Effect of tramadol on perioperative immune function in patients undergoing gastric cancer surgeries

Abstract

Background:

A prospective randomized controlled trial was designed to observe the effect of tramadol on T-lymphocyte subsets, activated T cell and natural killer (NK) cells of patients undergoing gastric cancer surgeries.

Subjects and Methods:

Thirty patients undergoing elective gastric cancer surgeries under general anesthesia were randomly divided into two groups. Before anesthesia induction, Group I did not receive any drugs and Group II received intramuscular tramadol 1 mg/kg. Peripheral venous blood samples were taken before anesthesia, 1 h after incision and postoperation. CD3⁺, CD3⁺ CD4⁺, CD3⁺ CD8⁺, CD3^–CD16⁺ CD56⁺ (NK) cells and CD3⁺ human leukocyte antigen (HLA)-DR⁺ (activated T cell) were measured by flow cytometer.

Results:

One hour after incision, CD3⁺, CD3⁺ CD4+, CD3⁺ CD4⁺/CD3⁺ CD8⁺, CD3^-CD16⁺ CD56⁺, and CD3⁺ HLA-DR⁺ cells in the experimental and control group were significantly decreased compared with their baselines (P < 0.05), while the values of Group I were lower than those of Group II (P < 0.05). After surgery, the values of Group I were lower than their baselines (P < 0.05). But the values of Group II had no significant difference compared with their baselines.

Conclusion:

Tramadol can reduce the decrease of T-lymphocytes subsets and NK cells, thus improve the cellular immune function in the perioperation of gastric cancer.

INTRODUCTION

Many studies both in the animal and in the human have revealed that surgery is associated with a relevant immunosuppression. Injuries and stressed caused by surgeries are the primary reasons of immunity depression.[1,2] However, the immune effect of anesthesia and pain relief should also be considered.[3,4] Many analgesics, for example, morphine used for the treatment of intraoperative pain decreased the quantity and activity of lymphoproliferation and natural killer (NK) cell. But analgesic drug tramadol could prevent the immunosuppression effect of surgery in rats.[5] Furthermore, it is not clear about the immune effect of tramadol in the cancer patients during the perioperation. A trial was designed to observe the expressions of peripheral blood T-lymphocyte subsets (CD3⁺, CD3⁺ CD4⁺ and CD3⁺ CD8⁺), NK cells (CD3⁻ CD16⁺ CD56⁺) and activated T cell (CD3⁺ HLA-DR⁺) in patients scheduled for gastric cancer through given tramadol before anesthesia.

SUBJECTS AND METHODS

Approval and consent obtained

The study was approved by the ethics committee of the Xiangyang Central Hospital and conducted according to the principles of the Helsinki Declaration. An informed, written consent was obtained from each of the clinical patients included in the study.

Patients’ selection

Thirty patients (age: 20-69) with American Society of Anesthesiologists (ASA) physical status I or II scheduled for gastric cancer surgeries under general anesthesia were enrolled in this trial. All the patients did not receive radiotherapy, chemotherapy, immunodepressants, or blood transfusion before the surgery. Patients who received intraoperative therapies of corticosteroids or blood transfusion were also excluded.

Anesthesia methods

Phenobarbital sodium 0.1 g and atropine 0.5 g were intramuscular injected 30 min before anesthesia. All the patients were randomly divided into Groups I and II. Before anesthesia induction, Group I did not receive any drugs and Group II received intramuscular tramadol 1 mg/kg. Midazolam 0.1 mg/kg, propofol 1-1.5 mg/kg, atracurium 0.6-1 mg/kg, and remifentanil 1-2 μg/kg induced anesthesia. Anesthesia was maintained with continuous infusion of remifentanil 0.2-0.3 ug/kg/min, propofol 0.05-0.07 mg/kg/min, and atracurium 8-10 ug/kg/min. Mean arterial blood pressure fluctuated between the 10% of the preoperation. All the patients did not receive patient control intravenous analgesia.

Study methods

Peripheral venous blood samples were taken before anesthesia, 1 h after incision and postoperation. CD3⁺, CD3⁺ CD4⁺, CD3⁺ CD8⁺, NK cells, and HLA-DR were measured by flow cytometer.

Statistical analyses

All the data were expressed as Mean ± SD (standard deviation). Statistical analyses were conducted using SPSS 16.0. Results were analyzed by one-way analysis of variance. Statistical significance was set at P < 0.05.

RESULTS

There was no significant difference between Group I and Group II with regard to age, weight, gender, ASA physical status, and surgery duration [Table 1].

Table 1.

