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PAIN MEDICINE

Propacetamol Versus Ketorolac for Treatment of Acute Postoperative Pain After Total Hip or Knee Replacement

Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas, Texas

Address correspondence and reprint requests to Paul F. White, PhD, MD, FANZCA, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., F2.208, Dallas, TX 75390-9068. Address e-mail to paul.white{at}utsouthwestern.edu

Abstract

We assessed the analgesic efficacy of IV propacetamol and ketorolac in a double-blinded, placebo-controlled study involving patients undergoing total hip or knee replacement procedures. On the first morning after major joint replacement surgery, 164 patients experiencing moderate-to-severe pain were randomly assigned to receive an IV infusion of propacetamol (2 g), ketorolac (15 or 30 mg), or placebo (saline). Patient-controlled analgesia with morphine was made available as a "rescue" analgesic on patient’s request during the 6-h postdosing evaluation period. The median time to onset of analgesia with propacetamol (8 [95% confidence interval 6,10] min) was shorter than ketorolac 15 mg (14 [7,16] min), and placebo (16 [8; not estimable] min) although the differences did not reach statistical significance. However, compared with ketorolac 30 mg, propacetamol had a shorter duration of analgesia (3.5 [2;5.4] vs 6 [3.3; not estimable] h). Analysis of pain intensity and pain relief scores demonstrated that propacetamol produced a significantly greater improvement in pain relief than saline from 45 min until 5 h after the injection. Propacetamol was not significantly different from ketorolac 15 mg and 30 mg with respect to the main analgesic efficacy variables during the 6-h assessment period. The most frequently reported adverse event with propacetamol was injection site pain (28% vs 19% for ketorolac 15 mg, 29% for ketorolac 30 mg, and 10% for placebo, respectively). In conclusion, propacetamol (2 g IV) possesses a similar analgesic efficacy to ketorolac (15 or 30 mg IV) after total hip or knee replacement surgery.

Implications: Propacetamol (2 g IV), an acetaminophen prodrug, was similar to ketorolac (15 mg and 30 mg IV) with respect to analgesic properties during a 6-h assessment period. However, the onset of analgesic action of propacetamol seems to be faster than ketorolac (15 mg IV) and its duration of action shorter than ketorolac (30 mg IV).

Opioid analgesics have been the primary form of therapy for patients experiencing moderate-to-severe postoperative pain. However, these drugs do not always provide adequate patient comfort and their use is associated with dose-related side effects (1,2). After major orthopedic and gynecologic surgery, the adjunctive use of nonsteroidal antiinflammatory drugs (NSAIDs) reduces postoperative opioid requirements and/or improves the quality of analgesia (3–5). Of interest, the parental NSAID, ketorolac, is as effective as morphine or meperidine for pain relief after some surgical procedures (6,7). However, because the use of ketorolac may be associated with increased operative site bleeding, gastrointestinal injury, and renal toxicity (8,9), there has been increasing interest in the use of other classes of nonopioid analgesics (e.g., acetaminophen).

Propacetamol, an injectable prodrug of acetaminophen, possesses similar analgesic efficacy to ketorolac when combined with patient-controlled analgesia (PCA) morphine (10). Because this earlier study (10) failed to include a placebo (control) group, the onset and duration of analgesia of these two nonopioid analgesics were not studied. Therefore, the aim of this placebo-controlled, double-blinded study was to compare the onset and duration of analgesia, as well as the analgesic efficacy, of IV propacetamol (2 g) and ketorolac (15 or 30 mg) in patients experiencing moderate-to-severe pain after total hip or knee replacement surgery.

Methods

One hundred seventy-two consenting patients undergoing total hip or knee replacement were initially entered into this IRB-approved study. Entry criteria included body weight of at least 50 kg, age >18 yr, ability to understand the use of pain scales, a stopwatch and a PCA device, and a baseline pain intensity of moderate-to-severe on a categorical rating scale. Exclusion criteria included known allergy, sensitivity, or contraindications to any opioid or nonopioid analgesic including aspirin or NSAIDs; ASA physical status > III at the time of surgery; a history of active peptic ulcer within the preceding 12 mo; a history of bleeding problems or anticoagulant use within the last month; patients who were pregnant or breast-feeding; a history of known or suspected drug abuse; patients who had taken NSAIDs within 12 h before administration of the study drugs. Patients in the study received either general anesthesia or spinal or epidural block as judged appropriate by the attending anesthesiologist.

