg group and the placebo group was statistically significant (P = 0.0088). Tachycardia was less frequent in the ketorolac 30-mg group (19.0%) and the ketorolac 10-mg group (16.3%) than in the placebo group (40.5%). The difference between the ketorolac 30-mg group and the placebo group was statistically significant (P = 0.0317). Tachycardia was rated mild in all cases and required no specific therapy. Pruritus tended to be less frequent in the ketorolac 30-mg group (9.5%) than in the placebo group (23.8%) and the ketorolac 10-mg group (18.6%). The difference between the ketorolac 30-mg group and the placebo group approached, but did not achieve, statistical significance (P = 0.0790). Somnolence tended to be less frequent in the ketorolac 30-mg group (2.4%) than in the placebo group (11.9%) and the ketorolac 10-mg group (20.9%); the difference between the ketorolac 30-mg group and the placebo group approached, but did not achieve, statistical significance (P = 0.0901). Hypotension tended to be less frequent in the ketorolac 30-mg group (7.1%) than in the placebo group (14.3%). The difference was not statistically significant (P = 0.1636).

AEs typically associated with NSAID use (i.e., abdominal pain, dyspepsia, hematemesis, fluid retention, and oliguria) were all reported by three or fewer subjects in any group.

Nasal events that mapped to the term "nasal passage irritation" were reported by five placebo subjects (11.9%), six 10-mg subjects (14.0%), and seven 30-mg subjects (16.7%). Events that mapped to "epistaxis" were reported by one placebo subject (2.4%), one 10-mg subject (2.3%), and three 30-mg subjects (7.1%). All these events were rated mild or moderate in intensity.

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. Reduction in pain severity, as reflected in SPID scores at 4 and 6 h, was significantly greater in the 30-mg ketorolac group than in both other treatment groups. Thus, even though the subjects in the 30-mg ketorolac group used less morphine, they experienced superior pain relief.

The safety analyses showed that the 30-mg ketorolac group had a side effect profile similar to that observed in the placebo group. The AEs observed were typical of the postoperative period. 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. This effect has been demonstrated in controlled clinical trials with ketorolac.8,9 The trends toward lower rates of pruritus, somnolence, and hypotension, and a significantly lower rate of tachycardia in the ketorolac 30-mg group, probably reflect the lower morphine consumption in that group. Previous studies have shown significantly decreased opioid side effects, including somnolence, in ketorolac recipients.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, such as anesthetic medications and intraperitoneal manipulation.

Nasal irritation was reported by more subjects in the 30-mg group (16.7%) and the 10-mg group (14.0%) than in the placebo group (11.9%). The reporting of this symptom by placebo recipients reflects the common occurrence of mucosal irritation with any nasal product. For intranasal ketorolac, 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.

Ketorolac administered as an intranasal aerosol appears to provide analgesic efficacy similar to other methods of parenteral administration, including IM13–17 and IV9,18–20 formulations. The current results confirm the combination of superior analgesic efficacy plus opioid sparing that has been described previously.11,12,16,21

The results of this study indicate that intranasal administration of ketorolac is an effective way of rapidly providing a potent analgesic to patients. With increasing numbers of patients leaving the hospital soon after major surgery, a strong analgesic medication that does not require injection or oral opioid administration could help ensure quality analgesia in both inpatient and ambulatory settings. These features might be particularly advantageous in emergency departments to provide effective and convenient analgesia while avoiding the side effects of opioids and their abuse and addiction potential.

The concept of "multimodal" or "balanced" analgesia using a NSAID in combination with an opioid to provide enhanced analgesia, fewer side effects, and shortened postoperative recovery time, is widely accepted.22–24 The demonstration of the efficacy of 30 mg of intranasal ketorolac in this study provides an alternative approach to the implementation of this concept in the postoperative setting.

In conclusion, this study demonstrated that intranasal ketorolac is well tolerated by patients with postoperative pain after major surgery, has good analgesic efficacy, and reduces the need for postoperative opioids.

ACKNOWLEDGMENTS

We thank the enthusiastic support of the administration and nursing staff of the Waikato Hospital throughout the course of this study.

Footnotes

Accepted for publication July 29, 2008.

Supported by Roxro Pharma LLC, Menlo Park, California.

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				ERRATUM Anesth. Analg., March 1, 2009; 108(3): 991 - 991. [Full Text] [PDF]

This Article Abstract Full Text (PDF) An erratum has been published Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Moodie, J. E. Articles by Bynum, L. Search for Related Content PubMed PubMed Citation Articles by Moodie, J. E. Articles by Bynum, L. Related Collections Drug Delivery Pain Medicine Clinical Pharmacology Pain Pharmacology