Exploring the neuroimmunopharmacology of opioids: an integrative review of mechanisms of central immune signaling and their implications for opioid analgesia.

Vastly stimulated by the discovery of opioid receptors in the early 1970s, preclinical and clinical research was directed at the study of stereoselective neuronal actions of opioids, especially those played in their crucial analgesic role. However, during the past decade, a new appreciation of the non-neuronal actions of opioids has emerged from preclinical research, with specific appreciation for the nonclassic and nonstereoselective sites of action. Opioid activity at Toll-like receptors, newly recognized innate immune pattern recognition receptors, adds substantially to this unfolding story. It is now apparent from molecular and rodent data that these newly identified signaling events significantly modify the pharmacodynamics of opioids by eliciting proinflammatory reactivity from glia, the immunocompetent cells of the central nervous system. These central immune signaling events, including the release of cytokines and chemokines and the associated disruption of glutamate homeostasis, cause elevated neuronal excitability, which subsequently decreases opioid analgesic efficacy and leads to heightened pain states. This review will examine the current preclinical literature of opioid-induced central immune signaling mediated by classic and nonclassic opioid receptors. A unification of the preclinical pharmacology, neuroscience, and immunology of opioids now provides new insights into common mechanisms of chronic pain, naive tolerance, analgesic tolerance, opioid-induced hyperalgesia, and allodynia. Novel pharmacological targets for future drug development are discussed in the hope that disease-modifying chronic pain treatments arising from the appreciation of opioid-induced central immune signaling may become practical.

Does intraoperative ketamine attenuate inflammatory reactivity following surgery? A systematic review and meta-analysis.

BACKGROUND: Reports regarding the ability of the anesthetic drug ketamine to attenuate the inflammatory response to surgery are conflicting. In this systematic review we examined the effect of perioperative ketamine administration on postoperative inflammation as assessed by concentrations of the biomarker interleukin-6 (IL-6). METHODS: This study was based on a systematic search in PubMed, Scopus, Web of Knowledge, and the Cochrane Library. English written randomized controlled trials conducted in humans were eligible. To be included in the analysis, outcome had to relate to inflammation or immune modulation. Each study was reviewed independently by 2 assessors. Data were analyzed according to the GRADE's approach and reported in compliance with the PRISMA recommendations. RESULTS: Fourteen studies were eligible for evaluation (684 patients). Surgery was performed under general anesthesia, and ketamine was given before or during the surgery in varied doses Eight studies involved cardiopulmonary bypass operations, 4 were for abdominal surgery, 1 thoracic surgery, and 1 cataract surgery. Three studies were deemed of low quality. Nine studies measured IL-6 concentrations within the first 6 hours postoperatively; but in 3 studies, other potent anti-inflammatory drugs were used as premedication or during the operation; thus 6 studies (n = 331) were included in the meta-analysis. Using postoperative IL-6 concentrations as an outcome, ketamine had an anti-inflammatory effect; the meta-analysis showed a mean preoperative-postoperative IL-6 concentration difference (95% confidence interval) of -71 (-101 to -41) pg/mL. CONCLUSIONS: It can be concluded that intraoperative administration of ketamine significantly inhibits the early postoperative IL-6 inflammatory response. Future studies should further examine the anti-inflammatory effect of ketamine during major surgery, determine whether ketamine treatment alters functional outcomes, elucidate the mechanisms of its anti-inflammatory effect, and suggest an appropriate dosing regimen.

Interleukin-1 signaling is required for induction and maintenance of postoperative incisional pain: genetic and pharmacological studies in mice.

