Anesth Analg 2001;93:363-369
© 2001 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Clonidine Suppresses Plasma and Cerebrospinal Fluid Concentrations of TNF-
During the Perioperative Period
Nader D. Nader, MD, PhD*,
Tracey A. Ignatowski, PhD*
,
Carlos J. Kurek, MD*,
Paul R. Knight, MD, PhD*, and
Robert N. Spengler, PhD*
Departments of *Anesthesiology and Pathology, SUNY-Buffalo, Buffalo, New York
Address correspondence and reprint requests to Nader D. Nader, MD, PhD, SUNY-Buffalo, Anesthesiology Service (128), Western New York VA Healthcare System, 3495 Bailey Ave., Buffalo, NY 14215. Address e-mail to nnader{at}med.va.gov
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Abstract
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The analgesic properties of 
2-agonists are well known. In experimental models, tumor necrosis factor (TNF)- regulates adrenergic responses in the brain. Constitutive TNF-, in brain regions involved in pain perception, is decreased after the administration of clonidine. We investigated patients undergoing lower-extremity revascularization. Seven patients were treated with clonidine 0.2 mg per os (low), and three patients received 0.4 mg per os clonidine (high) before surgery. Eight patients received placebo and served as controls. Continuous spinal anesthesia was provided by insertion of a pliable catheter into the subarachnoid space. Baseline plasma and cerebrospinal fluid (CSF) samples were obtained before injection of local anesthetic. Samples were analyzed for TNF- using a biologic assay. Systemic and central release of catecholamines were assessed by high-pressure liquid chromatography measurement of norepinephrine in plasma and CSF, vanillylmandelic acid and methoxy hydroxyl phenyl glycol in 24-h urinary excretion, respectively. Clonidine 0.2 mg pretreatment decreased TNF- concentrations both in plasma and CSF. Patients receiving clonidine had lower pain visual analog scale scores and required less morphine compared with the Placebo group (P < 0.01). Preoperative administration of clonidine decreased catecholamine release in the periphery, as well as in the central nervous system. A smaller norepinephrine concentration in plasma and CSF, and less secretion of vanillylmandelic acid (P < 0.01) and methoxy hydroxyl phenyl glycol in the urine, were observed. Larger dose clonidine (0.4 mg) resulted in no detectable TNF- in CSF. These results suggest that an interaction between TNF- and the function of adrenergic neurons in the central nervous system may contribute to the sedative and analgesic effects of adrenergic agonists.
IMPLICATIONS: Preoperative administration of clonidine decreases both plasma and cerebrospinal fluid concentrations of inflammatory cytokines, resulting in perioperative analgesia and decreased sympathetic tone.
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Introduction
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The central adrenergic nervous system has been implicated in the regulation of pain perception. The locus ceruleus (LC) contains adrenergic neuronal cell bodies representing the primary source of norepinephrine (NE) in the central nervous system (CNS) (1). NE is a neurotransmitter associated with the modulation of nociception and analgesia (2). Stimulation of presynaptic 2-adrenergic receptors located on adrenergic nerve terminals is a major mechanism involved in the auto-feedback inhibition of NE release (3). Drugs such as the 2-adrenergic agonists clonidine and dexmedetomidine act at adrenergic synapses and are useful in the management of chronic pain symptoms (4,5). Likewise, drugs that appear to modify adrenergic receptors in the CNS (e.g., amitriptyline) are effective, to varying degrees, in preventing or alleviating symptoms associated with chronic pain (allodynia, hyperalgesia) (4,6). The LC and the adjacent subceruleus also represent the major sources of noradrenergic nerve terminals to the spinal cord (7).
Coincident with increased levels of systemic proinflammatory cytokines, such as tumor necrosis factor (TNF)-, there have been reports of increases in pain perception, as well as changes in general mood status (8–10). Activation of the proinflammatory cytokine cascade, as occurs during systemic illness, can cause patients to experience mood changes, such as general malaise and somnolence; also, nondescript pain symptoms, such as polyarthralgias, myalgias, and hyperesthesia may occur (11,12). Volunteers administered TNF- IV for 1 day consistently develop lethargy and general malaise (8). Systemically administered cytokines may affect responses in the CNS; however, the regional TNF- levels achieved, as well as sites of cytokine action via this route, are not known.