In the postanesthesia care unit, when patients first requested analgesics, a PCA pump (Abbott Lifecare^®-PCA plus II; Abbott, Chicago, IL) containing morphine (1 mg/mL) was connected to the IV infusion. The PCA device was programmed to deliver 1-mL boluses of morphine on demand, with a lock-out interval of 6 min and a total dose not to exceed 20 mg of morphine during any 4-h period. If adequate pain relief could not be achieved with IV PCA device alone, supplemental "rescue" boluses of morphine, 2 mg IV, were given as needed.

On the morning of the first postoperative day, after completion of the routine nursing activities, the total amount of morphine delivered to the patient was recorded, and the PCA device was temporarily discontinued. When the level of pain reached moderate-to-severe intensity on the 4-point categorical scale (none, mild, moderate, severe), patients were randomized to one of the four treatment groups according to a computer-generated schedule. The four groups consisted of propacetamol 2 g, ketorolac 15 mg, ketorolac 30 mg, or saline. One solution containing either propacetamol or saline was infused for 15 min, and a second solution containing either ketorolac or saline was injected for 2 min. All study medication solutions were prepared by a hospital pharmacist who was not involved in the data collection. To preserve the double-blinded design, a double-dummy technique was used so that each patient received a 15-min IV infusion and a 2-min IV injection simultaneously. Patients were queried as to whether they experienced pain on injection of the study medication. Patients who experienced insufficient pain relief after the administration of the study medications could request PCA morphine as rescue medication at any time.

Time to onset of analgesia was estimated by using the double-click stopwatch method, which was defined as the time to a perceptible change in the severity of the patient’s pain. Pain assessments were made immediately before the administration of the study medications (T₀) and every 15 min for 1 h, and then at hourly intervals for 6 h postdosing (namely, at T1, T2, T3, T4, T5, and T6). Pain intensity was subjectively measured by using both a 4-point verbal rating scale (VRS), with 0 = none, 1 = mild, 2 = moderate and 3 = severe, and a 100-mm visual analog scale (VAS), with 0 = no pain and 100 = worst possible pain. Pain relief (relative to the baseline pain intensity) was rated by the patient on a 5-point categorical scale where 0 = none, 1 = a little, 2 = moderate, 3 = a lot, and 4 = complete. In addition, pain intensity with activity was assessed at T2 by asking the patient to raise the operated leg 1 to 5 cm above the bed. The global pain evaluation was performed at T6 by using a 4-point categorical scale (with 0 = poor, 1 = fair, 2 = good, 3 = excellent). Systolic and diastolic blood pressure and heart and respiratory rate were monitored immediately before the administration of the study medications and at T2 and T6. Sedation and nausea VAS scores were measured at T2, T4, and T6. The number of patients receiving rescue analgesic medication from the PCA device during the 6-h study period was also recorded.

From the primary analgesic efficacy data, the following variables were derived or computed to assess analgesic efficacy of study drugs: (1) the pain intensity differences (defined as PID for VRS and PAID for VAS) was the difference between the baseline pain intensity and the pain intensity at each evaluation time point, and (2) the pain relief intensity differences (PRID) was defined as the sum of the PID and the pain relief (PR).

A sample size of 162 patients was calculated based on a comparison of the Propacetamol, Ketorolac, and Saline groups by using a parallel design with = 0.05, ß = 0.1, and = 1.3 for pain relief scores. The Ketorolac group was further divided into two subgroups receiving either a 15-mg or 30-mg dose of ketorolac. Pain relief scores at rest (the primary criteria) and with activity, PID, PAID, PRID at each scheduled evaluation time, as well as the number of requested and actual administered bolus doses of rescue analgesic medication, were analyzed by using the repeated measures of analysis of variance for overall difference among treatments and Fisher’s protected least significant difference for multiple comparison. Time to onset of analgesia and time to remedication were analyzed by using the Stratified Gehan-Wilcoxon test. The number of patients requiring rescue medication, number and percentage of patients who experienced onset of analgesia, first perceptible and meaningful pain relief in the 6-h evaluation period, and the patient’s global evaluation were analyzed by using the Mantel-Haenszel test. Finally, adverse events were analyzed by using ² test or Fisher’s exact test as appropriate. P values < 0.05 were considered statistically significant in treatment comparisons.