Postoperative incisional pain is characterized by persistent acute pain in the area of the cut, and is associated with release of proinflammatory cytokines, including interleukin-1 (IL-1), which play important hyperalgesic and allodynic roles in various inflammatory conditions. In the present study, we tested the role of IL-1 signaling in postoperative incisional pain using three mouse strains impaired in IL-1 signaling due to deletion of the IL-1 type I receptor on a mixed genetic background (IL-1rKO) or congenic background (IL-1rKOCog), or due to transgenic over-expression of IL-1 receptor antagonist (IL-1raTG). We used the relevant wild-type (WT) mice both as controls for the mutant strains, and for assessing the effects of pharmacological blockade of IL-1-signaling. Mechanosensitivity was assessed using the von-Frey filament test before, and up to 4 days following plantar incision, an animal model of postoperative pain. WT mice developed significant allodynia in the incised, compared with the intact, hind-paw beginning 3h after the incision and lasting up to 48h postoperatively. In contrast, IL-1rKO, IL-1rKOCog, and IL-1raTG mice, as well as WT mice chronically treated with IL-1ra, did not display increased mechanical pain sensitivity in either hind-paw. To test the hypothesis that IL-1-signaling is also involved in the maintenance of postoperative pain, WT mice were acutely treated with IL-1ra 24h following the incision, when allodynia was already evident. This treatment reversed the allodynic response throughout the observation period. Together, these findings suggest that IL-1 plays a critical role in the development and maintenance of postoperative incisional pain.

Cytokines and cholinergic signals co-modulate surgical stress-induced changes in mood and memory.

Inflammatory cytokines and the cholinergic system have been implicated in the effects of stressors on mood and memory; however, the underlying mechanisms involved and the potential interrelationships between these pathways remain unclear. To address these questions, we administered neuropsychological tests to 33 generally healthy surgery patients who donated blood samples several days prior to undergoing moderate surgery (baseline), on the morning of the surgery (i.e., a psychological stressor), and one day after surgery. Eighteen control subjects were similarly tested. Serum levels of inflammatory cytokines, acetylcholinesterase (AChE) activity, and the stressor-inducible AChE-R variant were measured. An elevation in anxiety levels, an increase in depressed mood, and a decline in declarative memory were observed on the morning of the surgery, prior to any medical intervention, and were exacerbated one day after surgery. The surgical stressor-induced elevated IL-1 beta levels, which contributed to the increased depressed mood and to the post-surgery increase in AChE-R expression. The latter increase, which was also predicted by pre-surgery AChE-R and post-surgery mood disturbances, was associated with exacerbated memory impairments induced by surgery. In addition, elevated levels of AChE-R on the morning of the surgery predicted the post-surgery elevation in IL-6 levels, which was associated with amelioration of the memory impairments induced by surgery. Taken together, these findings suggest that exposure to a surgical stressor induces a reciprocal up-regulation of AChE-R and pro-inflammatory cytokines, which are involved in regulating the surgery-induced mood and memory disturbances.

IL-1 beta signaling is required for mechanical allodynia induced by nerve injury and for the ensuing reduction in spinal cord neuronal GRK2.

Many neurotransmitters involved in pain perception transmit signals via G protein-coupled receptors (GPCRs). GPCR kinase 2 (GRK2) regulates agonist-induced desensitization and signaling of multiple GPCRs and interacts with downstream molecules with consequences for signaling. In general, low GRK2 levels are associated with increased responses to agonist stimulation of GPCRs. Recently, we reported that in mice with reduced GRK2 levels, inflammation-induced mechanical allodynia was increased. In addition, mice with impaired interleukin (IL)-1 beta signaling did not develop mechanical allodynia after L5 spinal nerve transection (SNT). We hypothesized that in the L5 SNT model mechanical allodynia would be associated with reduced neuronal GRK2 levels in the spinal cord dorsal horn and that IL-1 beta signaling would be required to induce both the decrease in GRK2 and mechanical allodynia. We show here that in wild type (WT) mice L5 SNT induces a bilateral decrease in neuronal GRK2 expression in the lumbar spinal cord dorsal horn, 1 and 2 weeks after L5 SNT. No changes in GRK2 were observed in the thoracic segments. Moreover, spinal cord GRK2 expression was not decreased in IL-1R(-/-) mice after L5 SNT. These data show that IL-1 beta signaling is not only required for the development of mechanical allodynia, but also to reduce neuronal GRK2 expression. These results suggest a functional relation between the L5 SNT-induced IL-1 beta-mediated decrease in GRK2 and development of mechanical allodynia.

Genetic impairment of interleukin-1 signaling attenuates neuropathic pain, autotomy, and spontaneous ectopic neuronal activity, following nerve injury in mice.