A considerable amount of evidence supports a pronociceptive role for TNF- during chronic pain (9,13). Findings from our laboratory using an animal model of neuropathic pain have led us to hypothesize that proinflammatory cytokines, such as TNF-, synthesized in neurons within distinct regions of the CNS, are involved in promoting neuroplastic changes of adrenergic neurons involved in the perception of pain (14). Biologically active TNF- and TNF- mRNA can be detected in adrenergic regions of the rat brain (15–17). Therefore, we have postulated that changes in proinflammatory cytokine production by neurons within specific regions of the brain at the time of an acute insult/injury play an important role in the pathogenesis of chronic pain (14).
In the present study, we report on the role of CNS TNF- in the pathogenesis of perioperative pain. We hypothesize that central stimulation of 2-adrenergic receptors in the CNS modifies the release of TNF-, thereby decreasing the intensity of pain as well as adrenergic neurotransmission during the early postoperative period. To examine this interaction, we measured TNF- levels in the CNS as well as in the periphery and assessed the effects elicited by clonidine pretreatment.
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Methods
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The research protocol was approved by our IRB subcommittee on human subjects at VA Western New York Healthcare System. After obtaining written informed consent, 15 patients undergoing lower-extremity revascularization procedures were randomized in a prospective, double-blinded manner to receive either clonidine 0.2 mg per os or placebo before the surgery. Clonidine was administered in a divided dose (0.1 mg the night before surgery and 0.1 mg the next morning). In a nonrandomized manner, 3 additional patients were included who received a large dose of clonidine (0.4 mg in 2 divided doses, 0.2 mg the night before, and 0.2 mg the next morning). Patients undergoing surgical procedures in which continuous spinal anesthesia was indicated were eligible for this study. Exclusion criteria included patient refusal, coagulopathy, preexisting neuropathic pain, neurologic deficits, presence of previous cerebrovascular accident, allergic reaction to clonidine, and chronic administration of this medication for other pathology (e.g., hypertension).
All patients received 500 mL of lactated Ringer’s solution for prehydration in the holding area. An 18-gauge Touhy needle was advanced into the subarachnoid space and placement was confirmed by observing free flow of cerebrospinal fluid (CSF). A pliable epidural catheter (20 gauge) was introduced into the subarachnoid space and the needle was withdrawn. The catheter was taped to the skin and free flow of CSF was reconfirmed. Two milliliters of CSF and a 3-mL peripheral blood sample (3-mL tube) containing 100 U of heparin sulfate were obtained as the baseline, and then bupivacaine 6 mg was injected as an initial dose. The level of sensory and motor block was tested every 5 min, until a desirable level was obtained, and every 30 min thereafter. An additional dose of bupivacaine (2 mg) was injected whenever the highest sensory block level receded two segments.
Hypotensive episodes were treated with 200-mL boluses of fluid (lactated Ringer’s solution) and small IV boluses of phenylephrine (50–100 µg). The total amount of phenylephrine used to maintain blood pressure was recorded. Intraoperative sedation was assessed by verbal communication with the patient and graded on a scale of 0–4 as follows: 0 = normally sleeping, does not initiate a conversation, requires physical arousal; 1 = normally sleeping, does not initiate a conversation, responds to verbal command; 2 = calm but initiates conversation; 3 = frequently asks about the surgical procedure (apprehensive); and 4 = combative and complains about the position or surgery.
Postoperative CSF and plasma samples were obtained after complete recovery of motor and sensory function. The spinal catheter was removed after sampling. CSF samples were snap frozen in liquid nitrogen and stored at -70°C until examined. Blood samples were centrifuged at 1000g for 10 min at room temperature. Plasma samples were frozen and stored separately at -70°C for future testing. Urine was collected for 24 h from the time of anesthesia induction in an acidified container. Total amount of urine over 24 h was recorded, then two aliquots (30 mL) were sampled for vanillylmandelic acid (VMA) and methoxy hydroxyl phenyl glycol (MHPG) assays.
Fentanyl citrate (50–100 µg IV) was administered to all patients at the time of spinal catheter insertion. Conscious sedation for the procedure was provided with IV midazolam, as needed, and the total required dose to maintain adequate intraoperative sedation was recorded. The adequacy of conscious sedation was standardized according to the definition of the ASA.
The intensity of postoperative pain was assessed by using an average visual analog scale (VAS) of pain, from 0 to 10 (0 being pain-free and 10 being the most excruciating pain possible). VAS values were generally recorded on the chart at the end of each nursing shift according to verbal and visual chart assessment. The mean value was obtained by averaging the reported VAS score in the chart for a 24-h period. Analgesia was provided by self-administration of morphine through a pump (patient-controlled analgesia, PCA). The settings for the PCA pump were adjusted to boluses of morphine (1.5 mg) with a lockout interval of 6 min. The time for the first use of PCA and total amount of morphine (mg/kg) received in the first 24-h period were recorded.
