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Anesth Analg 2003;97:822-827
© 2003 International Anesthesia Research Society

PAIN MEDICINE

The Effects of Postoperative Pain Management on Immune Response to Surgery

Benzion Beilin, MD*, Yehuda Shavit, PhD§, Evelyn Trabekin, MD{ddagger}, Boris Mordashev, MD*, Eduard Mayburd, MD*, Alexander Zeidel, MD*, and Hanna Bessler, PhD{dagger}

*Department of Anesthesiology and {dagger}Research Institute, Rabin Medical Center, Golda-Hasharon Campus, affiliated with the Sackler School of Medicine, Tel-Aviv University; {ddagger}Department of Anesthesiology, Schneider Children’s Medical Center, Petah Tiqva; and §Department of Psychology, Hebrew University, Jerusalem, Israel

Address correspondence and reprint requests to Yehuda Shavit, PhD, Department of Psychology, Hebrew University, Jerusalem 91905, Isreal. Address e-mail to Udi.Shavit{at}huji.ac.il


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Surgery is associated with immune alterations, which are the combined result of tissue damage, anesthesia, postoperative pain, and psychological stress. In the present study, we compared the effects of several postoperative pain management techniques on postoperative immune function. Patients hospitalized for abdominal surgery were randomly assigned to one of three postoperative pain management techniques: opiates on demand (intermittent opiate regimen [IOR]), patient-controlled analgesia (PCA), and patient-controlled epidural analgesia (PCEA). Postoperative pain was assessed. Blood samples were collected before and 24, 48, and 72 h after surgery. Production of interleukin (IL)-1ß, IL-2, and IL-6, natural killer cell cytotoxicity, and lymphocyte mitogenic responses were assessed. Patients of the PCEA group exhibited lower pain scores in the first 24 h after surgery compared with patients of the IOR and PCA groups. Mitogenic responses were suppressed in all groups in the first 24 h, returned to preoperative values by 72 h in the PCEA group, but remained suppressed in the PCA group. Production of IL-1ß and IL-6 increased in the IOR and PCA groups, whereas it remained almost unchanged in the PCEA group. Patients receiving an epidural mixture of opiate and local anesthetics (PCEA group) exhibited reduced suppression of lymphocyte proliferation and attenuated proinflammatory cytokine response in the postoperative period.

IMPLICATIONS: The present study compared the effects of three pain management techniques, intermittent opiate regimen, patient-controlled analgesia, and patient-controlled epidural analgesia on several immune functions. Patients of the patient-controlled epidural analgesia group exhibited reduced postoperative pain, reduced suppression of lymphocyte proliferative response to mitogens, and attenuated proinflammatory cytokine response to surgery.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The postoperative period is associated with neuroendocrine, metabolic, and immune alterations, which are the combined result of tissue damage, anesthesia, postoperative pain, and psychological stress (1–3). Suppression of immune defense mechanisms has been demonstrated in the postoperative period. Such immune compromise could affect the postoperative infection rate, healing process, and the rate and size of tumor metastases disseminated during surgery (4).

Limited evidence indicates that pain management in the postoperative period can affect the outcome of the surgery, reducing cardiac, pulmonary, and metabolic complication (5). It is difficult to tease apart the contribution of postoperative pain per se from the surgery-induced immunosuppression, and there are little empirical data on the effects of postoperative pain management on immune function. In any case, it is clear that the immune and nervous systems bi-directionally communicate and influence each other (6); therefore, pain management may influence the immune response in the postoperative period.

Several pain management techniques are frequently used in the postoperative period. These techniques include traditional systemic administration of opiates on a regular schedule or on demand (intermittent opiate regimen [IOR]), patient-controlled analgesia (PCA), and patient-controlled epidural analgesia (PCEA). These techniques differ in the type, amount, and route of administration of the analgesic drugs used to alleviate pain. The IOR and PCA techniques are predominantly based on opiates, which are the most frequently used drugs for pain in the postoperative period. On the one hand, opiates suppress the immune system (7,8) and render the organism more susceptible to infections (9) and metastases (10). On the other hand, opiate-induced analgesia in the perioperative period attenuated the metastatic-enhancing effects of surgery in rats (11). Thus, opiates can modulate host-defense mechanisms and can either enhance or attenuate tumor metastases.