Peripheral nerve injury may lead to neuropathic pain, which is often associated with mechanical and thermal allodynia, ectopic discharge of from injured nerves and from the dorsal root ganglion neurons, and elevated levels of proinflammatory cytokines, particularly interleukin-1 (IL-1). In the present study, we tested the role of IL-1 in neuropathic pain models using two mouse strains impaired in IL-1 signaling: Deletion of the IL-1 receptor type I (IL-1rKO) and transgenic over-expression of the IL-1 receptor antagonist (IL-1raTG). Neuropathy was induced by cutting the L5 spinal nerve on one side, following which mechanical and thermal pain sensitivity was measured. Wild-type (WT) mice and the parent strains developed significant allodynia and hyperalgesia in the hind-paw ipsilateral to the injury compared with the contralateral hind-paw. The mutant strains, however, did not display decreased pain threshold in either hind-paw. Pain behavior was also assessed by cutting the sciatic and saphenous nerves and measuring autotomy scores. WT mice developed progressive autotomy, beginning at 7 days post-injury, whereas the mutant strains displayed delayed onset of autotomy and markedly reduced severity of the autotomy score. Electrophysiological assessment revealed that in WT mice a significant proportion of the dorsal root axons exhibited spontaneous ectopic activity at 1, 3, and 7 days following spinal nerve injury, whereas in IL-1rKO and IL-1raTG mice only a minimal number of axons exhibited such activity. Taken together, these results suggest that IL-1 signaling plays an important role in neuropathic pain and in the altered neuronal activity that underlies its development.

The transition from naïve to primed nociceptive state: A novel wind-up protocol in mice.

Wind-up (WU) is a progressive, frequency-dependent facilitation of spinal cord neurons in response to repetitive nociceptive stimulation of constant intensity. We identified a new WU-associated phenomenon in naïve mice (not exposed to noxious stimulation immediately prior to WU stimulation), which were subjected to a novel experimental protocol composed of three consecutive trains of WU stimulation. The 1st train produced a typical linear 'wind-up' curve as expected following a repeating series of stimuli; in addition, this 1st train sensitized ('primed') the nociceptive system so that the responses to two subsequent trains (inter-train interval of 10 min) were significantly amplified compared with the response to the 1st train. We named this augmented response potentiation-of-windup, or "PoW". The PoW phenomenon appears to be centrally mediated, as the augmented response was suppressed by administration of an NMDA receptor antagonist (MK-801) and by cutting the spinal cord. Furthermore, the PoW protocol is accompanied by enhanced pain behavior. The 'priming' effect of the 1st train could be mimicked by exposure to natural noxious stimuli prior to the PoW protocol. Presumably, the PoW phenomenon has not been previously reported due to a procedural reason: typically, WU protocols have been executed in 'primed' rather than naïve animals, i.e., animals exposed to nociceptive stimulation prior to the actual WU recording. Our findings indicate that the PoW paradigm can distinguish between 'naïve' and 'primed' states, suggesting its use as a tool for the assessment of central sensitization.

Interleukin-1 antagonizes morphine analgesia and underlies morphine tolerance.

Pain sensitivity reflects a balance between pain facilitatory and inhibitory systems. To characterize the relationships between these systems we examined the interactions between the analgesic effects of morphine and the anti-analgesic effects of the pro-inflammatory cytokine interleukin-1 (IL-1). We report that administration of a neutral dose of IL-1beta abolished morphine analgesia in mice, whereas acute or chronic blockade of IL-1 signaling by various IL-1 blockers (IL-1 receptor antagonist (IL-1ra), alpha-melanocyte-stimulating hormone, or IL-1 tri-peptide antagonist) significantly prolonged and potentiated morphine analgesia. Morphine-induced analgesia was also extended in strains of mice genetically impaired in IL-1 signaling (mice with transgenic over-expression of IL-1 receptor antagonist, deletion of the IL-1 receptor type I, or deletion of the IL-1 receptor accessory protein). The finding that IL-1 produces a marked anti-analgesic effect, suggests that it may also be involved in the development of opiate tolerance. Indeed, genetic or pharmacological blockade of IL-1 signaling prevented the development of tolerance following repeated morphine administration. Moreover, acute administration of IL-1ra in wild type mice, either immediately following the cessation of acute morphine analgesia, or following the development of chronic morphine tolerance, re-instated the analgesia, suggesting that blockade of the IL-1 system unmasks the analgesic effect of morphine. These findings suggest that morphine produces an IL-1-mediated homeostatic response, which serves to limit the duration and extent of morphine analgesia and which underlies the development of tolerance.