TNF- concentrations were measured in plasma and CSF by using a fibroblast (WEHI 164, subclone 13) cytolytic assay to determine biologically active protein. Because we were interested in detecting biologically active TNF-, this assay was selected over enzyme-linked immunosorbent assay or radioimmunoassay (18–20). The sensitivity of this assay was at the picogram range. A blocking anti-TNF- antibody was used to enhance the specificity of this biologic test. Stock human TNF- (Genzyme Corp., Cambridge, MA) was used to generate a standard curve for comparison. None of the drugs (such as clonidine or morphine) had a direct influence on the WEHI assay.
Plasma and CSF samples were drawn into ice-chilled tubes containing 1.7 mg/mL EGTA and 1.1 mg/mL reduced glutathione. After centrifugation (2000g for 10 min at 4°C), the samples were frozen and stored at -80°C. The samples were then thawed on the day of experimentation and analyzed for free NE by reverse-phase high-performance liquid chromatography with electrochemical detection after alumina-batch extraction as described by Eldrup et al. (21). These compounds are stable indefinitely at this temperature (22). MHPG and VMA were measured in urine samples using liquid chromatography and electrochemical detection as described by Rizzo et al. (23). The samples (20 µL) were injected into the chromatographic system after filtration. The potential of the conditioning cell used for electrochemical detection was set at +0.40 V to oxidize most of the MHPG present in the sample. The potential of the second detector was set at -0.45 V to obtain the highest signal from the MHPG together with the lowest noise, resulting in good baseline stability. The mobile phase consisted of 25 mmol/L sodium acetate adjusted to pH 5.0 with acetic acid, and contained per liter, 100 mg of EDTA and 150 mg of heptane sulfonic acid. This mobile phase was filtered through a 0.2-µm filter.
Power analysis based on the published results of VMA and MHPG was calculated at 0.80 for the number of patients examined. Data were expressed as median values and the range was provided for each variable. The results were analyzed within groups compared with baseline by using a nonparametric repeated measures analysis of variance with Dunn post-test as appropriate. Null hypotheses were rejected at P < 0.05.
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Results
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Demographic data of the 18 patients included in this study revealed no difference between the Clonidine group and Controls for age, ASA physical status, presence of other coexisting disease, or duration of surgical procedure. Table 1 shows a summary of data obtained for preoperative pain, intraoperative sedation, and midazolam used during the intraoperative period. The dose of local anesthetic (bupivacaine) depended on the duration of the surgical procedure and was not different among cohort groups and controls. The median for the highest sensory block during surgery was similar in both groups (T8-9). There was also no difference in time of recovery from the sensory block between Clonidine and Placebo groups from the time of arrival at the postanesthesia care unit. The incidence of hypotension (>20% of baseline) and other hemodynamic variables during the intraoperative period were similar between the Clonidine and Control groups.
Plasma concentrations of TNF- increased to 164 pg/mL (range, 124–221 pg/mL) during surgery from baseline values of 62 pg/mL (45–90 pg/mL) in the Placebo group (P < 0.05). Baseline plasma concentrations of TNF- were smaller in patients treated with 0.2 mg of clonidine (47 pg/mL [25–68 pg/mL]) than those in the Placebo group. Plasma concentrations of TNF- were below the detectable range in two of three patients receiving a larger dose of clonidine. The administration of clonidine abolished both baseline and postsurgical surges of TNF- in plasma (Fig. 1, lower panel). Concentrations of TNF- in the CSF were closely related to plasma concentrations. Surgical stimulus resulted in increased concentrations of TNF- in the CSF. The Clonidine-Treated group demonstrated decreased levels of TNF-, both preoperatively and immediately after surgery (Fig. 1, upper panel).
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Figure 1. Seven patients were treated with 0.2 mg of clonidine (C and D) and three patients with 0.4 mg of clonidine (E and F), preoperatively. Eight patients were used as the Placebo Control group (A and B). Samples were obtained preoperatively (A, C, and E) from cerebrospinal fluid (CSF) (upper panel) and plasma (lower panel). Postoperative samples (B, D, and F) were also obtained from CSF and plasma. The asterisks show a statistical significance when compared with placebo.  = statistical significance when postoperative concentrations were compared with baseline values.
