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Pain Management After Elective Hallux Valgus Surgery

A Prospective Randomized Double-Blind Study Comparing Etoricoxib and Tramadol

Brattwall, Metha, MD*; Turan, Ibrahim, MD, PhD; Jakobsson, Jan, MD, PhD

doi: 10.1213/ANE.0b013e3181e3d87c
Analgesia: Research Reports
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BACKGROUND: Pain is a common complaint after day surgery, and there is still a controversy surrounding the use of selective cyclooxygenase-2 (COX-2) inhibitors. In the present prospective, randomized, double-blind study we compared pain management with a selective (COX-2) inhibitor (etoricoxib) with pain management using sustained-release tramadol after elective hallux valgus surgery.

METHODS: One hundred ASA 1 to 2 female patients were randomized into 2 groups of 50 patients each; oral etoricoxib 120 mg × 1 × IV + 90 mg × 1 × day V–VII and oral tramadol sustained-release 100 mg × 2 × VII. Pain, pain relief, satisfaction with pain management, and need for rescue medication were evaluated during the first 7 postoperative days. A computed tomography scan evaluating bone healing was performed 12 weeks after surgery. A clinical evaluation of outcome (healing, mobility, and patient-assessed satisfaction) was performed 16 weeks after surgery.

RESULTS: Two patients withdrew before discharge from the hospital. Ninety-eight patients, 81 ASA 1 and 17 ASA 2 (82 nonsmokers and 14 smokers), mean age 49 years (19–65), weight 64 (47–83) kg, and height 167 (154–183) cm were evaluated. Overall pain was well managed, but the mean visual analog scale (VAS) was significantly lower among etoricoxib patients evaluated during the entire 7-day period studied (12.5 ± 8.3 vs. 17.3 ± 11, P < 0.05). patient's grading of pain relief (92 ± 12 vs. 85 ± 15, P < 0.05) and satisfaction with pain medication (47/49 vs. 39/49, P < 0.05) was higher among etoricoxib patients. Patients receiving tramadol reported significantly more side effects. Six patients, all in the tramadol group, discontinued the study because of side effects (P < 0.05). At 14-day follow-up 1 patient in the etoricoxib group and 5 patients in the tramadol group exhibited minor irritation in the wound area. The 12-week computed tomography scan showed good healing in 82 patients, 43 in the etoricoxib group, and 39 in the tramadol group. The study found ongoing healing in 11 patients, 4 in the etoricoxib group and 7 in the tramadol group. The 16-week patient-assessed Health Profile Quality of life revealed high patient satisfaction overall; 47 patients in each study group rated the outcome as satisfactory and the mean change in the patient-assessed quality of life VAS score was 6.2 and 2.6 for the etoricoxib and tramadol groups, respectively. Clinical follow-up at 16 weeks showed high functionality and no signs or symptoms of improper healing in any patient.

CONCLUSION: Etoricoxib was found to be more effective and associated with fewer side effects in comparison with tramadol sustained release as a component of multimodel analgesia after elective hallux valgus surgery. There were no signs of impaired wound or bone healing associated with the use of etoricoxib.

Published ahead of print June 28, 2010

From the *Department of Anaesthesia, Sahlgrenska Academy, University Hospital Möndal, Gothenburg, Sweden; Foot & Ankle Surgical Centre, Stockholm, Sweden; Department of Anaesthesia & Intensive Care, Karolinska Institutet, Institution for Physiology & Pharmacology, Stockholm, Sweden.

The institution received a grant from Merck Sharp & Dome.

Jan Jakobsson is currently affiliated with Foot & Ankle Surgical Centre, Stockholm, Sweden.

Conflict of Interest: The study had financial support by a grant from Merck Sharp & Dome

Address correspondence and reprint requests to Jan Jakobsson, Professor, Foot & Ankle Surgical Centre, Storängsvägen 10, 11542 Stockholm, Sweden. Address e-mail to Jan.jakobsson@ki.se.

Accepted March 30, 2010

Published ahead of print June 28, 2010

Pain and nausea are common complaints after day case orthopedic surgery. Simple and effective pain medication after discharge is of importance to maintain quality of care.1,2 The goal in optimizing postoperative pain management is to reduce pain, improve the quality of recovery, and facilitate resumption of the normal activities of daily living.3 Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be effective analgesics in the early postoperative phase.47 The selective cyclooxygenase-2 (COX-2) inhibitors may provide perioperative analgesia without the impaired hemostasis associated with nonselective NSAIDs. For example, Desjardins et al. found rofecoxib 50 mg significantly more effective than was diclofenac sodium 100 mg for total pain relief, onset time, and duration of response after bunionectomy.8

