The Effect of Cyclooxygenase-2 Inhibition on Analgesia and Spinal Fusion

Reuben, Scott S. MD; Ekman, Evan F. MD

Journal of Bone & Joint Surgery - American Volume: March 2005 - Volume 87 - Issue 3 - p 536–542
doi: 10.2106/JBJS.D.02283
Scientific Articles
Supplementary Content

Background: Cyclooxygenase (COX)-2-specific inhibitors demonstrate analgesic efficacy comparable with that of conventional nonsteroidal anti-inflammatory drugs but are associated with reduced gastrointestinal side effects and an absence of antiplatelet activity. Thus, they can be administered to patients undergoing spinal fusion surgery without an added risk of bleeding. However, concerns regarding a possible deleterious effect on bone-healing have limited their routine use. Celecoxib, a COX-2 inhibitor, recently was approved for the treatment of acute pain. The goals of the present study were to examine the analgesic efficacy of celecoxib and to determine the incidence of nonunion at one year following spinal fusion surgery.

Methods: Eighty patients who were scheduled to undergo spinal fusion received either celecoxib or placebo one hour before the induction of anesthesia and every twelve hours after surgery for the first five postoperative days. Pain scores and morphine use were recorded one hour after arrival in the post-anesthesia care unit and at four, eight, twelve, sixteen, twenty, and twenty-four hours later. Intraoperative blood loss was recorded. The status of the fusion was determined radiographically at the time of the one-year follow-up.

Results: There were no differences in demographic data or blood loss between the two groups. Pain scores were lower in the celecoxib group at one, four, eight, sixteen, and twenty hours postoperatively. There were no differences between the two groups with regard to the pain scores at twelve and twenty-four hours postoperatively. Morphine use was lower in the celecoxib group at all postoperative time-intervals. There was no difference between the celecoxib group and the placebo group with regard to the incidence of nonunion at the time of the one-year follow-up (7.5% [three of forty] compared with 10% [four of forty]).

Conclusions: The perioperative administration of celecoxib resulted in a significant reduction in postoperative pain and opioid use following spinal fusion surgery. In addition, the short-term administration of this COX-2-specific non-steroidal anti-inflammatory drug had no apparent effect on the rate of nonunion at the time of the one-year follow-up.

Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.

1 Baystate Medical Center and Tufts University School of Medicine, 759 Chestnut Street, Springfield, MA 01199. E-mail address: scott.reuben@bhs.org

2 Southern Orthopaedic Sports Medicine and Parkridge Surgery Center, 1718 St. Julian Place, Columbia, SC 29204

Article Outline

Nonsteroidal anti-inflammatory drugs act to produce analgesia and antinociception after surgical trauma by inhibiting cyclooxygenase both in the peripheral tissues and in the central nervous system1,2. Nonsteroidal anti-inflammatory drugs have demonstrated efficacy when administered as the sole analgesic following minor surgical procedures2 and may have an important role as adjuvants to other analgesics after major surgery3. It is currently recommended that nonsteroidal anti-inflammatory drugs be used in a multimodal analgesic approach for the treatment of perioperative pain4. Proposed and documented benefits of multimodal therapy include improved pain relief, reduction of the perioperative stress response, reduced opioid-related side effects, shorter hospital stays, decreased hospital costs, improved patient satisfaction, and a reduction in postoperative morbidity and mortality5,6. Furthermore, it is currently believed that there is a continuum of pain after surgery ranging from acute to chronic and that effective treatment of acute pain may prevent the development of chronic pain syndromes7,8.

Cyclooxygenase (COX)-2 inhibitors are the newest class of nonsteroidal anti-inflammatory drugs with analgesic efficacy comparable with that of conventional nonsteroidal anti-inflammatory drugs, but they are associated with reduced gastrointestinal side effects and an absence of antiplatelet activity9,10. Therefore, these COX-2-specific nonsteroidal anti-inflammatory drugs can be administered preemptively to patients undergoing surgery without the added risk of increased perioperative bleeding that has been reported in association with conventional nonsteroidal anti-inflammatory drugs11-13. However, because of a possible deleterious effect on bone-healing, the routine use of COX-2 inhibitors for patients undergoing spinal fusion surgery has remained controversial. Many investigators have recommended that nonsteroidal anti-inflammatory drugs should not be utilized in the multimodal treatment of acute pain in patients undergoing spinal fusion surgery14-17.

