For many years, it has been known that undergoing and recovering from surgery suppresses immune function; however, the possibility that pain is a mediator of such consequences has been studied only in the past 15 years. Only 20 years ago, the first study exploring the impact of nontissue damaging painful stress on the immune system emerged.1 Studies regarding pain management and immune sequelae of surgery in both humans and animals has been accelerating since the early 1990s. This article provides a critical summary of human and animal investigations focusing on the hypothesis that pain is a significant mediator of surgery-induced immune suppression and also provides evidence supporting the suggestion that relieving pain improves surgery outcomes.

Immune Function Outcomes: A Brief Primer

The immune system can be conceptualized as two integrated systems that communicate with each other, as well as with the neuroendocrine system. Granulocytes, macrophages, and natural killer (NK) and dendritic cells are constituents of the innate immune system, the first line of defense against antigens such as bacteria, viruses, and some types of circulating tumor cells. Humoral or adaptive immunity comprises the antibody mediated adaptive functions that require more time to respond, as specific antibodies are developed in response to antigen exposure. The innate and adaptive systems are integrally related in that innate responses to an antigen include presenting the antigen for antibody production and the production of cytokines to stimulate adaptive responses. There is generally a balance between the innate and adaptive immune systems, such that suppression of one is likely associated with enhancement of the other (see Figure 1).2

Figure 1. Innate and adaptive immune systems and their cell populations depicted as a balance between systems. Increased activity by one system is generally balanced by a decrease in activity of the other system.

A key cell population that is a focus of many postoperative immune function studies is the NK cell, a subpopulation of large granular lymphocytes. Without prior sensitization, NK cells recognize and kill an array of virally infected and tumor targets, and initiate protection from some types of bacterial pathogens.3 The cytotoxic activity of NK cells can be assessed in the dish, ex-vivo, against tumor or virally derived target cells, and is a strong indicator of innate immune competence. Blood is withdrawn, processed, and co-incubated with radiolabeled target cells, such that the killing of the target cell releases the radioactive compound from the cytoplasm so it can be measured in a gamma counter.

A second and highly important function of the immune system is the production of cytokines, protein products of cell activation, that affect the function of the cells themselves in autocrine fashion or other cells both in close proximity, paracrine, or distant from the producing cell, endocrine.2,4 Cytokine production reflects immune cell activation, so an increase in the level of a given cytokine reflects the activation of one or more types of immune cells, giving a rough picture of immune responsiveness. Changes in the balance of circulating cytokines can affect immune cell function, as well as the function of other cells, notably those in the peripheral and central nervous system. For example, local inflammatory cytokines associated with tissue damage, such as tumor necrosis factor (TNF), interleukins (IL) IL-1 and IL-6, effectively reduce the activation threshold of peripheral nociceptors, resulting in greater sensitivity to pain impulse transmission to the brain.5 Further, increases in the production of inflammatory cytokines in the brain, as is common in infection, underlies the sickness behavior symptom cluster, including fever, malaise, anhedonia, and fatigue.6

Cytokines can be measured in plasma as a snapshot at the time of blood withdrawal or their production can be assessed in stimulation assays following incubation with an immune stimulant for 24 to 48 hours. Cytokine production can be stimulated using mitogens, such as lipopolysaccharide (LPS) or phytohemagglutinin (PHA), to reflect immune cell responsiveness and enable direct comparison of individual responses to a similar level of activation, mitogen dose. Stimulation assays are becoming more common in studies assessing potential consequences of surgery on the functional balance between innate and adaptive immunity. In general, cytokines that promote innate immune activity reduce humoral immunity and vice versa.

Cytokine nomenclature is often referred to as Th1 and Th2, relating to T lymphocytes, a subset of lymphocytes that do not produce antibody. T lymphocytes are active in cell-mediated immunity (CMI). In general, Th1 cytokines promote innate immune functions and Th2 cytokines promote humoral immunity, suppressing macrophage function, again reflecting a balance between these two modes of immune defense.4Table 1 provides a summary of selected cytokines and their actions.

TABLE 1. Selected Cytokines: Origins and Actions

Surgery Exerts Global Suppression of Immune Functions

There are widespread and significant surgery-induced alterations in an array of immune functions, including NK cell activity, lymphocyte cell numbers and proliferation, and cytokine secretion by immune cells in response to mitogen stimulation. NK cell activity is suppressed within hours of surgery and lasts for days,7-10 and has been shown to be more prolonged in individuals with cancer,7 although not consistently.8 Several studies have shown by direct comparison that a more invasive surgery is associated with a greater magnitude of NK suppression.7,11 Although there are some studies in humans in which no surgery-induced NK suppression is evident,12 there is substantial corroboration in animal studies that undergoing and recovering from surgery is a powerful suppressor of NK activity13-15 and that greater surgical invasiveness yields greater decrements in NK cell activity.16 Taken together, these findings show that individuals undergoing major surgery for cancer are at greatest risk for a profound reduction in NK cell activity that is also the longest lasting.