The potential negative effects from long-term NSAID use on the healing process have always been controversial.9 Studies involving postoperative administration of COX-2 selective inhibitors for 10 to 14 days after cardiac surgery demonstrated an increased risk of postoperative wound infection and cardiovascular complications.10,11 This has led physicians to question the wisdom of using COX-2 selective inhibitors after orthopedic surgery,12 which was compounded by the withdrawal of several COX-2 selective inhibitors,13 and the retractions of Scott Reuben's studies on NSAIDs.a

A recent meta-analysis from the Cochrane library supports the utility of a single dose of etoricoxib 120 mg for postoperative pain in low-risk patients. One study suggests that a 120-mg etoricoxib dose is as effective as, or better than, other commonly used analgesics.14 The effects of etoricoxib for pain management for a longer period of time (e.g., up to 1 week after surgery) has not been extensively studied. We have observed in noncontrolled studies the analgesic efficacy of etoricoxib after ligament repair and bunion surgery.15,16

The aim of the present prospective, randomized, double-blind study was to compare the analgesic efficacy of etoricoxib to that of tramadol sustained release as a component of multimodal analgesia during the first 7 days after elective hallux valgus surgery.

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METHODS

The study protocol was approved by the local ethical committee (2008/828 to 319) and EudraCT registered (EudraCT 2008 to 000,791–24) before inclusion of any patients. After receiving written informed consent, 100 female ASA 1 to 2 patients were randomized into 2 groups by computer randomization:

  • (a) etoricoxib 120 mg oral once daily for 4 days followed by 90 mg oral once daily for 3 days;
  • (b) tramadol sustained release 100 mg twice daily for 7 days.

The first dose was provided immediately after the end of surgery when patients were adequately awake in the recovery area. The study medication was prepared by a hospital pharmacist in identical-appearing capsules according to a computer-generated random number schedule. The patients, nurses, surgeons, and anesthesiologists directly involved in patient care were blinded to the content of the oral study medication capsules.

Patients were provided oral and written pain medication information, and instructed on how to complete pain questionnaires (visual analog scale [VAS] 0 to 10, with 10 defined as the worst possible pain), medication pain relief questionnaire (VAS scale 0 to 100, with 100 defined as perfect pain relief), satisfaction with pain medication (binary, satisfied/unsatisfied), and presence of any side effects (asked as an open question). No adverse symptoms were explicitly asked for, and no scale was used for grading of side effects.

All patients followed the same perioperative protocol. Patients fasted after midnight on the night before surgery. Upon arrival in the operating room, IV access was established, and 8 mg IV betamethasone was given. Anesthesia was induced with 3 to 3.5 μg/kg alfentanil and 2.5 mg/kg propofol. Ten milliliters 1% lidocaine was injected in the wound area before washing and dressing. Anesthesia was maintained with sevoflurane in an oxygen–air mixture. Sevoflurane was titrated to maintain heart rate and arterial blood pressure within 15% of baseline. Patients breathed spontaneously through a facemask. Administration of sevoflurane was stopped when skin suturing began. Surgery was performed with a standardized technique including an osteotomy of the first metatarsal bone, excision of the exostosis, and a split fixation of the osteotomy to allow full weight bearing immediately after surgery.17 All procedures were performed by a senior orthopedic surgeon (Ibrahim Turan) with >25 years of experience in forefoot surgery.

All patients were fast-tracked to the step-down unit, where they were provided the initial dose of study medication in combination with 30 mg paracetamol per kilogram orally.

Before discharge a dedicated research nurse instructed all patients on how to take study and rescue medications, if needed, and how to complete the daily diary during the first 7 days after surgery. Study medication and rescue analgesics were provided at discharge. All patients were provided oral paracetamol 1 g as first-line rescue and oral oxycodone 5 mg as second-line rescue analgesia and instructed how to take rescue analgesia in an escalating manner, when needed.

A dedicated research nurse phoned each patient 1 to 2 days after discharge to reinforce adherence to the study protocol. All patients were seen by a research nurse 12 to 16 days after surgery to assess wound healing and remove stitches.

A computed tomography (CT) scan with multiplanar reformatted images along the axis of the first metatarsal was conducted at 12 weeks to assess bone healing. The CT scans were evaluated by 2 physicians blinded to the randomization and otherwise not involved in the study. The images were assessed on a 3-grade scale: well-established healing, ongoing bone healing, and limited bone healing.

The Euro Quality 5 Dimension (EQ-5D) questionnaire was used for a patient-assessed health profile quality of lifeb at baseline before surgery and at 16 weeks in conjunction with an outpatient clinical assessment of healing and functionality by the patient and a physician otherwise not involved in the study. The EQ-5D questionnaire is a generic tool commonly used for assessing health profile quality of life. It addresses the self-assessed experience of pain, mobility, activity, self-care, and mood/depression with a pregraded scale (impaired or yes/some impairment or some symptoms/no symptoms = adequate function). It also consists of a quality of life VAS scale, 100 = excellent quality of life and 0 = death. Functionality was assessed by a defined protocol with pregraded scales: satisfied, neutral, or dissatisfied.