Demographic data and surgery duration

CD3⁺, CD4⁺, CD3⁺ CD8⁺ and CD3⁺ CD4⁺/CD3⁺ CD8⁺

There was no significant difference between the baselines of CD3⁺, CD3⁺ CD4⁺ and CD3⁺ CD4⁺/CD3⁺ CD8⁺ of two groups [Table 2]. One hour after incision, CD3⁺, CD3⁺ CD4⁺ and CD3⁺ CD4⁺/CD3⁺ CD8⁺ of two groups decreased compared with their baselines (P < 0.05), while those of Group I was lower than those of Group II (P < 0.05). After surgery, CD3⁺, CD3⁺ CD4⁺ and CD3⁺ CD4⁺/CD3⁺ CD8⁺ of Group I was lower than their baselines, but CD3⁺, CD3⁺ CD4⁺ and CD3⁺ CD4⁺/CD3⁺ CD8⁺ of Group II had no significant difference compared with their baselines. CD3⁺ CD8⁺ of two groups at different time points had no significant difference. In the Figure 1, the values of CD3⁺, CD3⁺ CD4⁺, CD3⁺ CD8⁺ were in the upright.

Table 2.

The value of CD3⁺, CD3⁺CD4⁺, CD3⁺CD8⁺, CD4⁺/CD8⁺, CD3^-CD16⁺CD56⁺, and CD3⁺HLA–DR⁺ in the two groups

Figure 1.

The scatterplots of CD3⁺, CD3⁺CD4⁺, CD3⁺CD8⁺ in the two groups. The values of CD3⁺, CD3⁺CD4⁺, and CD3⁺CD8⁺ were in the upright

CD3^-CD16⁺ CD56⁺ (NK cells)

There was no significant difference between the baselines of two groups. One hour after incision, NK cells of Group I and Group II decreased compared with their lines (P < 0.05). After surgery, NK cell of Group I was lower than the baselines (P < 0.05), but NK cell of Group II returned to the baselines. In the Figure 2, the values of CD3^-CD16⁺ CD56⁺ were in the upleft.

Figure 2.

The scatterplots of CD3^–CD16⁺CD56⁺ in the two groups. The values of CD3^–CD16⁺CD56⁺ were in the upleft

CD3⁺ HLA-DR⁺

There was no significant difference between the baselines of two groups. One hour after incision, CD3⁺ HLA-DR⁺ of Group I and Group II were lower than their baseline (P < 0.05). After surgery, CD3⁺ HLA-DR⁺ of Group I was still lower than the baseline (P < 0.05), while CD3⁺ HLA-DR⁺ of Group II returned to the baseline. In the Figure 3, the values of CD3⁺ HLA-DR⁺ were in the upright.

Figure 3.

The scatterplots of CD3⁺HLA-DR⁺ in the two groups. The values of CD3⁺HLA-DR⁺ were in the upright

DISCUSSION

Gastric cancer patients commonly undergo surgical procedures, and the perioperative period is characterized by immunosuppression and may predispose already immunosupressed cancer patients to tumor spread.[6] Possible mediating factors for immunosuppression during the operation include anesthetic agents,[7] blood transfusions,[8] pain,[4] and surgical stress.[9]

T-lymphocytes and NK cells are the important immune active cells in the peripheral blood circulation, whose expressions of surface antigen and some receptors are vital for the immune system. It caused tumor spread in the gastric cancer patients that the surgery decreased T cells and NK cells during the operation. HLA-DR molecules are expressed on the surface of professional antigen-presenting cells such as macrophages, dendritic cells, and B-cells and on activated T-lymphocytes, activated NK cells and human progenitor cells. CD3⁺ HLA-DR⁺ cells are the activated T-lymphocytes. As they are required for antigen presentation and activation of T-lymphocytes, they play a central role in the specific immune response to infection.[10,11,12] In our study, CD3⁺, CD3⁺ CD4⁺, CD3⁺ CD4⁺/CD3⁻ CD8⁻, CD3⁻ CD16⁺ CD56⁺, and CD3⁺ HLA-DR⁺ cells were lower than their lines of two groups 1 h after incision, which showed that the surgery decreased T-cells and NK cells in all the patients and so caused perioperative immunosuppression.

Many authors reported that tramadol could increase NK cell and T-lymphocyte proliferation in vivo and in vitro. Gaspani, et al.,[5] have revealed that the analgesic drug tramadol prevents the effect of surgery on NK cell activity and metastatic colonization in rats. Wang, et al.,[13] showed that the administration of tramadol improved immune functions during postoperation in gastric cancer patients. So Group II, we given the anesthetic drug tramadol before the anesthesia. One hour after incision, the T cells, activated T cells, and NK cells of Group II were lower than their baseline. After surgery, the immune function returned to the baseline in the Group II, but the immune function was lower than the baseline in the Group I. The results showed that the administration of tramadol improved the immunosuppression due to surgery and returned to the baselines more quickly.

CONCLUSION

Our data suggest that the anesthetic drug tramadol can reduce the decrease of T-lymphocytes subsets and NK cells, thus improve the cellular immune function in the perioperation of gastric cancer. The improvement of immune function of gastrointestinal cancer patients with postoperative infection and tumor metastasis remains to be further research.