Because macrophages and NK cells are among the first response immune cells, their communications with other immune cells via cytokine production is highly important in assessing the immune consequences of surgery, with particular implications for postsurgical infection. In addition to evidence of a primary suppressive factor from surgery on NK cells,10 local factors released from damaged tissue, such as prostaglandins, are well-known contributors to inflammation and hence, inflammatory cytokine production.17 Tumor necrosis factor, IL-1, and IL-6 are key inflammatory cytokines that have been associated with surgery-induced decrements in immune functions including CMI18,19 and NK cell activity in both humans7 and animals.20 IL-6 production was also shown to be greater in more versus less invasive surgery.11

Conceptualizing the Role of Pain in Surgery-induced Immune Suppression

Given that pain is an exquisite stressor with both psychological and biological components, an important issue is the relative contribution of these two aspects of the pain experience to the outcome. Nonpainful stressors, such as public speaking and medical examinations, have been studied extensively and are well-known to be immune suppressive.21,22 Activation of the central nervous system (CNS) and hypothalamic-pituitary-adrenal (HPA) axis pathways affects immune function via multiple mechanisms and, in turn, the immune system also interacts with the CNS and HPA axis. Painful stressors that do not involve tissue damage have also been shown to suppress immune function in both humans (cold pressor)23 and animals (footshock).24

An additional major complication with regard to surgery-induced pain is the requisite tissue damage and associated release of local factors that lead to inflammation. In addition to promoting the early healing process, factors released from injured tissue, as well as those released by phagocytes attracted to the injury site, affect immune competence.25 Local inflammatory changes are a robust initiator of hyperalgesia (an exaggerated pain response to a painful stimulus) as well as allodynia (a pain response to a stimulus that would not normally cause pain).

The assessment of neuroendocrine and immune responses to a stressor requires consideration of several issues that relate to both the stressor and the methods for data acquisition. The interactions among the neuroendocrine and immune system are dynamic, and most reports of biologic responses to stress are a snapshot of the outcome at a discrete sampling time or several sampling times. Given the dynamic nature of biologic responses to stress, varying the sampling time can give very different findings. For example, sympathetic activation mobilizes white blood cell (WBC) subpopulations from the marginating pool at stressor onset and cells return to the marginating pool over time upon stress resolution, and [beta]-adrenergic receptors on NK cells mediate suppression of their cytotoxic abilities.26 Given that changes in NK cell activity can be related to cytotoxic activity per NK cell or a change in the concentration of circulating NK cells per volume of blood, variations in the timing of blood withdrawal relative to the stressor can lead to quite different numbers of circulating NK cells and quite different levels of circulating catecholamines. Current techniques for assessing NK cell activity typically include co-incubation of a specific number of target cells with a specific number of peripheral mononuclear blood cells (PMBC), of which NK cells are a subpopulation; thus, changes in the concentration of NK cells within the PMBC population could underlie observed differences in NK activity. Unless NK cells are specifically counted, it is unknown whether differences are attributable to this change in cell concentration or the cytotoxic activity per NK cell. NK cell counts are not typically assessed in clinical studies.7-9,27,28 A recent provocative study29 is a case in which electric shock was shown to be NK-enhancing, possibly due to a greater percentage of NK cells within the WBC population that was co-incubated with target cells in the ex-vivo assay.

There are a substantial number of studies that have tested the impact of pain-relieving anesthesia techniques or perioperative analgesia administration on surgery-induced immune suppression. In large part, interventions directed toward the reduction of surgery-induced inflammation have relieved suppression of CMI,18 or reduced circulating levels,30,31 or production32,33 of inflammatory cytokines. Opioid administration is less clear; however, low dose fentanyl was shown to be associated with earlier recovery of NK cell activity,8 and tramadol improved NK activity early in the postoperative period.12

A more effective anesthesia technique for pain management is the complete block of ascending afferent transmission via spinal or epidural injection of local anesthesia or opioids; however, this strategy is most effective for surgery below the waist. There is consistent evidence that the use of local anesthetics reduces the immune consequences of surgery including the reduction of NK cell activity suppression,27,28 maintenance of Th1 cell numbers,34,35 and the reduction of IL-1[beta] and IL-6 production with increased IL-2 production.36 Importantly, Beilin et al36 also showed their epidural regimen reduced postoperative pain levels. Although spinal or epidural opioids have been shown to be effective in combination with local anesthetics in ameliorating the immune consequences of surgery,28,35,36 the benefits of spinal or epidural opioids alone are less apparent.37,38