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The group of patients receiving preoperative clonidine demonstrated a denser analgesia during the first 24 h after surgery. VAS pain scores were lower in the Clonidine group when compared with the Placebo group (2 [1–4] vs 5 [4–7]), P < 0.05 (Fig. 2, upper panel). Similarly, patients receiving a larger dose of clonidine had lower pain scores when compared with the Placebo group (2 [1–3]). Patients receiving clonidine at either dose used smaller amounts of morphine in a 24-h period when compared with the Placebo group (Fig. 2, lower panel).
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Figure 2. Box plots in the upper panel demonstrate the visual analog score (VAS) of postoperative pain. The lower panel shows the differences in usage of morphine in a 24-h period as an indicator of analgesia. Data are expressed as median and range. The asterisks indicate a statistical significance when data were compared with placebo treatment. CLN-0.2 = clonidine 0.2 mg, CLN-0.4 = clonidine 0.4 mg.
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Clonidine-treated patients had lower systemic and central adrenergic activity and catecholamine release as determined by NE concentrations in CSF and plasma and 24-h urinary excretion of VMA and MHPG. Peripherally, the baseline plasma NE concentration was 527 pg/mL (327–990 pg/mL) in the Placebo group and increased to 954 pg/mL (681–1799 pg/mL) during surgery (P < 0.05). Small dose (0.2 mg) clonidine pretreatment decreased both the baseline and postoperative plasma NE concentrations (333 pg/mL [85–612 pg/mL] and 624 pg/mL [225–906 pg/mL], respectively, P < 0.05). In those patients treated with large-dose clonidine (0.4 mg), the baseline plasma concentration of NE was even smaller (125 pg/mL [72–389 pg/mL]) and was not affected by the surgical procedure (101 pg/mL [65–350 pg/mL]) (Fig. 3, upper panel). The CSF concentration of NE showed a similar pattern to its plasma concentration. In the Placebo group, the baseline CSF concentration was 135 pg/mL (52–423 pg/mL), which increased to 191 pg/mL (108–592 pg/mL) during surgery. Both small and large doses of clonidine effectively decreased the CSF concentrations of NE to 52 pg/mL (18–241 pg/mL) and 11 pg/mL (4–15 pg/mL), respectively (P < 0.01). These levels remained unaffected during the surgical procedure (Fig. 3, upper panel).
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Figure 3. Norepinephrine (NE) levels were measured in cerebrospinal fluid (CSF) (upper panel) and plasma (lower panel). Samples A, C, and E were obtained preoperatively and samples B, D, and F were obtained postoperatively. A and B samples were obtained from placebo-treated patients. C and D samples were obtained from patients treated with 0.2 mg of clonidine and samples E and F were collected from patients treated with 0.4 mg of clonidine. The asterisks indicate a statistical significance when compared with placebo. = statistical significance when postoperative concentrations were compared with baseline values.
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VMA excretion decreased to 0.9 mg/24 h (0.5–1.4 mg/24 h) in patients treated with clonidine (0.2 mg) from 2.3 mg/24 h (0.9–4.4 mg/24 h) (P < 0.01) in the Placebo group. The larger dose of clonidine further decreased VMA secretion to 0.5 mg/24 h (0.3–0.7 mg/24 h) (Fig. 4, upper panel). MHPG, similarly, decreased from 818 µg/24 h (720–1205 µg/24 h) in the Placebo-Treated group to 85 µg/24 h (42–205 µg/24 h) in patients treated with 0.2 mg clonidine and in urine obtained from patients receiving clonidine in the preoperative period (Fig. 4, lower panel).
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Figure 4. Box plots depicting the alterations in catecholamine end metabolites excreted in 24-h urine. Vanillylmandelic acid (VMA) results are depicted in the upper panel and methoxy hydroxyl phenyl glycol (MHPG) levels are shown in the lower panel. Statistical significance is shown by asterisks. CLN-0.2 = clonidine 0.2 mg, CLN-0.4 = clonidine 0.4 mg.
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Discussion
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These findings are novel in that activation of central 2-adrenergic receptors with 0.4 mg of clonidine per os completely abolished the increased plasma and CSF TNF- concentrations observed during pain. The detection of TNF- in the CSF has been associated with inflammatory responses in the CNS (24). The origin of TNF- in the CSF may be attributed to two different sources. Either this cytokine is generated in the CNS or it is transported through the blood-brain-barrier. Our findings indicate that changes in plasma and CSF concentrations of TNF- occur in parallel, supporting a probable peripheral as well as CNS source of this cytokine. However, we have observed in rats, during the chronic constriction injury model of neuropathic pain, significantly larger CNS levels than plasma levels of TNF- (14).