Results

Although 172 patients were initially randomized into the study groups, 164 patients received the study medication and were included in the intent-to-treat analysis. The reasons that 8 patients did not receive the study medication included: 2 patients in the Propacetamol group withdrew their consent, 1 patient in the Propacetamol group was withdrawn because of a technical error, 1 patient each in the Ketorolac 15-mg and 30-mg groups withdrew their consent, and 3 patients in the Placebo group were excluded because of withdrawal of consent, intake of acetaminophen before study drug administration, and a high baseline plasma creatinine level.

The treatment groups did not differ significantly with respect to any of the demographic, anesthetic or surgical characteristics (Table 1). Pain intensity mea-sured at rest immediately before the study drug administration was moderate (71%) or severe (29%) on the VRS and was 61.2 ± 17.1 mm on the VAS. With activity, baseline pain intensity was moderate (26%) or severe (74%) on the VRS and 80.7 ± 16.1 mm on the VAS. There were no significant differences among the four treatment groups with regard to PCA morphine consumption and pain intensity measured immediately before the study drug administration (Table 1).

With respect to pain relief scores at rest, propacetamol was statistically superior to placebo, but was not different from ketorolac 15 mg and 30 mg from T0.75 h until T5 h (Fig. 1). Similarly, propacetamol was superior to placebo with regard to PID (Fig. 2), PAID, and PRID (Fig. 3) at rest, but was not significantly different from ketorolac 15 mg and 30 mg through the 4-h assessment point. With activity, the three active treatment groups were significantly superior to the Placebo group with respect to PR and PRID scores. However, no significant differences were observed among the three active treatment groups for these variables (Table 3). With respect to the patients’ global evaluation, propacetamol and ketorolac 30 mg were superior to the Saline group. However, no significant difference was observed among the three active treatment groups (Table 4).

View larger version (15K): [in this window] [in a new window]   Figure 1. Pain Relief (PR) scores at rest (mean ± SEM). A score of 0 = none, 1 = a little, 2 = moderate, 3 = a lot, and 4 = complete pain relief. Propacetamol was statistically superior to saline and did not differ from ketorolac 15 and 30 mg from T0.75 h until T5 h after the administration of the study medication. *P < 0.05, **P < 0.001 propacetamol versus placebo.

View larger version (17K): [in this window] [in a new window]   Figure 2. Pain Intensity Difference (PID) was the difference between the resting baseline pain intensity and the pain intensity at each evaluation time point by using a 4-point verbal rating scale (mean ± SEM). Propacetamol was statistically superior to placebo from T1 h through the 4-h time point assessment and was not different from ketorolac 15 and 30 mg through the 4-h time point assessment. *P < 0.05 propacetamol versus placebo.

View larger version (16K): [in this window] [in a new window]   Figure 3. Pain Relief and Intensity Difference (PRID) was the sum of the pain relief and the pain intensity difference scores at rest (mean ± SEM). Propacetamol was statistically superior to placebo from T0.75 h through the 5-h assessment interval and was not different from ketorolac 15 and 30 mg through the 5-h time point assessment. *P < 0.05, ** P < 0.01 propacetamol versus placebo.

With respect to sedation, nausea, and vomiting, no significant differences were detected among the treatment groups at the 2-h, 4-h, and 6-h postdosing intervals (data not presented). Finally, the changes in blood pressure, heart rate, and respiratory rate did not differ from the baseline values at 2 and 6 h (data not presented).