Although the data are conflicting, a large body of literature derived from laboratory animal studies suggests that COX-2 inhibitors either delay or inhibit bone-healing14-16. However, in those studies, nonsteroidal anti-inflammatory drugs were administered over several weeks to months at doses greater than that approved for the treatment of acute pain. We are not aware of any clinical investigation in which the blood levels of therapeutic nonsteroidal anti-inflammatory drugs have been measured. Therefore, these findings cannot be extrapolated to the short-term perioperative use of such drugs in humans. There also have been important methodological flaws in human spinal fusion studies17. Numerous uncontrolled patient and surgical factors, marginal power, and retrospective study design all detract from the credibility of these negative findings. We are not aware of any published prospective studies that have examined the effect of nonsteroidal anti-inflammatory drugs on bone-healing in humans.

We previously examined the analgesic effect of celecoxib and rofecoxib following spinal fusion surgery in humans18. That study revealed that the administration of either 50 mg of rofecoxib or 200 mg of celecoxib one hour before surgery significantly reduced opioid use in the twenty-four hours after surgery. Since the publication of that study, celecoxib has been approved by the United States Food and Drug Administration for the treatment of acute pain. The recommended celecoxib dose for the treatment of acute pain is 400 mg followed by an additional 200 mg within the first twenty-four hours. Although previous studies have examined the efficacy of 200 or 400 mg of celecoxib for the treatment of postoperative pain9,18-23, we are not aware of any study that has examined the efficacy of this drug when administered under the current Food and Drug Administration guidelines.

The goals of the present prospective, randomized, double-blind study were to examine the analgesic effects of celecoxib when administered according to the current acute-pain guidelines and to determine the incidence of nonunion at one year after spinal fusion surgery.

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Materials and Methods

After institutional review board approval, informed written consent was obtained from eighty patients who were scheduled to undergo elective decompressive lumbar laminectomy with instrumented posterior spinal fusion as performed by a single surgeon. Spinal fusion was performed at either one or two levels from the fourth lumbar vertebra to the sacrum with use of similar carbon fiber cages with pedicle screw and plate instrumentation. Patients were eligible for participation if they were at least eighteen years old, weighed >40 kg, and could operate a patient-controlled analgesia device. Exclusion criteria included any known allergy, sensitivity, or contraindication to sulfa, morphine, or any nonsteroidal anti-inflammatory drug; renal insufficiency; a history of peptic ulcer; a history of bleeding diathesis; a current history of smoking; and pregnancy. Before surgery, all patients were evaluated with standing anteroposterior, lateral, and oblique radiographs of the lumbosacral spine.

Anesthesia was induced with propofol (2 mg/kg) and fentanyl (5 mg/kg) and was maintained with isoflurane in a mixture of 70% nitrous oxide and 30% oxygen. Patients were connected to a patient-controlled analgesia pump (PCA Plus; Abbott, Chicago, Illinois) on arrival in the post-anesthesia care unit. The patient-controlled analgesia solution contained morphine (1 mg/mL). The initial settings were an incremental dose of 2.0 mL, a lockout interval of eight minutes, and a four-hour limit of 40 mL. The incremental dose was increased to 2.5 mL and the four-hour limit was increased to 50 mL if analgesia was inadequate after one hour. If analgesia remained inadequate after an additional hour, the incremental dose was further increased to 3.0 mL.

All patients received patient-controlled morphine. Forty patients were assigned to one of two treatment groups in a double-blinded, randomized manner. The celecoxib group received two 200-mg celecoxib capsules (total dose, 400 mg) one hour before the induction of anesthesia and one 200-mg celecoxib capsule every twelve hours after surgery for the first five postoperative days. The placebo group received two placebo capsules one hour before the induction of anesthesia and one capsule every twelve hours after surgery for the first five postoperative days. In both groups, the capsules were taken orally with a sip of water. The placebo capsules were identical matches to the active drug capsules.