The PCEA technique is usually based on a mixture of local anesthetics and opiates. Such a mixture allows for reducing the dose of opiates while increasing the efficiency of the postoperative analgesia (12). In addition, local anesthetics have an antiinflammatory effect of their own, and in this way, they may also contribute to the attenuation of the postoperative pain (13).

The goal of the present study was to examine to what extent postoperative pain management modulates the surgery-induced alterations of the immune response, specifically, to compare the effects of three pain management techniques (IOR, PCA, and PCEA) on several immune functions.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
One-hundred-fifteen patients (ASA physical status I–III) were included in this study after we obtained approval from the Hospital Human Studies Committee and informed consent from the patients. Patients undergoing recurrent operation were excluded from the study, as were patients with inflammatory bowel disease. All patients were scheduled for elective lower abdominal surgery (Table 1). On the preoperative visit by the anesthesiologist, patients were assigned to 1 of 3 study groups (n = 35 per group): (a) postoperative analgesia on IOR, (b) PCA, and (c) PCEA. On the same visit, patients were familiarized with the visual analog pain scale (VAS) and were instructed on the use of the PCA and PCEA pumps.


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  		Table 1. Characteristics of the Patients According to the Postoperative Pain Management Group
 
Patients were premedicated with lorazepam (1–2 mg, orally) 90 min before the induction of anesthesia, followed by IV 2–3 mg of midazolam on arrival in the operating room. An epidural catheter was placed in patients assigned to the PCEA group via the T12-L1 or L1-2 interspace and advanced 3–4 cm. To exclude placement of the epidural catheter in the cerebrospinal fluid, a test dose of 3 mL of lidocaine 2% was used.

General anesthesia was induced using fentanyl 2–3 µg/kg, thiopental 4–6 mg/kg, and vecuronium 0.1 mg/kg IV. Anesthesia was maintained with N2O, isoflurane, and additional fentanyl. Arterial and central venous catheters were used as indicated. Mean arterial blood pressure was maintained within 20% of baseline values with isoflurane and fentanyl. Volume was replaced by crystalloids and hydroxyethyl starch 6%. Patients received upper body forced-air warming, and IV fluids were warmed to 37°C. Patients requiring blood transfusion during the perioperative period were not included in this study.

Patients of the IOR group received pethidine 50–75 mg IM on demand. On arrival to the postanesthesia care unit, patients of the PCA group received an initial loading dose of morphine (3–4 mg) to relieve the intensity of pain. The PCA pump (Abbott Life Care Infuser, Chicago, IL) was set to deliver a 1-mg IV bolus of morphine per demand with a lockout time of 6–8 min and a maximum dose of 25 mg in any 4-h period, without continuous background infusion. If a patient reported a pain score >=4 on the VAS, an additional IV bolus of 1–2 mg of morphine was given. On arrival to the postanesthesia care unit, patients of the PCEA group were connected to the PCEA pump (Pain Management Provider, Abbott, Chicago, IL) and received 3 mL of 0.1% bupivacaine plus 2 µg/mL of fentanyl per demand (lockout time 10 min), with continuous background infusion of 6 mL/h.

A 10-cm VAS (with end-points labeled "no pain" and "worst possible pain") was used to assess pain intensity in rest and after coughing at 4, 8, 12, 24, and 48 h after completion of surgery.

Venous blood samples (15 mL) were collected on the morning of the surgery and at 24, 48, and 72 h after surgery. Peripheral blood mononuclear cells (PBMC) were isolated from heparinized venous blood using a histopaque (Sigma, St. Louis, MO) gradient centrifugation. PBMC were washed twice in RPMI-1640 medium containing 1% penicillin, streptomycin, and nystatin and supplemented with 10% fetal calf serum (FCS; designated complete medium [CM]). Cells were suspended in FCS containing 10% dimethyl sulfoxide (DMSO; Sigma) and frozen at -70°C until used. On the day of assay, cells were thawed quickly, washed three times in CM, and their viability tested by trypan blue dye exclusion. The viability was more than 95%.