Discussion

Propacetamol is rapidly metabolized to acetaminophen and diethylglycine in a 1:1 ratio by nonspecific plasma esterases. Therefore, a 2-g dose of propacetamol yields 1 g of acetaminophen and 1 g of diethyl-glycine. Compared with saline, propacetamol (2 g) resulted in a larger proportion of patients experiencing superior pain relief scores both at rest and with physical activity. Although propacetamol 2 g had a shorter duration of analgesia than ketorolac 30 mg, the analgesic response was not different from either ketorolac 15 mg and 30 mg with respect to the main analgesic variables in the six-hour assessment period. These data are consistent with the findings of McQuay et al. (11), where acetaminophen 1 g orally was found to be similar to ketorolac 10–20 mg orally for postoperative orthopedic pain.

The concept of "balanced analgesia" suggests that a combination of analgesic drugs may enhance analgesia and thereby reduce side effects after surgery. Propacetamol (2 g) and ketorolac (30 mg) possess a similar morphine-sparing effect when combined with IV PCA after gynecologic surgery (10). After spinal disk surgery, the combination of propacetamol and ketoprofen was associated with lower VAS scores than propacetamol or ketoprofen alone (12). Furthermore, the use of ketorolac as an adjuvant to PCA morphine resulted in a morphine-sparing effect ranging from 16% to 33% during the postoperative period (13–15). The addition of oral acetaminophen (1 g every four hours) to IV PCA with morphine also improved the quality of pain relief and patient satisfaction after orthopedic surgery (16).

Propacetamol is also useful as a monotherapy in the management of postoperative pain (17,18). However, in this major joint replacement study, neither propacetamol (2 g) nor ketorolac (15 or 30 mg) produced a significant reduction in postoperative morphine consumption. This may relate to the fact that only one dose was administered during the six-hour observation period. In other studies, there is evidence that, later in the postoperative period as the intensity of pain begins to subside, NSAIDs alone can provide adequate analgesia. In a comparison of IM ketorolac 30 mg and morphine 10 mg for pain relief after cholecystectomy, ketorolac alone provided poor pain relief in the early postoperative period compared with morphine (19). However, the analgesic effectiveness of the two drugs was similar on the first postoperative day.

Early evaluations of NASIDs for postoperative pain relief involved comparison with opioids by using an "either/or" study design. With a greater understanding of postoperative pain, there has been a growing emphasis on the advantages of balanced analgesia (20,21). Concurrent use of systemic opioids with centrally mediated actions and NSAIDs with peripheral sites of action may provide advantages over either class of drug alone. It is unlikely that NSAIDs will completely replace opioids in patients suffering moderate-to-severe postoperative pain. In this study, the majority of patients received the PCA-morphine rescue medication during the six-hour assessment period. The number of patients receiving rescue medication and the amount of morphine consumption were not different among the four treatment groups. These findings confirm that, in the treatment of patients experiencing moderate-to-severe acute postoperative pain, propacetamol and ketorolac should be considered adjuncts to opioid analgesic therapy.

The incidences of TEAEs that were considered to be crelated to the study drug were more frequent in the Propacetamol and Ketorolac 30-mg groups compared with the Saline group as a result of pain at the IV injection site. There were no significant differences between treatment groups with respect to sedation and emesis in the six-hour postdosing observation period. The occurrence of postoperative wound hematoma formation was more frequent in the Ketorolac 30-mg group (9% versus 0% in the Propacetamol group), although this difference did not achieve statistical significance. This finding is in agreement with previous reports demonstrating that hemostasis was more difficult to achieve in patients receiving ketorolac (22). In addition, the bleeding time is longer in patients treated with ketorolac (10).

In conclusion, propacetamol was more effective than saline and not different from ketorolac (15 and 30 mg) with respect to the main analgesic variables when administered on the first day after a total hip or knee replacement surgery. Injection pain was the most frequently reported adverse event with propacetamol. These data suggest that propacetamol (2 g IV) may be a useful alternative to ketorolac (15–30 mg IV) as a complementary drug to opioids in the treatment of moderate-to-severe postoperative pain.

Acknowledgments

This study was supported in part by a grant from UPSA Inc., France, and in part by the White Mountain Institute (a non–for-profit public charity) in Los Altos, CA.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999