Effects of surgical stress on brain prostaglandin E2 production and on the pituitary-adrenal axis: attenuation by preemptive analgesia and by central amygdala lesion.

Surgical stress is the combined result of tissue injury, anesthesia, and postoperative pain. It is characterized by elevated levels of adrenocorticotropin (ACTH), corticosterone (CS), and elevated levels of prostaglandin E2 (PGE2) in the periphery and in the spinal cord. The present study examined the effects of perioperative pain management in rats undergoing laparotomy on serum levels of ACTH, CS, and on the production of PGE2 in several brain regions, including the amygdala. The amygdala is known to modulate the pituitary-adrenal axis response to stress. We, therefore, also examined the effects of bilateral lesions in the central amygdala (CeA) on laparotomy-induced activation of the pituitary-adrenal axis in rats. In the first experiment, rats either underwent laparotomy or were not operated upon. Half the rats received preemptive analgesia extended postoperatively, the other received saline. ACTH, CS serum levels, and ex vivo brain production of PGE2 were determined. In the second experiment, rats underwent bilateral lesions of the CeA. Ten days later, rats underwent laparotomy, and ACTH and CS serum levels were determined. Laparotomy significantly increased amygdala PGE2 production, and CS and ACTH serum levels. This elevation was markedly attenuated by perioperative analgesia. Bilateral CeA lesions also attenuated the pituitary-adrenal response to surgical stress. The present findings suggest that the amygdala plays a regulatory role in mediating the neuroendocrine response to surgical stress. Effective perioperative analgesia attenuated the surgery-induced activation of pituitary-adrenal axis and PGE2 elevation. The diminished elevation of PGE2 may suggest a mechanism by which pain relief mitigates pituitary-adrenal axis activation.

Impairment of interleukin-1 (IL-1) signaling reduces basal pain sensitivity in mice: genetic, pharmacological and developmental aspects.

The cytokine interleukin-1 (IL-1) has been implicated in modulation of pain perception under various inflammatory conditions. The present study examined the hypothesis that IL-1 signaling is also involved in pain sensitivity under normal, non-inflammatory states, using three mouse models of impaired IL-1 signaling: targeted deletion of the IL-1 receptor type I or the IL-1 receptor accessory protein, and transgenic over-expression of IL-1 receptor antagonist within the brain and spinal cord. Thermal and mechanical pain sensitivity was assessed using the paw-flick, hot-plate, and von Frey tests. All mutant strains displayed significantly lower pain sensitivity, compared with their respective wild-type control strains, and with their parent strains (C57BL/6, CBA and 129), in all tests. In contrast, mice with targeted deletion of the p55 or p75 TNF receptor, or of interleukin-18, displayed normal or higher pain sensitivity compared to their respective controls. To differentiate between developmental vs. on-going effects of IL-1, mice were chronically treated with IL-1 receptor antagonist (IL-1ra) via osmotic micropumps, either in adulthood or prenatally (throughout the last 2 weeks of gestation). Adult mice that were treated with IL-1ra either in adulthood or in utero, displayed lower pain sensitivity, similar to mice with impaired IL-1 signaling. These findings suggest that basal pain sensitivity is genetically, developmentally and tonically influenced by IL-1 signaling.

Neuropsychological functioning in major depression and responsiveness to selective serotonin reuptake inhibitors antidepressants.