PBMC 0.1-mL suspension (2 x 106 cells/mL) was aliquoted into each well of 96-well plates (flat bottom; Nunc, Wiesbaden, Germany) containing 0.1 mL of CM or phytohemagglutinin (PHA-M; 2%; Difco, Sparks, MD), concanavalin A (Con A, 10 mg/mL), or pokeweed mitogen (PWM; 20 µg/mL; Sigma). Cultures set up in triplicates were incubated for 3 days. Methyl-[3H]-thymidine (5 µCi/mmol; Amersham, England) was added (0.5 µCi/well) 18 h before harvesting. Radioactivity was measured with LKB liquid scintillation counter model 3380.

PBMC (2 x 106) suspended in 1 mL of Roswell Park Memorial Institute (RPMI)-1640 supplemented with 5% FCS were incubated for 24 h in the presence of 10 ng/mL of lipopolysaccharide (Sigma) for interleukin (IL)-1ß and IL-6. For IL-2 production, 2 x 106 PBMC were suspended in 1 mL of CM and were incubated for 48 h with 1% PHA-M. After the incubation period, culture media were collected, cells were removed by centrifugation, and the supernatants were kept at -70°C until assayed for cytokine content.

Cytokine concentration in the supernatant was tested using enzyme-linked immunosorbent assay kits specific for human IL-1ß (Biosource International, Camarillo, CA), IL-6, (Pharmingen, San Diego, CA), and IL-2 (R&D Systems, Minneapolis, MN), as detailed in the guideline provided by the manufacturers. The detection levels of these cytokines in the assays were 30 pg/mL for IL-1ß and IL-2 and 15 pg/mL for IL-6.

Natural killer cell cytoxicity was assessed by a standard chromium specific release assay with 51Cr labeled K562 erythroleukemia cell line used as target cells and PBMC serving as effector cells. Final effector to target ratio was 100:1. After 4 h of incubation at 37°C, supernatants were collected, and the radioactivity was determined by a {gamma} counter (LKB). All reactions were performed in triplicates, and the specific 51Cr release was calculated as described previously (14).

The number of observations varies slightly among assays as a result of an occasional missing sample or an occasional problem in a particular assay. Data of all immunological assays are expressed as difference scores of postoperative minus preoperative values. Data were analyzed for each measure using analysis of variance with repeated measures (time periods before and after surgery) (15). Post hoc Bonferroni procedure was conducted as appropriate, correcting for multiple comparisons (15). Whenever the Bonferroni procedure revealed a significant group effect, contrasts between group means at individual time points were calculated. Probability values of P < 0.05 were considered significant. The results are expressed as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The groups were similar in body weight, age, and duration of surgery (Table 1). Men-to-women ratio was similar in all groups. Averaged over the first 48 h after surgery, patients of the IOR group received a cumulative dose of (mean ± SD) 410 ± 68.79 mg of pethidine IM; patients of the PCA group received 73 ± 22.93 mg of morphine IV; and patients of the PCEA group received a total volume of 429 mL of 0.1% bupivacaine + 2 µg/mL of fentanyl.

Pain scores revealed similar trends between the measures taken at rest or during coughing. There were significant differences among the study groups (F(2,87) = 16.61 or 22.20; P < 0.0001) for VAS at rest or VAS during coughing, respectively (Fig. 1, A and B). In the first 48-h period, the highest pain scores were observed in patients of the IOR group, followed by the PCA group. Pain scores of the PCEA group were significantly smaller during coughing in the first 24 h after surgery.



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  		Figure 1. Visual analog pain scores (VAS) at (A) rest and (B) during coughing beginning 4 h and up to 72 h after surgery for patients receiving one of three pain management techniques: intermittent opiate regimen (IOR), patient-controlled analgesia (PCA), or patient-controlled epidural analgesia (PCEA). Pain intensity was significantly greater in patients of the IOR group in the first 48-h period, both at rest and during coughing, compared with the other groups. Pain intensity in the PCEA group was significantly smaller in the first 24 h, during coughing, compared with the other groups. Values are mean (± SEM).

 
Lymphocyte proliferative response to all mitogens was suppressed in the first 24 h after surgery (Fig. 2A–C). Proliferative responses to all mitogens of the PCEA group returned to preoperative values by 72 h and were significantly higher compared with both IOR and PCA groups for PWM (P < 0.014 and P < 0.006, respectively) and only with the PCA group for Con A (P < 0.013). In the IOR group, the proliferative responses at 72 h approximately returned to the preoperative values for the Con A (significantly higher compared with the PCA group; P < 0.007) and PHA-M and remained suppressed for the PWM. Suppression of the proliferative response to all mitogens was still evident at 72 h in patients of the PCA group.