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Statistics

All data are presented as mean and SD unless stated otherwise. Data were analyzed using analysis of variance (ANOVA) and χ2 analysis as appropriate. Continuous variables were evaluated using ANOVA. When multiple comparisons of continuous data (e.g., pain scores) were performed between the treatment groups, a Bonferroni correction was applied. Categorical variables were evaluated using χ2 contingency table analysis. For all statistical analyses, P values <0.05 were considered to be statistically significant after correction for multiple comparisons.

The number of patients studied was estimated from a power analysis based on earlier findings of the experience of pain and need for rescue analgesics after hallux valgus surgery. A group size of 48 was chosen to have a 90% power to detect a difference with a P < 0.05 for the number of patients requiring rescue opioid analgesic. To compensate for an estimated dropout of 2 patients in each group, 100 patients were randomized.

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RESULTS

One hundred two female patients were screened, and 100 were enrolled in the study. All randomized patients were in good health. No patient had therapy-dependent chronic pain. Two patients withdrew on the day of surgery. A CONSORT flow chart is provided in Figure 1. Ninety-eight patients received study medication. Table 1 summarizes the demographics and preoperative quality-of-life scores for patients receiving study medication.

Figure 1

Figure 1

Table 1

Table 1

Surgery and anesthesia were uneventful. All patients were discharged within 2 hours after the end of surgery (Table 2).

Table 2

Table 2

No major complications were reported during the 2-week follow-up period (Table 3). Six patients discontinued study medication because of side effects: nausea, dizziness, and sleepiness. During the examination on day 14, we found minor surgical site irritation and incomplete wound closure in 6 patients: 5 active controls (tramadol) and 1 in the etoricoxib group.

Table 3

Table 3

Thirty-three patients, 20 in the etoricoxib group and 13 in the tramadol group, did not take any rescue medication during the 7-day follow-up period. Twenty-five patients took at least 1 dose of oxycodone as a rescue analgesic. There was no significant difference between the groups (Table 3) in the use of oxycodone.

Forty patients reported side effects. Side effects (predominantly nausea, dizziness, and sleepiness) were reported more frequently by the tramadol group (Table 3). One patient in the tramadol group had minor bleeding from the nose. No cardiovascular side effects or symptoms were reported. Satisfaction with pain management was rated significantly higher among the etoricoxib patients (P < 0.05) (Table 3).

VAS pain scores were generally low. The maximum daily pain VAS grading showed a distinct pattern with a peak on days 2 and 3 after surgery and a reduction thereafter. The mean maximum VAS was significantly lower among etoricoxib patients evaluated during the entire 7-day period studied (12.5 ± 8.3 vs. 17.3 ± 11 P < 0.05). A significant difference in daily maximum pain VAS scores was seen on days 3, 4, and 7 (P < 0.05) (Fig. 2). Pain relief from study medication was rated as high for patients in both groups, but was significantly higher for the etoricoxib group (P < 0.05) on days 2, 3, and 5 (Fig. 2).

Figure 2

Figure 2

Ninety-three patients had a CT scan, showing a generally reassuring healing process. Eighty-two patients had well-established healing, 43 in the etoricoxib group and 39 in the tramadol group. Eleven patients were graded as ongoing bone healing, 4 in the etoricoxib group and 7 in the tramadol group. None of the CT scans showed limited bone healing. There was no association between smoking, age, or body weight and grading of the CT image for bone repair. The 11 patients graded as showing ongoing bone healing reported more pain in their health profile questionnaire at 16 weeks than did those with well-established healing: 3/11 vs. 14/82 among the 93 patients assessed by CT scan.

At the 16-week follow-up visit there was satisfactory healing and functionality in all patients (Table 4A, B). No signs of impaired bone or wound healing were observed. All patients scored healing, mobility, and satisfaction with surgery as high (Table 4A). The blinded physician assessment at the 16-week follow-up visit did not reveal any between-groups differences (Table 4B). The patient-assessed quality-of-life health profile, EQ-5D, showed modest improvement and no differences between groups (Table 5). The patients' self-assessed quality-of-life VAS increased by 6.2 in the etoricoxib group and 2.6 in the tramadol group, respectively. Satisfaction with surgical outcome was high, with 47 patients in each group assessing the outcome as satisfactory (Table 5).