BACKGROUND: Only two thirds of patients with major depression (MD) respond to antidepressants. Thus, far applicable predictors of responsiveness to selective serotonergic reuptake inhibitors (SSRIs) have not been found. Cumulative evidence linking serotonergic depletion and cognition led us to hypothesize that the neuropsychological functioning of major depression patients may predict their responsiveness to SSRI antidepressants. METHODS: Fifty-five patients meeting DSM-IV criteria for major depression and strict inclusion and exclusion criteria underwent an extensive clinical and neuropsychological assessment prior to the initiation of selective serotonergic treatment. Following 6 weeks of treatment, severity of depression was reassessed, yielding a responsiveness score by which classification of each subject as a responder or nonresponder was made. The study was double blind. RESULTS: Logistic regression yielded neuropsychological indices, which significantly predicted the probability of depressed patients to respond favorably to SSRIs. Responders were characterized by better functioning in "simple" tasks and by worse functioning in "complex" tasks compared to nonresponders. No differences were found for more lateralized right or left hemisphere functions between responders and nonresponders. LIMITATIONS: Drug treatment comprised of SSRIs but was not standardized. Responsiveness was assessed following 6 weeks of treatment providing for initial amelioration rather than full remission. Placebo response was not controlled for. These limitations may influence the interpretation of the findings. CONCLUSIONS: The present findings suggest that responders and nonresponders to SSRIs might be distinguished by their neuropsychological functioning before treatment. If our findings are replicated, more efficient treatment might be practiced.

Chronic blockade of interleukin-1 (IL-1) prevents and attenuates neuropathic pain behavior and spontaneous ectopic neuronal activity following nerve injury.

Neuropathic pain is a chronic pain state resulting from peripheral nerve injury, characterized by hyperalgesia and allodynia. We have reported that mice with genetic impairment of IL-1 signaling display attenuated neuropathic pain behavior and ectopic neuronal activity. In order to substantiate the role of IL-1 in neuropathic pain, WT mice were implanted subcutaneously with osmotic micropumps containing either IL-1ra or vehicle. Two days following the implantation, two models of neuropathic pain were used; partial nerve injury (spinal nerve transection, SNT), or complete nerve cut (spinal neuroma model). Mechanosensitivity was assessed seven consecutive days following SNT, and on day 7 recordings of spontaneous ectopic activity were performed. In the spinal nerve neuroma model, autotomy scores were recorded up to 35 days. Vehicle-treated mice developed significant allodynia and autotomy, and clear ectopic activity (4.1±1.1% of the axons); whereas IL-1ra-treated mice did not display allodynic response, displayed delayed onset of autotomy and markedly reduced severity of autotomy scores, and displayed reduced spontaneous activity (0.8±0.4% of the axons). To test whether IL-1 is involved in maintenance of mechanical allodynia, a separate group of WT mice was treated with a single injection of either saline or IL-1ra four days following SNT, after the allodynic response was already manifested. Whereas saline-treated mice displayed robust allodynia, acute IL-1ra treatment induced long-lasting attenuation of the allodynic response. The results support our hypothesis that IL-1 signaling plays an important role in neuropathic pain and in the ectopic neuronal activity that underling its development.

Comparison of two patient-controlled analgesia techniques on neuropsychological functioning in the immediate postoperative period.

Pain may contribute to cognitive decline, which is a common complication in the early postoperative period. We compared the effects of two common pain management techniques, intravenous patient-controlled analgesia (PCA-IV) and patient-controlled epidural analgesia (PCEA), on cognitive functioning in the immediate postoperative period. Patients hospitalized for elective surgery were randomly assigned to one of the treatment groups (30 patients per group). A battery of objective, standardized neuropsychological tests was administered preoperatively and 24 hours after surgery. Pain intensity was also evaluated. Nonoperated volunteers served as controls. Patients of the PCA-IV group exhibited significantly higher pain scores than did patients of the PCEA group. PCA-IV patients exhibited significant deterioration in the postoperative period in all the neuropsychological measures, while the PCEA patients exhibited significant deterioration only in one cognitive index, compared to controls.

Comparison of postoperative pain management techniques on endocrine response to surgery: a randomised controlled trial.