Patients were asked, by a blinded observer, to quantify their pain on a verbal rating scale between 0 and 10 (with 0 representing no pain and 10 representing the worst pain imaginable). Pain assessments and morphine use were recorded one hour after arrival in the post-anesthesia care unit and at four, eight, twelve, sixteen, twenty, and twenty-four hours later. Intraoperative blood loss was determined by combining the blood collected in the suction canister as well as by estimating the blood present in the surgical sponges. Bed rest was enforced for the first twenty-four hours postoperatively. Progressive walking was then begun in conjunction with physical therapy. Twenty-four hours after the completion of surgery, the patient-controlled analgesia pump was discontinued and one to two tablets of acetaminophen (325 mg) with oxycodone (7.5 mg) were administered every four hours as needed for pain relief. No nonsteroidal anti-inflammatory drugs were prescribed during the one-year period after surgery.

The status of the fusion was determined on the basis of anteroposterior, oblique, and flexion-extension radiographs and either tomography or computerized tomographic scanning (when necessary) at the time of the one-year follow-up. For a fusion to be termed solid, strict criteria were utilized as described in previous studies24-26. Anteroposterior radiographs had to show bridging bone bilaterally between transverse processes with trabeculation that was confluent across the fusion mass, oblique radiographs had to demonstrate the presence of fusion bone in a confluent pattern between transverse processes, and flexion-extension radiographs had to show <2° of motion. The criteria that were used to diagnose nonunion included evidence of radiolucency around the hardware, collapse of graft height with a gap between the vertebral end plate and the bone graft, a shift in the position of the graft, and loss of fixation due to hardware loosening or dislodgement. In addition, ≥4 mm of horizontal motion as seen on dynamic anteroposterior and lateral radiographs and ≥10° of angular motion as seen on lateral radiographs made with the patient bending indicated a nonunion. The fusion status was determined solely on the basis of radiographic findings by a radiologist who served as an independent blinded observer.

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Statistical Analysis

Demographic data (age, height, and weight), the duration of the procedure, and blood loss were analyzed with analysis of variance. The incidence of nonunion was evaluated by means of contingency analysis and the chi-square test. Pain scores and morphine doses were analyzed at each postoperative time-interval with an independent t test. If a significant result was obtained, Wilcoxon testing was performed to determine between which groups there was significance; a Bonferroni adjustment was made for multiple comparisons. To integrate the cumulative morphine usage and the cumulative pain scores over the seven time-intervals, an “area under the curve” was computed with use of the trapezoidal rule. This method is commonly used to find an approximate value for a definite integral or to integrate into a single measurement two relevant dimensions that are measured longitudinally (for example, the amount of pain or morphine use and the duration of pain or morphine use). The power analysis that was performed before the investigation involved two assumptions: (1) a 50% difference in pain scores and (2) a 30% difference in morphine use during the first twenty-four hours. With these assumptions, for a power of 90% and an alpha of 0.05, the pain-score comparison required the largest number of patients (twenty-two). For the frequency-of-nonunion comparison, a required sample size of thirty-six patients in each group was determined by means of a power analysis that involved three assumptions: (1) that 10% of the patients would experience nonunion if no nonsteroidal anti-inflammatory drugs were administered27, (2) that a 20% increase in the nonunion rate (i.e., a 30% nonunion rate28) would be considered to be of clinical importance if celecoxib had been administered; and (3) an alpha of 0.05 and a beta of 0.10. The level of significance was set at p < 0.05. Statistical calculations were performed with use of SAS/STAT User's Guide (version 8.2; SAS Institute, Cary, North Carolina).

