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Abstract

Objective:

To investigate whether preincisional parecoxib administration can reduce postoperative pain and modulate the inflammatory cytokine response to a greater extent than preincisional parecoxib administration in total hip replacement patients.

Methods:

Patients were randomized to receive 40 mg parecoxib intravenously either before or after skin incision (preincisional and postincisional groups, respectively). Morphine was administered for postoperative analgesia. Visual analogue pain scale (VAS) scores and morphine consumption were recorded at 1, 6, 18 and 24 h postoperation. Plasma levels of interleukin (IL)-6, IL-8 and tumour necrosis factor-a were measured 30 min before skin incision and 6 h postoperation.

Results:

Compared with the post - incisional group, VAS pain scores at 1 and 6 h postoperation were significantly lower in the preincisional group. Morphine consumption was significantly lower in the preincisional group at 6, 18 and 24 h postoperation. In both groups, IL-6 and IL- 8 levels increased significantly at 6 h postoperation compared with pre - operation, and the preincisional group had significantly lower levels of IL-6 and IL-8 at 6 h postoperation compared with the postincisional group.

Conclusions:

Preincisional parecoxib administration reduced postoperative pain and morphine consumption compared with post - incisional administration, and attenuated IL-6 and IL-8 production 24 h after hip replacement surgery.

Keywords

Parecoxib Cyclo-oxygenase-2 inhibitor Total hip replacement Preincisional analgesia Pain Cytokine response

Introduction

Surgical trauma is a psychologically and physically stressing condition, which can trigger a systemic response regulated by a complex network of neural, endocrinal and immunological mechanisms.¹ Tissue injury associated with surgery sets off an inflammatory reaction, which is accompanied by increased levels of proinflammatory cytokines, including tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8. These proinflammatory cytokines can induce peripheral and central nervous system sensitization, leading to hyperalgesia, through a cyclo-oxygenase-2 (COX-2)-dependent pathway.^2,3 It is also possible that perioperative pain contributes to increased proinflammatory cytokines via a feedback cascade between nociception and proinflammatory cytokines.⁴ Although the primary role of the stress response after surgery is to enhance the healing process, overactivity of host defence mechanisms can lead to negative consequences, and the concept has been raised that an inhibited stress response may be favourable.^5,6 The immunosuppressive effects of painful experiences have also been confirmed in both humans and animals.^7,8 Thus, both perioperative inflammatory response modulation and pain control are of great clinical significance.

Preincisional analgesia is a pain management technique in which analgesic treatment begins prior to surgical incision. One of the main goals of preincisional analgesia is to reduce postoperative pain and modulate the perioperative inflammatory response.^3,9 In a meta-analysis, preincisional administration of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with decreased postoperative analgesic use and prolonged time to first analgesic need when compared with the same analgesic regimens initiated after surgical incision.¹⁰ The effects of preoperative administration of diclofenac, a NSAID COX-2 inhibitor, in attenuating cytokine synthesis and release compared with placebo have also been demonstrated.¹¹ Furthermore, it has been reported that, in comparison with postincisional administration, the same dose of parecoxib (a highly selective COX-2 inhibitor) administered before skin incision improved analgesia immediately after surgery, reduced morphine consumption without influencing the side-effects of morphine and attenuated IL-6 production 24 h after colorectal cancer surgery.³

Joint replacement surgery is associated with high levels of proinflammatory cytokines and severe postoperative pain. Both pain and excessive inflammatory reactions are not conducive to functional recovery after the procedure.¹² A randomized, double-blind trial reported that preoperative administration of rofecoxib, which is a selective COX-2 inhibitor, reduced pain (and general and local inflammatory reactions) compared with placebo, following total knee joint replacement.¹² Thus, the present prospective study compared the effects of preincisional versus postincisional administration of 40 mg parecoxib on pain management and inflammatory cytokine response, in patients receiving total hip replacement.

Patients and methods

Study Population

All consecutive patients (aged 18 – 70 years) of American Society of Anesthesiologists (ASA) physical status I – II who were scheduled to receive hip joint replacement in the First People's Hospital of Jingzhou, Jingzhou, Hubei, China, between January 2008 and December 2011, were eligible for enrolment in the study. The exclusion criteria were: severe cardiac, pulmonary or renal insufficiency; use of analgesic medication during the week before surgery; history of peptic ulcer, inflammatory bowel disease or allergy to NSAIDs; ongoing therapies with immunoregulatory drugs; any contraindication to parecoxib.

