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Anesth Analg 2003;96:1397-1402
© 2003 International Anesthesia Research Society

PAIN MEDICINE

Local Anesthetics Differentially Inhibit Sympathetic Neuron-Mediated and C Fiber-Mediated Synovial Neurogenic Plasma Extravasation

Christian Pietruck, MD, Stefan Grond, MD, Guo-Xi Xie, MD PhD, and Pamela P. Palmer, MD PhD

Department of Anesthesia and Perioperative Care, University of California-San Francisco, San Francisco, California

Address correspondence and reprint requests to Pamela Pierce Palmer, MD, PhD, Department of Anesthesia, University of California-San Francisco, 513 Parnassus Ave., S-455, San Francisco, CA 94143-0464. Address e-mail to palmerp{at}anesthesia.ucsf.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Local anesthetics are used for local irrigation after many types of operations. However, recent evidence of toxic effects of local anesthetics at large concentrations during continuous administration suggests an advantage of using decreased local anesthetic concentrations for irrigation solutions. In this study, we determined whether smaller concentrations of local anesthetics may maintain an antiinflammatory and, therefore, analgesic effect without the risk of possible toxicity. Lidocaine and bupivacaine were studied for their ability to inhibit both components of neurogenic inflammation—C fiber-mediated and sympathetic postganglionic neuron (SPGN)-mediated inflammation—in the rat knee joint. Intraarticular lidocaine 0.02% reduced 5-hydroxytryptamine (5-HT)-induced (SPGN-mediated) plasma extravasation (PE) by 35%, and further decreases were obtained by perfusing larger concentrations of lidocaine. Intraarticular bupivacaine 0.025% inhibited 5-HT-induced PE by 60%, and a 95% inhibition was obtained with bupivacaine 0.05%. Larger local anesthetic concentrations were necessary to inhibit C fiber-mediated PE than those required to inhibit SPGN-mediated PE. Lidocaine 0.4% was required to reduce mustard oil-induced PE by 60%. Lidocaine 2% inhibited mustard oil-induced PE to baseline levels. Bupivacaine 0.1% was required for an 80% reduction of PE. Bupivacaine 0.25% inhibited mustard oil-induced PE to baseline levels. Our results demonstrate differential effects of local anesthetics on SPGN- and C fiber-mediated PE but confirm the concept of using smaller concentrations of local anesthetics to achieve inhibition of postoperative inflammation.

IMPLICATIONS: Local anesthetic wound irrigation is often used to treat postoperative surgical pain. Large concentrations of local anesthetics are usually used, and these concentrations may have possible neurotoxic and myotoxic effects. Our results demonstrate antiinflammatory effects of lidocaine and bupivacaine at concentrations smaller than used clinically.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Clinically, local anesthetics are used in relatively large, axonal-blocking concentrations for local irrigation after many types of operations (1–3). Yet there are significant data demonstrating the neurotoxic and myotoxic effects of local anesthetics at large concentrations during continuous administration (4–8). In animal models, it is relatively straightforward to determine the toxicity of large-dose application of local anesthetics. However, it is difficult to assess the possible cellular toxicity and clinical effect of local anesthetic irrigations in the clinical setting, because tissue damage and subsequent scarring or neuropathic pain are often attributed to surgical trauma. Because there is increasing evidence that, in addition to axonal-blocking actions, local anesthetics have significant antiinflammatory properties, it is possible that a smaller concentration of local anesthetic than is currently used may maintain an antiinflammatory and, therefore, analgesic effect with a decreased risk of toxicity.

The antiinflammatory effects of local anesthetics have been extensively studied (9). For example, lidocaine and bupivacaine inhibited peritonitis induced by hydrochloric acid in a rat model (10). Green et al. (11) demonstrated an inhibitory effect of intraarticular lidocaine on bradykinin-induced plasma extravasation (PE) in a knee-perfusion model. Furthermore, the neurogenic inflammatory response of rat skin is decreased by the application of lidocaine (12). Other local anesthetics, such as ropivacaine (13) and lidocaine-prilocaine cream (14), have significant antiinflammatory effects as well.

There are some studies, however, that fail to demonstrate antiinflammatory effects of local anesthetics. Lidocaine or bupivacaine injected into a rat temporomandibular joint displayed no inhibition of mustard oil-induced edema (15). Lidocaine also failed to inhibit human nasal mucosa PE induced by bradykinin (16). Furthermore, rat knee joint PE produced by platelet-activating factor was not affected by lidocaine (11).