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Results

All eighty patients completed the study and were evaluated with regard to radiographic evidence of nonunion one year after surgery. There were no significant differences between the two groups with respect to age, gender, height, weight, the duration of surgery, the number of vertebral levels fused, or intraoperative blood loss (Table I). No other postoperative complications such as wound hematoma or dehiscence, gastroduodenal perforation, ulcers, or episodes of bleeding were observed during the study period. Pain scores were significantly lower in the celecoxib group than in the placebo group as determined in the post-anesthesia care unit and at four, eight, sixteen, and twenty hours postoperatively (Table II). There were no differences between the two groups with regard to pain scores at twelve and twenty-four hours postoperatively.

The mean morphine dose was significantly increased in the placebo group compared with the celecoxib group at all seven postoperative intervals (p < 0.0001 for the first six intervals and p < 0.003 at twenty-four hours) (Fig. 1).

The cumulative morphine dose over the twenty-four-hour period was significantly lower in the celecoxib group than in the placebo group (93 ± 13 mg compared with 135 ± 17 mg; p < 0.0001).

There was no significant difference between the celecoxib group and the placebo group with regard to the incidence of nonunion at one year (7.5% [three of forty] compared with 10% [four of forty]).

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Discussion

The present study revealed that the perioperative administration of celecoxib resulted in a significant reduction in postoperative opioid use and pain following spinal fusion surgery. Celecoxib had no significant effect on the incidence of perioperative bleeding. In addition, the short-term administration of this COX-2-specific nonsteroidal anti-inflammatory drug had no effect on the nonunion rate at the time of the one-year follow-up.

Celecoxib (Celebrex; Pharmacia, Peapack, New Jersey and Pfizer, New York, NY) was the first COX-2-specific non-steroidal anti-inflammatory drug approved by the Food and Drug Administration, in December 19989. Previous studies have demonstrated analgesic efficacy in association with the perioperative administration of 200 mg of celecoxib to patients undergoing dental, orthopaedic, and otolaryngological procedures9,18-22. However, those clinical investigations may have underestimated the analgesic efficacy of celecoxib because they did not utilize the appropriate dose for postoperative pain. For acute pain, it is recommended that an initial 400-mg dose of celecoxib be administered followed by an additional 200-mg dose on the first day if necessary. The need for an initial loading dose of celecoxib is related to its large volume of distribution.

The present study is the first clinical investigation to document the analgesic efficacy of celecoxib when administered for the treatment of postoperative pain according to the current guidelines of the Food and Drug Administration. We demonstrated a 31% reduction in morphine use during the first twenty-four hours postoperatively as well as a significant decrease in pain scores in association with the administration of a 400-mg dose of celecoxib before spinal fusion surgery, followed by an additional 200-mg dose twelve hours later. These findings represented a significant improvement in analgesic efficacy compared with that in our previous study18, in which we noted only a 9% reduction in morphine use when a single 200-mg dose of celecoxib was administered before spinal fusion surgery. In addition to decreased morphine use, the administration of celecoxib resulted in significantly lower pain scores at all postoperative time-intervals except at twelve and twenty-four hours after surgery, which coincides with the time at which the drug needs to be readministered.

A multimodal analgesic approach is recommended for the treatment of perioperative pain4. The recent practice guidelines for the treatment of acute pain in the perioperative setting state that, “unless contraindicated, all patients should receive around-the-clock regimen of nonsteroidal anti-inflammatory drugs, coxibs, or acetaminophen.”29 Although the perioperative administration of nonspecific nonsteroidal anti-inflammatory drugs may provide effective analgesia, their ability to decrease platelet aggregation and to increase bleeding time may increase the risk of perioperative bleeding2,3,30. This concern has led to the recommendation that non-steroidal anti-inflammatory drugs be discontinued before a patient undergoes elective surgery11,30. Continuing conventional nonsteroidal anti-inflammatory drugs before major orthopaedic surgery has been associated with a twofold increase in the incidence of perioperative bleeding, resulting in higher transfusion requirements12. The use of nonsteroidal anti-inflammatory drugs has been associated with other postoperative complications, including wound hematoma, upper gastrointestinal tract bleeding, and hypotension11. In one study, the likelihood of these complications was found to be 5.8 times greater for patients who received nonsteroidal anti-inflammatory drugs twenty-four hours before surgery than for those who did not11.