The Biological Consequences of Postoperative Pain

The biological consequences of the above-mentioned, ex-vivo alterations are difficult to assess. For example, the amount of immune suppression necessary to result in greater risk for infection or some other surgery-associated health consequence is not known and is often a point of discussion in studies using ex-vivo immune outcomes. A handful of studies in humans provide some support for the suggestion that pain plays a role in health outcomes related to surgery-induced immune suppression. As opposed to open abdominal rectopexy, laparoscopic rectopexy was associated with fewer morbidities, as well as lower surgery-associated stress measures including serum cortisol and C-reactive protein, and urinary secretion of catecholamines.11 Postoperative indomethacin administration was associated with a reduced rate of opportunistic infections,18 as was epidural block.39,40 Pain reduction strategies also enable patients to more rapidly recover mobility and promote earlier discharge and also are important factors in the observed improvement in operative outcomes.

There is a substantial literature showing that low NK cell activity during the perioperative period for cancer surgery is associated with higher rates of cancer recurrence and mortality in patients with colorectal,41-43 breast,44 head and neck,45 and lung cancers.46 This evidence corroborates the animal literature that has provided causal evidence that NK cells are key defenders against metastatic development. Further, and important to this review, it is this evidence that also supports the hypothesis that pain per se is a mediator of surgery-induced suppression of NK activity.

It has been determined by using well-established mouse and rat tumor models that NK cells are crucial in controlling metastatic development. Whereas the administration of antibodies or drugs that disable NK cells has been shown to result in greatly increased susceptibility to metastasis,47 augmenting NK activity is protective against metastatic development.48 By using tumor lines that are controlled by NK cells, findings would have implications for both in vivo NK function and in metastatic susceptibility, thus providing some indication of possible biologic consequences of NK suppression. Admittedly, no animal tumor model is an ideal reflection of the complete metastatic process; however, when thoughtfully employed, tumor models can provide a means by which to causally attribute factors, such as pain, to immune alterations, as well as providing a measurable biologic consequence of surgery.

Surgery has long been known to promote metastatic development.49 The first publication testing the possible benefit of providing perioperative analgesia on surgery-induced increases in tumor growth was published only 14 years ago and showed that the provision of morphine before and after major abdominal surgery significantly reduced the tumor burden of a colon carcinoma cell line.50 Subsequent to this study, multiple reports of various analgesia interventions have been shown to decrease surgery-induced enhancement of metastatic outcomes, including the systemic administration of opioids, such as morphine,51-53 fentanyl,54 and tramadol,12 and the nonsteroidal anti-inflammatory drug (NSAID), indomethacin.20,55 Additionally, spinal injection of a local anesthetic combined with a very low dose of morphine also ameliorated surgery-induced increases in metastatic susceptibility.54,56 Taken together, it could be suggested that providing pain relief is protective against surgery-induced increases in metastasis. Important to this suggestion, several studies also documented postoperative behaviors consistent with the relief of surgical pain.20,51,53

With the exception of the inaugural study50 using the colon carcinoma cell line, all of the above studies employed an experimental design that provided adequate controls for defending against some specific effect of the drugs on the tumor or on the animal. Most used a simple 2x2 design, surgery versus control by drug treatment versus no treatment. In virtually all studies, whereas the drug did little or compromised host tumor resistance in the unoperated animals, among the operated animals, the provision of analgesia improved host tumor resistance. Thus, one could infer that only in the context of surgery and the associated postoperative pain, opioids, NSAIDs, and spinal anesthesia and analgesia provided protection against the tumor-enhancing, NK-suppressing, effects of the surgery. This distinction is an important one, as there is a consistent literature showing that opioids are immune suppressive or tumor enhancing.57-59 These latter opioid and immune studies were undertaken in otherwise normal animals and the opioid doses were typically greater than necessary to provide analgesia, suggesting that in the organism without pain, opioids are indeed harmful. The interaction between the pain and the opioid is key in attributing improved post-surgical metastatic outcomes to the beneficial effects of opioids.

Summary

There is strong evidence that undergoing and recovering from surgery suppresses immune function and that the invasiveness of the surgery, as well as the preoperative health of the individual, is a moderator of these effects. That the pain of undergoing and recovering from surgery is a mediator of surgery-induced immune suppression is supported by studies in humans showing pain-relieving anesthesia and analgesia techniques ameliorate some degree of postoperative immune suppression. In vivo experimental evidence in animals provides causal evidence that perioperative pain relief improves surgery-induced decreases in host resistance against metastatic development, providing one example of a biologic consequence of immune suppression. Although it cannot be assumed that findings in animals can be directly applied to the human situation, one must consider the possibility that if such biological relationships hold in humans, perioperative pain management becomes more than a matter of patient comfort, it becomes a matter of physiologic necessity.

References