The study was approved by the Medical Ethics Committee of the First People's Hospital of Jingzhou (No. 2008GJJ012) and written informed consent was obtained from all patients prior to entry to the study.

Study Interventions

Patients were randomly assigned to receive parecoxib either before skin incision (preincisional group) or after skin incision (postincisional group), by selection of sealed envelopes. The preincisional group received a solution of 100 ml normal saline with parecoxib 40 mg intravenously (i.v.) 30 min before skin incision and 100 ml normal saline i.v. 30 min after skin incision. The postincisional group received a solution of 100 ml normal saline i.v. 30 min before skin incision and 100 ml normal saline with parecoxib 40 mg i.v. 30 min after skin incision. The surgical team and procedures were similar in the two groups and the surgical teams were blinded to the randomization.

At the preoperative visit by the anaesthesiologist, patients became familiarized with a 100-mm visual analogue scale (VAS) for pain (0 mm, no pain; 100 mm, worst possible pain). They were also taught how to use the patient-controlled analgesia pump (Pain Management Provider™; Abbott, Abbott Park, IL, USA). General anaesthesia was induced with 3 μg/kg fentanyl, immediately followed by 3 mg/kg propofol, and was maintained with 3% sevoflurane in oxygen. A continuous remifentanil infusion (0.2 μg/kg per min) was used for intraoperative analgesia. All patients received a standardized (0.1 mg/kg) morphine i.v. loading dose for postoperative pain control before incision closure. Mean arterial blood pressure was maintained within 20% of baseline values. Standard monitoring included pulse oximetry, electrocardiography, capnography and invasive arterial blood pressure. All patients received upper-body forced-air warming and i.v. fluids were warmed to 37 °C.

On arrival at the postanaesthesia care unit, patients were connected to the patient-controlled analgesia pump, to enable them to self-administer morphine (1.0 mg i.v. per time; lockout time was 5 min and there was no 4-h dose limitation). The postanaesthesia care unit staff were blinded to the randomization. At 1, 6, 18 and 24 h after completion of surgery the VAS was used to assess pain intensity at rest and after coughing, and total morphine consumption was also recorded at these times.

Blood Sample Collection

Venous blood samples (5 ml) were obtained from each patient via the antecubital vein 30 min before skin incision and 6 h postoperatively. Blood was collected into 10ml Vacutainer^® tubes containing 150 IU sodium–heparin (Becton, Dickinson & Co., Franklin Lakes, NJ, USA). For cytokine measurements, blood samples were centrifuged at 4000 g for 10 min at 4°C and the plasma was stored at –80 °C until analysis. Plasma concentrations of IL-6, IL-8 and TNF-α were measured by enzyme-linked immunosorbent assays (BioRad Laboratories, Hercules, CA, USA) according to the manufacturer's instructions. Minimum detectable concentrations were 0.06 pg/ml for TNF-α, 0.08 pg/ml for IL-6 and 0.11 pg/ml for IL-8. All samples were measured in duplicate and the mean of the two values was used in the statistical analysis.

Statistical Analyses

The mean ± SD were calculated and statistical analyses were performed using the SPSS^® software package, version 17.0 (SPSS Inc., Chicago, IL, USA) for Windows^®. Data between the preincisional and postincisional groups were compared using an unpaired Student's t-test; data within groups were compared using a paired Student's t-test. All tests were two-tailed. A P-value < 0.05 was considered to be statistically significant.

Results

The study recruited 65 consecutive patients: 33 in the preincisional group and 32 in the postincisional group. There were no statistically significant differences between the two groups in terms of age, gender, body weight, blood loss and length of surgical procedure (Table 1).

TABLE 1:

Characteristics of the total hip replacement patients who were enrolled in the present study and received either intravenous preincisional or postincisional 40 mg parecoxib analgesia during surgery

Variable	Preincisional analgesia n = 33	Postincisional analgesia n = 32
Age, years	53 ± 7	58 ± 7
Gender, males/females	13/20	10/22
Weight, kg	66 ± 5	64 ± 6
Length of operation, min	178 ± 36	185 ± 41
Blood loss, ml	450 ± 48	421 ± 56

Data presented as mean ± SD.

No statistically significant between-group differences (P  0.05); unpaired Student's t-test.