In contrast to nonspecific nonsteroidal anti-inflammatory drugs, the use of COX-2-specific inhibitors may represent a significant therapeutic advance in the treatment of perioperative pain. Selective inhibition of COX-2 produces analgesia with substantial safety advantages compared with existing nonsteroidal anti-inflammatory drugs31. Conventional non-steroidal anti-inflammatory drugs nonspecifically inhibit the COX-1 and COX-2 isoforms32. The therapeutic activity of nonsteroidal anti-inflammatory drugs is primarily the inhibition of COX-2, whereas the toxicity results from inhibition of COX-133. Because platelets express only COX-1 and are incapable of expressing COX-234, selective COX-2 inhibitors do not inhibit platelet function. Celecoxib has been shown to have no effect on platelet function as measured on the basis of serum thromboxane production and ex vivo platelet aggregation35. In fact, the administration of celecoxib in doses of 1200 mg/day for ten consecutive days in healthy adults demonstrated no effect on platelet aggregation or bleeding time35. The present study revealed that the preoperative and continued postoperative administration of celecoxib had no effect on the incidence of perioperative bleeding following spinal fusion surgery. No other postoperative complications (for example, wound hematoma or dehiscence, gastroduodenal perforation, ulcers, or bleeds) were observed during the study period.

Another concern regarding the perioperative use of nonsteroidal anti-inflammatory drugs is the possible deleterious effect on osteogenesis and spinal fusion14-16. Prostaglandins have been known for many years to have potent effects on bone metabolism (including both osteoblastic and osteoclastic activity) and to be essential for bone repair36. The exact mechanism by which nonsteroidal anti-inflammatory drugs impair spinal fusion has not yet been elucidated. It has been hypothesized that the effect may be mediated by an inhibition of the inflammatory process with concomitant reduction in blood flow in the early period of osteogenesis, decreased mesenchymal cell proliferation, or inhibition of calcification of the bone matrix14-16.

The use of nonsteroidal anti-inflammatory drugs has received considerable attention with regard to this effect on spinal fusion. To the best of our knowledge, there have been only three studies that have examined the effect of nonsteroidal anti-inflammatory drugs on spinal fusion in humans27,28,37. In a retrospective study of eighty-three patients undergoing posterolateral arthrodesis for the treatment of isthmic spondylolisthesis, single-level fusions were associated with an overall union rate of 82% and two-level fusions were associated with an overall union rate of 74%37. However, patients who continued to take nonsteroidal anti-inflammatory drugs for more than three months postoperatively showed significantly lower rates of union and success (44% and 37%, respectively) (p < 0.001). In a retrospective study of 288 patients undergoing spinal fusion surgery, Glassman et al.28 demonstrated that nonunion was five times more likely to occur in patients who received ketorolac (a parenteral nonsteroidal anti-inflammatory drug) postoperatively than in those who received no nonsteroidal anti-inflammatory drugs. There was a dose-dependent relationship between the nonunion rate and ketorolac use. Both studies revealed that nonsteroidal anti-inflammatory drugs had a significant deleterious effect on spinal fusion (p < 0.001), and Glassman et al.28 recommended that nonsteroidal anti-inflammatory drugs should be avoided in the early postoperative period. However, the nonsteroidal anti-inflammatory drugs in those two studies28,37 were not administered according to current clinical practice guidelines for the treatment of acute pain. Nonsteroidal anti-inflammatory drugs were administered either for a prolonged period of time37 or at an excessive dose28.