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  		Figure 2. Proliferative response of peripheral blood lymphocytes to the three mitogens (A) concanavalin A (Con A), (B) phytohemagglutinin (PHA), and (C) pokeweed mitogen (PWM) in the three pain management groups of intermittent opiate regimen (IOR), patient-controlled analgesia (PCA), or patient-controlled epidural analgesia (PCEA). Data are expressed as difference scores of postoperative minus preoperative values (cpm) and presented as mean (± SEM). Proliferative responses to all mitogens were suppressed in the first postoperative 24-h period, gradually returning to preoperative values. Proliferative responses to all mitogens of the PCEA group completely recovered by 72 h, whereas they remained suppressed in the PCA group.

 
Cytokine production was assessed ex vivo in lipopolysaccharide- or PHA-stimulated PBMC. There was a significant difference in IL-1ß production among the study groups at 24 h (F(2,99) = 3.68; P < 0.03; Fig. 3A). Levels of IL-1ß were increased in the IOR and PCA groups and remained unchanged in the PCEA group. This increase was significant at 24 h and gradually diminished by 72 h.



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  		Figure 3. Production of (A) interleukin-1ß (IL-1ß) and (B) IL-6 by peripheral blood mononuclear cells in the three pain management groups of intermittent opiate regimen (IOR), patient-controlled analgesia (PCA), or patient-controlled epidural analgesia (PCEA). Data are expressed as difference scores of postoperative minus preoperative values and presented as mean (± SEM). Levels of both proinflammatory cytokines were more increased in the IOR and PCA groups and least increased in the PCEA group.

 
There was a significant difference in IL-6 production among the study groups at 72 h (F(2,82) = 5.41; P < 0.006; Fig. 3). IL-6 levels were least increased in the PCEA group, almost returning to preoperative values by 72 h. In contrast, IL-6 levels were most increased in the IOR group and still increasing at 72 h, whereas in the PCA group, IL-6 levels were intermediate (Fig. 3B).

IL-2 production was suppressed after surgery. This suppression was most evident at 24 and 48 h after surgery, gradually recovering by 72 h. No significant differences among the study groups were observed (data not shown).

Confirming our previous findings (14), natural killer cell cytotoxicity was suppressed in all study groups at 24 h, partially recovering to preoperative values by 72 h after surgery. No significant differences among the study groups were observed (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Patients in the PCEA group experienced less severe postoperative pain, whereas those in the IOR group reported the largest VAS scores. These results were observed up to 48 hours after surgery, especially during movement, and are in accordance with earlier reports (12).

The lymphocyte proliferative response to mitogens was most suppressed in patients of the PCA group and least suppressed in patients of the PCEA group. These findings may be related to the dose of opiates administered or to the route of administration. Although the average doses of opiates received by the study groups did not seem to differ remarkably, it is hard to compare them because each group received a different opiate substance via a different route. In two groups, IOR and PCA, opiates were administered systemically, whereas in the PCEA group, fentanyl was administered epidurally. Earlier reports have shown that the immunosuppressive effects of opiates are mediated by brain opiate receptors rather than peripherally (7,16). In corroboration of the present findings, in rats, morphine suppresses lymphocyte proliferative response to mitogens when given systemically but not when given intrathecally (17).

Ex vivo production of the proinflammatory cytokines IL-1ß and IL-6 was more increased in the IOR and PCA groups compared with the PCEA group, especially at 24 hours after surgery. Patients of the first two groups were treated with opiates, whereas patients of the PCEA group were treated with a mixture of opiates and local anesthetics; this may account for the attenuated levels of proinflammatory cytokines in the PCEA group. Local anesthetics can reduce the postoperative inflammatory response in two ways: they block neural transmission at the site of tissue injury and thus may attenuate the neurogenic inflammation (18), or they have systemic antiinflammatory properties of their own (13). Brodner et al. (19) have reported that a group of patients receiving PCEA after major urologic surgery demonstrated reduced postoperative inflammatory nutrition index. The authors state that the explanation for this finding is unknown. In view of the present findings, it may be possible to attribute the reduced inflammatory response in the latter study to the use of continuous epidural analgesia, consisting of local anesthetics and opiates.