Table 4

Table 4

Table 5

Table 5

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DISCUSSION

NSAIDs are frequently used in day case surgery as part of multimodal pain management to provide adequate pain relief and to reduce the risk of opioid-related side effects.18 Hallux valgus surgery has been suggested as a useful model for testing multiple-day analgesic therapy. It has also been used for studying the effects of opioid analgesics as well as NSAIDS.8,19,20 We found a structured 7-day pain analgesic protocol to be associated with acceptable pain levels and high patient satisfaction after elective hallux valgus surgery. The etoricoxib group had lower maximum pain scores during the entire 7-day period and significantly better analgesic effects on the most painful days (days 2 and 3 after surgery). Etoricoxib was also associated with fewer side effects and thus overall higher patient satisfaction with pain medication. In our view, the most important observation is that we found no differences in the healing process. Both the clinical assessment and the CT scan at 12 weeks demonstrated equivalent healing of the wound and the bone in both groups.

We could not verify our primary outcome variable, a difference in need for rescue medication. However, pain VAS scores were lower and satisfaction with pain medication was higher in the etoricoxib group. Toivonen et al. compared the effects of a single 120- mg dose of etoricoxib given 1 hour before placebo control in patients undergoing arthroscopic acromioplasty performed under regional anesthesia. They found beneficial effects on pain and a reduced need for rescue analgesia during the entire 7-day study period from a single dose.21 Sun et al. studied the effects of celecoxib 200 mg twice daily for 3 days after plastic surgery, and found less need for opioid analgesics than for placebo during the 3-day study.22 We did not include a placebo, but an active control, tramadol slow release twice daily. Tramadol is a well-known centrally acting analgesic with an analgesic potency of about 10% of morphine but with less effect on ventilation.23,24 Tramadol has been shown to be effective for the treatment of orthopedic postoperative pain.25 We chose tramadol sustained release in a fixed dose of 100 mg twice daily as a comparison. While this may have been a low dose, resulting in less analgesia when compared with the etoricoxib dose, it was associated with a higher incidence of side effects. We could increase the analgesic effect by giving the subjects a larger dose of tramadol, but would have seen increased complications.

We did not see any clinical or radiological signs of impaired healing, but our findings should be put into perspective. Evaluation of the bone-healing process is not easy. Modeling of the CT image may improve the accuracy of evaluation,26 which is why we used multiplanar reformatted CT images to improve evaluation of nonunion of fractures. However, our study cannot absolutely exclude an increase of clinical pseudoarthrosis from impaired wound healing.

There is a growing body of evidence suggesting that the effects of NSAIDs on bone repair are of limited clinical importance. In a recent animal study no impairment in wound healing was observed from the administration of ketorolac.27 The effect of nonselective NSAIDs on bone healing was also analyzed in a retrospective study in children who had major spine surgery. No signs of impaired bone healing were seen in this retrospective analysis.28 A 2-year follow-up study of patients who received celecoxib postoperatively for 14 days after total knee replacement found no signs of increased risk of loosening of the prosthesis, and concluded that celecoxib may be used safely in conjunction with total knee replacement.29 Because we studied ASA 1 to 2 patients only, and the dose of etoricoxib was reduced for the last 3 days, our findings might not apply to patients given larger doses, patients given doses for a longer period of time, or patients who have other risk factors for poor healing such as smoking, corticosteroids use, diabetes, or delayed healing or nonunion of a fracture.12

We used the EQ-5D to assess patients' evaluation of and satisfaction with outcome, an accepted tool for evaluation of outcomes in health care.20 There were no differences between the groups at 16 weeks.

Our findings are limited to healthy, ASA 1 to 2 patients. The cardiovascular and thrombotic risks associated with NSAIDs will be higher in a less healthy population.30,31 We studied only female patients, who are more prone to postoperative pain, nausea, and vomiting.32,33 We studied a peripheral orthopedic procedure, not a major procedure such as a joint replacement or spine surgery. Additionally, all patients were provided a multimodal analgesia, including the use of local anesthesia infiltration before incision, IV betamethasone, oral paracetamol upon arrival in the step-down unit, and perioperative opioids. Lastly, we used an active control rather than a placebo control. This was done for both ethical reasons, and because tramadol is well established as an effective analgesic.

We conclude that etoricoxib 120 mg oral once daily for 4 days followed by 90 mg oral once daily for 3 days provides better analgesia than does tramadol sustained-release 100 mg twice daily for 7 days. We also conclude that in ASA 1 to 2 patients this regimen of postoperative etoricoxib is not associated with deleterious effects on the healing process.

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ACKNOWLEDGMENTS

We would like to thank Aleris Diagnostics and Dr. Tengvar for support with CT imaging and evaluation of CT scans.

a See http://www.aaeditor.org/HWP/Retraction.Notice.pdf.
Cited Here...

b See http://www.euroqol.org/.
Cited Here...

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