The present study compared three postoperative pain management techniques in patients undergoing lower abdominal surgery: intermittent opiate regimen (IOR), patient-controlled analgesia (PCA), and patient-controlled epidural analgesia (PCEA), on cortisol and prolactin levels during the first 48 h postoperatively. Ninety-two patients scheduled for a lower abdominal surgery, were randomly assigned to one of three study groups: IOR (N=31), PCA (N=31), and PCEA (N=30). Patients of the IOR group received postoperatively 50-75 mg of pethidine IM on demand. Patients of the PCA group received a loading dose of morphine (3-4 mg), followed by 1mg bolus of morphine IV per demand. Patients of the PCEA group received 3 ml of 0.1% bupivacaine plus 2 microg/ml of fentanyl per demand, with continuous background infusion of 6ml/h. Venous blood samples were collected preoperatively, and 24 and 48 h after surgery, and were later assayed for serum cortisol and prolactin levels. Patients of the PCEA group exhibited diminished postoperative elevation of serum cortisol levels at 24 and 48 h (24.4, 18.6 microg/dl, respectively) compared with both IOR (31.9, 21.9) and PCA (28.5, 22.3) groups. Similarly, patients of the PCEA group exhibited diminished postoperative elevation of serum prolactin level (20.7, 15.7 ng/mL) compared with PCA (24.9, 17.1) group. The present results indicate that the PCEA technique offers an advantageous treatment associated with reduced postoperative pain, and attenuated neuroendocrine response.

Postoperative pain management and proinflammatory cytokines: animal and human studies.

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. Limited evidence indicates that pain management in the postoperative period can affect the outcome of the surgery, reducing cardiac, pulmonary, and metabolic complications. Recent evidence indicates that pain and immune factors, especially proinflammatory cytokines, mutually interact and influence each other. A series of animal studies demonstrates that effective preemptive analgesia improved postoperative recovery, and this effect was enhanced by coadministration of IL-1ra together with the preemptive analgesics. Furthermore, preemptive analgesia attenuated surgery-induced PGE(2) production in the amygdala and the activation of the HPA axis. IL-1 signaling is required for the production of amygdala PGE(2) in response to surgical stress, and may thus affect the physiological and psychological aspects of surgical stress. These reports suggest that short-term effective analgesia can have long-lasting beneficial effects on surgery recovery. They further suggest that IL-1 blockade should be considered in the clinical management of pain associated with peripheral or nerve injury. Another series of human studies describes an interaction between the effectiveness of postoperative pain relief and surgery-associated immune alterations: In three separate studies, the more effective pain management technique was associated with diminished surgery-induced immune alterations, especially diminished elevation of IL-1. Reduced elevation of postoperative IL-1 and effective pain relief may both contribute to an attenuated illness response and a better surgery outcome.

The involvement of glucocorticoids and interleukin-1 in the regulation of brain prostaglandin production in response to surgical stress.

BACKGROUND: This study examined the role of glucocorticoids (GC) and interleukin-1 (IL-1) in regulating the production of brain prostaglandin E(2) (PGE(2)) in response to surgical stress. METHODS: Surgical stress was induced in rats by laparotomy or exploration of the carotid. PGE(2) ex vivo production was measured in the frontal cortex or central amygdala of adrenalectomized rats, or of rats treated with either the GC type II receptor blocker (RU38486) or synthetic GC (dexamethasone). IL-1 involvement in mediating PGE(2) response to surgical stress was examined in IL-1 receptor type I deficient (IL-1rKO) mice. RESULTS: Surgical stress elevated serum corticosterone and increased PGE(2) production by the frontal cortex and the central amygdala. A more pronounced PGE(2) response was found in adrenalectomized rats and in rats treated with RU38486, whereas administration of dexamethasone inhibited stress-induced PGE(2) production. IL-1rKO mice exhibited lower PGE(2) production in the frontal cortex under basal condition and failed to increase PGE(2) production in response to surgical stress. CONCLUSIONS: Surgical stress-induced production of brain PGE(2) is specifically regulated by GC via the mediation of type II corticosteroid receptors. Normal IL-1 signaling is required for the production of brain PGE(2) under basal conditions and in response to surgical stress.

The effects of perioperative pain management techniques on food consumption and body weight after laparotomy in rats.