The overall age of the patients was lower than expected, as 16 older patients (between 65 and 76 years of age, ASA physical status III) were excluded from the study: five were excluded for arterial hypertension, seven for bronchopulmonary disease and four for renal insufficiency. In addition, some younger patients (between 30 and 45 years of age), who received hip replacement for severe hip fracture caused by trauma or femoral head necrosis caused by excessive drinking, were included.

The VAS pain scores at rest and after coughing at 1, 6, 18 and 24 h postoperation are shown in Table 2. The VAS pain scores at rest and after coughing at 1 and 6 h postoperatively were significantly lower in the preincisional group compared with the postincisional group (all P < 0.05). No differences were observed in the VAS pain scores between the two groups at rest and after coughing, at 18 and 24 h postoperatively (Table 2).

TABLE 2:

Visual analogue scale (VAS) pain scores and patient-controlled analgesia morphine consumption in total hip replacement patients who received either intravenous preincisional or postincisional 40 mg parecoxib analgesia during surgery

Pain or analgesia parameter	Preincisional analgesia n = 33	Postincisional analgesia n = 32	Statistical significance
1 h postoperation
VAS, rest	3.79 ± 0.47	4.80 ± 0.51	P = 0.002
VAS, cough	4.46 ± 0.58	5.22 ± 0.64	P = 0.017
Morphine consumption, mg	8.09 ± 1.32	8.52 ± 1.37	NS
6 h postoperation
VAS, rest	3.52 ± 0.42	4.41 ± 0.68	P = 0.009
VAS, cough	3.97 ± 0.55	4.88 ± 0.72	P = 0.012
Morphine consumption, mg	19.64 ± 3.36	23.31 ± 4.87	P = 0.006
18 h postoperation
VAS, rest	2.95 ± 0.33	3.14 ± 0.36	NS
VAS, cough	3.66 ± 0.55	3.98 ± 0.44	NS
Morphine consumption, mg	23.83 ± 3.29	38.43 ± 5.17	P < 0.001
24 h postoperation
VAS, rest	2.38 ± 0.39	2.54 ± 0.40	NS
VAS, cough	2.81 ± 0.22	2.92 ± 0.25	NS
Morphine consumption, mg	25.72 ± 4.08	39.14 ± 5.39	P < 0.001

Unpaired Student's t-test was used for between-group comparisons.

NS, not statistically significant (P  0.05).

Total morphine consumption was significantly lower in the preincisional group compared with the postincisional group at 6 h (P = 0.006), 18 h (P < 0.001) and 24 h (P < 0.001) postoperatively (Table 2). Patients in the preincisional group used 34% less morphine during the first postoperative day.

Plasma concentrations of IL-6, IL-8 and TNF-α for each group 30 min before skin incision and 6 h postoperatively are shown in Table 3. There were no significant differences in plasma concentrations of IL-6, IL-8 and TNF-α 30 min before skin incision for patients in the preincisional and postincisional groups. In both groups, plasma concentrations of IL-6 and IL-8 increased significantly 6 h postoperatively compared with preoperative levels (all P < 0.001). The preincisional group also had significantly lower levels of IL-6 and IL-8 6 h postoperatively compared with the postincisional group (P = 0.002 and P = 0.005, respectively). The plasma level of TNF-α at 6 h postoperatively showed no statistically significant differences between the pre- and postoperation measurements, or compared with the plasma level of TNF-α 30 min before skin incision (Table 3).

TABLE 3:

Plasma levels of interleukin-6, interleukin-8 and tumour necrosis factor-α 30 min before skin incision and 6 h postoperatively, in total hip replacement patients who received either preincisional or postincisional 40 mg parecoxib intravenously during surgery

Cytokine	Preincisional analgesia n = 33	Postincisional analgesia n = 32	Statistical significance
Interleukin-6, pg/ml
30 min before skin incision	1.55 ± 0.25	1.62 ± 0.34	NS
6 h postoperation	5.78 ± 0.58	7.14 ± 0.67	P = 0.002
Statistical significance	P < 0.001	P < 0.001
Interleukin-8, pg/ml
30 min before skin incision	36.73 ± 3.62	35.40 ± 3.85	NS
6 h postoperation	49.24 ± 5.78	58.69 ± 6.29	P = 0.005
Statistical significance	P < 0.001	P < 0.001
Tumour necrosis factor-α, pg/ml
30 min before skin incision	6.25 ± 0.72	6.14 ± 0.83	NS
6 h postoperation	6.49 ± 0.81	6.71 ± 0.66	NS
Statistical significance	NS	NS

Unpaired Student's t-test was used for between-group comparisons; paired Student's t-test was used for within-group comparisons.