Several animal studies involving rat and rabbit models have provided evidence to suggest that nonselective nonsteroidal anti-inflammatory drugs either delay union or increase the rate of nonunion14-16. Subsequently, Long et al.38 examined the effect of celecoxib, a selective COX-2 inhibitor, on spinal fusion in a rabbit model. In that study, the animals received either celecoxib (10 mg/kg), indomethacin (10 mg/kg), or saline solution orally for eight weeks after single-level intertransverse posterolateral arthrodesis with use of autogenous iliac crest bone. There was a significant difference between the indomethacin and control groups (p = 0.002) but not between the celecoxib and control groups. The investigators concluded that celecoxib does not significantly inhibit the rate of spinal fusion and that the inhibitory effects of nonsteroidal anti-inflammatory drugs on bone-healing are likely mediated by inhibition of COX-1. However, subsequent animal studies have demonstrated that selective COX-2 inhibitors have deleterious effects on bone-healing. Simon et al.39 reported that COX-2 function is essential for bone-healing. Those investigators demonstrated impaired fracture-healing in mice that were homozygous for a null mutation in the COX-2 gene. They also examined fracture-healing in rats that had been treated with indomethacin (1 mg/kg), celecoxib (4 mg/kg), or rofecoxib (3 mg/kg) for eight consecutive weeks, beginning two days before fracture. All three nonsteroidal anti-inflammatory drugs inhibited fracture-healing to varying degrees, but the effects were more profound in association with the selective COX-2 inhibitors. However, whereas the doses of indomethacin and celecoxib that were used in the rats were roughly equivalent to those used in humans, the dose of rofecoxib was four times that used to treat acute pain. Furthermore, when COX-2 inhibitors are used for the treatment of acute pain, they are typically administered for a short term (a few days to one week) rather than continuously for eight weeks as in the animal study by Simon et al.39.

Recently, Gerstenfeld et al. suggested that the deleterious effects of COX-2 inhibitors on fracture-healing may be reversible following short-term use40. Those investigators quantified the relative changes in the normal expression of COX-1 and COX-2 mRNAs over a forty-two-day period of fracture-healing in the rat model and concluded that COX-2 prostaglandin production plays a primary functional role in the early stages after injury but is less important during later periods of bone-healing. Using the same fracture model, those authors examined the effects of ketorolac, valdecoxib (a COX-2-specific inhibitor), or vehicle over a seven or twenty-one-day time-course41. The data from that study suggested that both COX-2-specific inhibitors and nonselective nonsteroidal anti-inflammatory drugs delay fracture-healing, but the magnitude of the effect was related to the duration of treatment and was greater for the COX-2-specific inhibitor, valdecoxib. The authors concluded that “extrapolation of these findings to a clinical setting suggests that management of fracture-associated pain with inhibitors of COX-2 should neither impair nor delay healing as long as the duration of treatment is consistent with current standards of care.”41

The results of the present study concur with these findings. We observed no significant increase in the incidence of nonunion when celecoxib was administered for five consecutive days in doses approved for the treatment of acute pain. We currently administer selective COX-2 inhibitors for a period of less than one week to all of our patients undergoing spinal fusion surgery. For patients who require long-term administration of nonsteroidal anti-inflammatory drugs, we reinstitute these drugs after six weeks, by which time bone-healing has already begun. We believe that denying patients these medications may pose a greater risk than nonunion. The administration of non-steroidal anti-inflammatory drugs to patients undergoing spinal fusion surgery has been associated with substantial benefits, including improved analgesia (as indicated by decreased opioid use and pain scores), improvement in postoperative walking, shorter hospitalization, and a decreased frequency of nausea, vomiting, and sedation18,42-44. A reduction in acute pain also may be beneficial in reducing the prevalence of chronic pain7,8. It is believed that early intervention with COX-2-specific inhibitors may thwart the progression of acute pain to chronic pain45.

In conclusion, the present study revealed that the perioperative administration of celecoxib resulted in a significant reduction in postoperative pain and opioid use following spinal fusion surgery. In addition, the short-term administration of this COX-2-specific nonsteroidal anti-inflammatory drug had no apparent effect on the nonunion rates after one year of follow-up. ▪

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from Pfizer Pharmaceuticals. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Investigation performed at Baystate Medical Center and Tufts University School of Medicine, Springfield, Massachusetts, and Southern Orthopaedic Sports Medicine and Parkridge Surgery Center, Columbia, South Carolina

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