UNLABELLED: We examined the effects of two perioperative pain management techniques on recovery after laparotomy, as assessed by body weight (BW) and food consumption (FC). All rats received a preoperative intrathecal mixture of morphine plus bupivacaine combined with one of two treatments: (a) injection of slow-release morphine at the end of the surgery or (b) an antiinflammatory drug, interleukin-1 receptor antagonist (IL-1ra), combined with the preoperative mixture. Laparotomy significantly decreased FC and BW. Both analgesic treatments resulted in a faster recovery of FC and BW. This beneficial effect was more pronounced in the group receiving preoperative analgesics combined with IL-1ra. IMPLICATIONS: Effective perioperative pain management can improve postoperative recovery. We studied the effects of two preoperative pain management techniques on recovery after laparotomy in rats. Both analgesic treatments resulted in a faster recovery, especially preoperative analgesics combined with interleukin-1 receptor antagonist.

Effects of fentanyl on natural killer cell activity and on resistance to tumor metastasis in rats. Dose and timing study.

OBJECTIVES: Opiates, which serve an integral role in anesthesia, suppress immune function, particularly natural killer cell cytotoxicity (NKCC). NK cells play an important role in tumor and metastasis surveillance. We reported that large-dose fentanyl anesthesia induced prolonged suppression of NKCC in patients undergoing abdominal surgery. The immune modulatory effects of opiates may depend on the interaction between dose and time of administration. The present study examined the effects of different doses of fentanyl, administered at different time points relative to tumor inoculation, on NKCC and on experimental tumor metastasis in rats. METHODS: Fischer 344 rats were injected with low or high doses of fentanyl, 6 or 2 h before, simultaneously with or 1 h after being inoculated intravenously with MADB106 tumor cells. Lung tumor retention (LTR) was assessed 4 h after, and lung tumor metastases were counted 3 weeks after tumor inoculation. NKCC was assessed 1 h after the fentanyl injection. RESULTS: At all time points, except 6 h before tumor inoculation, fentanyl (0.1-0.3 mg/kg) induced a dose-dependent increase in MADB106 LTR (2.3- to 74-fold). An intermediate dose of fentanyl (0.15 mg/kg) doubled the number of lung metastasis, and, within animal, suppressed NKCC and increased MADB106 LTR in a correlated manner. CONCLUSION: These findings indicate that fentanyl suppresses NKCC and increases the risk of tumor metastasis. Suppression of NK cells at a time when surgery may induce tumor dissemination can prove to be critical to the spread of metastases. It is suggested that the acute administration of a moderate dose of opiates during surgery should be applied cautiously, particularly in cancer patients.

The effects of postoperative pain management on immune response to surgery.

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)-1beta, 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-1beta 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.

Effects of preemptive analgesia on pain and cytokine production in the postoperative period.

BACKGROUND: The postoperative period is associated with increased production of proinflammatory cytokines, which are known to augment pain sensitivity, among other effects. In a previous study, the authors found that patients treated with patient-controlled epidural analgesia (PCEA) exhibited attenuated proinflammatory cytokine response in the postoperative period. In the present study, the authors examined whether preemptive analgesia continued with PCEA may further attenuate the proinflammatory cytokine response and reduce pain sensitivity in the postoperative period. They compared cytokine production in two groups of patients, one receiving PCEA, the other receiving preemptive epidural analgesia continued by PCEA. METHODS: Female patients hospitalized for transabdominal hysterectomy were randomly assigned to one of two pain management techniques: PCEA or preemptive epidural analgesia followed by PCEA (PA + PCEA). Postoperative pain was assessed using the visual analog scale. Blood samples were collected before, 24, 48, and 72 h following surgery. Production of the following cytokines was assessed in stimulated peripheral blood mononuclear cells: interleukin (IL)-1beta, tumor necrosis factor alpha, IL-6, IL-1ra, IL-10, and IL-2. RESULTS: Patients of the PA + PCEA group exhibited lower pain scores throughout the 72 h postoperatively, compared with patients of the PCEA group. In patients of the PA + PCEA group in the postoperative period, production of IL-1beta, IL-6, IL-1ra, and IL-10 was significantly less elevated, while IL-2 production was significantly less suppressed. CONCLUSIONS: Proinflammatory cytokines are key mediators of illness symptoms, including hyperalgesia. The present results suggest that preemptive epidural analgesia is associated with reduced postoperative pain and attenuated production of proinflammatory cytokines.