The present findings may be related to the postoperative pain experienced by patients of the three groups. Patients of the IOR and PCA groups have reported higher levels of pain while demonstrating larger production of IL-1ß and IL-6. It has been argued that nociception and proinflammatory cytokines play a mutual up-regulatory role (20); thus, increased production of proinflammatory cytokines may contribute to more severe pain and vice versa. The proinflammatory cytokines IL-1ß and IL-6 mediate hyperalgesia. IL-1ß contributes to pain mechanisms and hyperalgesia in several ways, including upregulation of Cox-2 (21), increased production of substance-P (22), and nerve growth factor (23). IL-1ß and IL-6 are involved in the mechanisms of allodynia and possibly in the development of postoperative neuropathic and chronic pain (24,25). Hyperalgesia induced by subcutaneous formalin is significantly enhanced by spinal administration of IL-1 (26) and reduced by spinal administration of IL-1ra (27), corroborating the significance of spinal IL-1 in the mechanisms of inflammatory hyperalgesia.

Because of the feedback cascade between nociception and proinflammatory cytokines, it is also possible that the experience of pain contributes to higher levels of proinflammatory cytokines. Peripheral nerve injury activates glia cells, which in turn increase the production of proinflammatory cytokines in the central nervous system (CNS). Increased levels of proinflammatory cytokines in the CNS leads to neuroinflammation, central pain sensitization, and, under certain conditions, to the development of chronic or neuropathic pain in the late postoperative period (24,28). Epidural analgesia effectively reduces postoperative pain, decreases the endocrine response to surgery, and thus may attenuate surgery-induced immune alterations (29). These findings may be related to the present observation that patients in the PCEA group exhibited reduced postoperative pain and exhibited reduced production of proinflammatory cytokines. Furthermore, we have reported that patients receiving preemptive analgesia that was continued with PCEA exhibited reduced postoperative pain and reduced production of proinflammatory cytokine in comparison with those receiving PCEA alone (30).

Whether opiates in the perioperative period augment or attenuate the surgery-induced immunosuppression remains unclear. As mentioned previously, opiates in the perioperative period can modulate host-defense mechanisms and can either enhance (7) or attenuate (11) tumor metastases. Several factors may account for these conflicting results. The immune suppressive effects of opiates were observed in pain-free individuals (31) or after the administration of relatively moderate to large doses (14), whereas the beneficial effects of opiates were observed when administered in an analgesic dose to a host experiencing postoperative pain (11). It has been reported that spinal blockade, comprised of opiate and local anesthetic, attenuated the tumor-promoting effects of surgery to a greater degree than systemic opiate alone (32). This further attenuation by spinal blockade could be attributed to the use of a smaller dose of morphine in combination with local anesthetic and to the route of administration.

In conclusion, the present study shows that patients in the PCEA group exhibited reduced postoperative pain, reduced suppression of lymphocyte proliferative response to mitogens, and attenuated proinflammatory cytokine response to surgery. Other studies have reported that attenuating surgery-associated immunosuppression by regional analgesia may reduce the incidence of postoperative infection (33) and the risk of metastatic development (32). Furthermore, proinflammatory cytokines are key mediators of illness symptoms (34); their attenuation in the PCEA group may have contributed to attenuated illness response, to reduced postoperative pain, and possibly to reduced risk of developing chronic pain.


   Acknowledgments
 
Supported, in part, by a grant no. 3701 from the Chief Scientist’s Office of the Ministry of Health, Israel, and a grant from the Hebrew University Intramural Research Fund-Basic Project Award (YS). Facilitated by the Leon and Clara Sznajderman Chair of Psychology (YS).


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 7, 2003.




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C.-T. Wu, S.-W. Jao, C. O. Borel, C.-C. Yeh, C.-Y. Li, C.-H. Lu, and C.-S. Wong
The Effect of Epidural Clonidine on Perioperative Cytokine Response, Postoperative Pain, and Bowel Function in Patients Undergoing Colorectal Surgery
Anesth. Analg., August 1, 2004; 99(2): 502 - 509.
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press