Studies have conclusively demonstrated not only that the supporting glial cells of the CNS are important sources of cytokines (25) but that neurons secrete selected cytokines as well (17,26). Constitutive TNF-, present in several brain regions, is significantly decreased after the administration of the 2-adrenergic agonist clonidine (0.6 mg/kg, intraperitoneally, twice daily) to rats for either 1 or 14 days, without a change in TNF- mRNA expression in the LC (17).
In experimental models, we found that TNF- regulates adrenergic responsiveness by inhibiting depolarization-induced release of [3H]-NE from brain slices obtained from a region of the brain rich in adrenergic nerve terminals (15–17). Both TNF- and the 2-adrenergic agonist, clonidine, in a concentration-dependent manner, normally inhibit electrical field-stimulated [3H]-NE release from adrenergic neurons. These studies demonstrate the interdependence between the functional response elicited by 2-adrenergic receptor activation and adrenergic sensitivity to TNF-. The present study demonstrates that global decreases in TNF- concentrations in the CNS also occur secondary to preoperative clonidine treatment.
We propose that, during the initial afferent barrage associated with peripheral pain, there is an induction in TNF- synthesis in the LC, resulting in TNF- release at adrenergic nerve terminals throughout the CNS. An increase in TNF- levels within select nuclei of the brain increases autoregulation of NE release by 2-adrenergic activation such that activation of this receptor has an increased inhibitory response of further NE release. In particular, this occurs in the hippocampus (14). Consequently, descending adrenergic pathways manifest decreased NE release at the appropriate spinal cord levels, culminating in decreased adrenergic activity. In addition to an inhibitory effect on NE release as an autoreceptor, activation of the 2-adrenergic receptor also triggers TNF- production and release from neurons, as is well established with macrophages (18,27). In fact, activation of this receptor decreases TNF- levels in the brain (16). A decrease in TNF- levels in the brain would antagonize the induction of TNF- elicited during persistent pain. Consequently, the decreased NE release occurring in the brain during pain would also decrease NE levels available to inhibit TNF- production, culminating in increased TNF- production, and thus an increased perception of pain. Therefore, this model predicts that activation of the 2-adrenergic receptor would alleviate pain, similar to its known therapeutic efficacy. In addition, we also predict that blockade of TNF- activity (microinfusion of TNF- Abs into the brain) during development of the central component of pain response would block hyperalgesia (14).
We also demonstrated that the administration of clonidine improves both intraoperative and postoperative pain control. The analgesic state intensifies, as was evident by improving pain scores and decreasing 24-h morphine requirements. The analgesic property of clonidine is not a novel finding. Similar to opioids, 2-agonists produce analgesia by both supraspinal and spinal mechanisms that involve activation of inhibitory G proteins (Gi) (4,28). Clonidine, therefore, is extensively used to treat pain via parenteral and intrathecal routes (29–31). Despite the beneficial effects of clonidine in pain management, this drug is always used as an adjunct to other analgesics (e.g., opioids or nonsteroidal antiinflammatory drugs).
NE, the endogenous agonist for 2-adrenergic receptors, is produced by neurons that have cell bodies in the rostral nervous system and connect to the postsynaptic spinal neurons by their axonal projections (32). Surgical stress is associated with increases in free catecholamines and their metabolites in serum (33). Our findings indicate that, even in the presence of successful neuraxial sensory block, surgical stimulation results in increases in adrenergic tone. We speculate that local tissue injury, resulting in the release of cytokines, may play a role in upregulating sympathetic tone. The administration of clonidine in these patients resulted in a decrease in both central adrenergic and peripheral sympathetic outflow as evidenced by smaller concentrations of NE in CSF and plasma, as well as decreased urinary excretion of VMA and MHPG. A similar finding has been reported by Ellis et al. (34). These investigators demonstrated that preoperative administration of an 2-adrenergic agonist results in perioperative sympatholysis along with smaller levels of catecholamines.
Preoperative treatment with an 2-adrenergic agonist, clonidine, effectively diminished the surgical stress response of both central and peripheral TNF- production and resulted in perioperative sympatholysis. Furthermore, this treatment provided adequate operative sedation and decreased postoperative analgesic requirement. Therefore, we conclude that the addition of this class of adrenergic agonists offers advantages in the management of pain in acutely ill patients.
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Acknowledgments
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Supported, in part, by a multidisciplinary grant from SUNY-Buffalo (NDN-150-8120-S) and a grant awarded to RNS (1993) from the Spinal Cord Research Foundation.
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Accepted for publication April 11, 2001.
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Abstract
Introduction