NS, not statistically significant (P  0.05).

Discussion

According to the present study, patients who received preincisional parecoxib at a dose of 40 mg showed a lower VAS pain score at 1 and 6 h after surgery and reduced morphine consumption during the first postoperative day, compared with those who received postincisional administration at this dose. In addition, preincisional parecoxib administration resulted in a lower level of proinflammatory cytokines (IL-6 and IL-8) and, therefore, attenuated surgery-induced immune changes.

The mean age of the patients in the present study appeared to be slightly lower than might be expected for patients undergoing total hip replacement surgery. This was because some older patients with an ASA physical status of III were excluded and some younger patients, who received hip replacement for severe hip fracture caused by trauma or femoral head necrosis caused by excessive drinking, were included.

The present study was consistent with previous studies. For example, pre-emptive pain management with pentoxifylline (a nonspecific cytokine inhibitor) was shown to provide beneficial postoperative analgesic effects and inhibited proinflammatory cytokine production in patients undergoing cholecystectomy.¹³ Preincisional analgesia with pentoxifylline in patients undergoing colorectal cancer surgery attenuated perioperative cytokine response, reduced morphine consumption and improved recovery of bowel function compared with placebo.⁷ In patients undergoing elective general surgical procedures, preoperative administration of parecoxib compared with postoperative administration was more effective for pain relief during the postoperative period.¹⁴ In patients with total knee joint replacement, preincisional rofecoxib administration reduced postoperative pain, and general and local inflammatory reactions, compared with placebo.¹² These studies indicate that analgesic intervention may need to be started before the surgical stimulus begins, in order to block nociception completely. This afferent blockade of nociceptive impulses is then continued throughout the intra- and postoperative periods.¹⁵

Surgical stress and pain may be harmful to the body.^8,16 Hyperinflammation may cause suppression of the immune system.¹⁷ Proinflammatory cytokines can also produce long-lasting hyperalgesia.¹⁸ COX-2, which was discovered in the early 1990s,¹⁹ is an induced enzyme that is located in inflammatory tissues such as synovial cells, endothelial cells and macrophages. Under the influence of external inflammatory stimulating factors, escalating production of COX-2 promotes the synthesis of inflammatory mediators and induces an inflammatory reaction.²⁰ Thus, COX-2 has become a common target for preventing inflammation and pain, and NSAIDs (which nonselectively inhibit COX-2) are frequently used for perioperative analgesia.^12,21

The plasma level of IL-6, which is one of the main proinflammatory cytokines, increases with increasing severity of surgery and magnitude of tissue injury, and this can lead to hyperalgesia.^2,22 IL-8 was the first endogenous mediator to be shown to induce hyperalgesia involving the sympathetic nervous system.²³ TNF-α can also induce central sensitization and cause enhancement of pain.² Previous investigators have shown that inhibiting central COX-2 activity may reduce centrally generated inflammatory hypersensitivity. Preincisional administration of parecoxib has been shown to decrease serum levels of IL-6 compared with postincisional administration,³ and preincisional administration of rofecoxib has also been shown to reduce IL-6 levels, in comparison with placebo.¹² Administration of celecoxib in patients with distal colorectal adenocarcinoma, in comparison with healthy controls, caused a significant decrease in the concentration of IL-8.²⁴ Preincisional versus postincisional administration of parecoxib in the present study also inhibited IL-6 and IL-8 production after hip joint replacement surgery.

The level of plasma TNF-α did not change over time in the present study, and was not significantly different between the preincisional and postincisional groups; this is also in agreement with previous studies where postoperative circulatory TNF-α changes were not detected.^3,25 One study reported a significant increase in the postoperative TNF-α level in wound and peritoneal fluids, although plasma TNF-α exhibited no change.²⁶ This is because the level of TNF-α in the area of tissue injury was significantly higher than that in plasma,²⁶ and it is conceivable that TNF-α may still play an important role in mechanical nociceptor hypersensitivity and perioperative hyperalgesia.²⁷

In conclusion, the present prospective study indicated that preincisional parecoxib administration can reduce pain intensity, decrease morphine consumption and attenuate IL-6 and IL-8 production after hip joint replacement surgery, compared with postincisional administration. Although these results are interesting, more research is needed in order for this finding to be demonstrated conclusively.

Footnotes

The authors had no conflicts of interest to declare in relation to this article.

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