The effects of local anesthetics on a major component of inflammation, neurogenic inflammation, have not been thoroughly studied. Previous studies used only one local anesthetic or studied only a single concentration and did not differentiate between C fiber-mediated and sympathetically mediated neurogenic inflammation. Neurogenic PE is the result of the release of multiple inflammatory mediators from activated C fibers or sympathetic postganglionic neurons (SPGN). Mustard oil is often used to produce C fiber-mediated neurogenic inflammation and PE (15,17). The PE produced by mustard oil has been shown to not rely on any contribution from sympathetic efferent terminals (17). In contrast, sympathectomy, but not C-fiber depletion, dramatically reduced 5-hydroxy-tryptamine (5-HT)-mediated synovial PE (18). Therefore, in the following study, 5-HT was selected to produce SPGN-dependent PE, and mustard oil was used to produce C fiber-mediated PE in the rat knee joint. The dose-dependent effects of lidocaine and bupivacaine were studied on both types of neurogenic PE.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The Committee on Animal Research of the University of California, San Francisco, approved the following studies. Male Sprague-Dawley rats (Bantin and Kingman, Fremont, CA) weighing 320 to 350 g, which were housed at 25°C under controlled lighting conditions (lights 6:00 AM to 6:00 PM) with food and water ad libitum, were used. Rats were anesthetized with sodium pentobarbital (65 mg/kg intraperitoneally). The animals then received a tail vein injection of Evans Blue dye (50 mg/kg in a concentration of 20 mg/mL), used as a marker for PE. The knee-joint capsule was exposed by excising the overlying skin, and a 30-gauge needle was inserted into the joint for the infusion of fluid (200 µL/min; Fig. 1). After perfusion of approximately 200 µL of fluid, a 25-gauge outflow needle was placed into the joint space to extract fluid at 200 µL/min. The infusion and extraction rate was controlled by an SP120p push-pull syringe pump (WPI, Sarasota, FL). Perfusate samples were collected over 5-min intervals for 45 min. Samples were then analyzed for Evans Blue dye concentration by spectrophotometric measurement of absorbance at 620 nm (Spectronic 21D; Spectronic Instruments, Inc., Rochester, NY), which linearly correlates with its concentration (19).



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  		Figure 1. Schematic representation of placement of inflow and outflow needles in the rat knee joint.

 
Baseline PE levels were obtained by perfusing 0.9% saline (for 5-HT or mustard oil controls), the specific test concentrations of lidocaine (Elkins-Sinn Inc., Cherry Hill, NJ), or bupivacaine (Sensorcaine-MPF; Astra USA Inc., Westborough, MA) for 15 min and measuring the absorbance of the collected sample every 5 min. After baseline samples were collected, either 1 µM 5-HT (Sigma, St. Louis, MO) or 1% mustard oil (allyl isothiocyanate; Sigma) was then perfused alone or co-perfused with a local anesthetic intraarticularly for an additional 30 min. Samples were collected to measure absorbance every 5 min. 5-HT was diluted in 0.9% saline, and mustard oil was dissolved first in 40% ethanol and 20% Tween 80, with a final concentration of 1% ethanol and 0.5% Tween 80. (This vehicle alone did not affect PE.) Lidocaine and bupivacaine were diluted in 0.9% saline.

Some knees were excluded from the study because of improper needle placement detected by blood or inflow and outflow discrepancy. Differences in the magnitude of PE for the various treatment groups were assessed by analysis of variance with Fisher’s post hoc analysis.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Only knees with baseline levels averaging less than 0.04 absorbance were used in this study to exclude high baseline PE from injury due to needle insertion. There were no differences among baseline PE levels in all groups (average area under the curve [AUC], 0.014 ± 0.004 for all groups; data not shown). 5-HT (1 µM) and mustard oil (1%) produced a similar degree of PE as measured by the AUC (AUC for 5-HT, 0.597 ± 0.083; mustard oil, 0.636 ± 0.120) (Figs. 2 and 3).



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  		Figure 2. A, Inhibition of 5-hydroxy-tryptamine (5-HT) (1 µM)-induced synovial plasma extravasation (PE) by increasing concentrations of lidocaine. B, Inhibition of 5-HT (1 µM)-induced synovial PE by increasing concentrations of bupivacaine. PE is measured by absorption of light by Evans Blue dye at 620 nm. *P = 0.5; **P < 0.01; ***P < 0.001.

 


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  		Figure 3. A, Inhibition of mustard oil (M. O.) (1%)-induced synovial plasma extravasation (PE) by increasing concentrations of lidocaine. B, Inhibition of mustard oil (1%)-induced synovial PE by increasing concentrations of bupivacaine. PE is represented by absorption of light by Evans Blue dye at 620 nm. *P < 0.5; **P < 0.01; ***P < 0.001.

 
Intraarticular lidocaine inhibited 5-HT-induced PE in a dose-dependent manner (Fig. 2A). Lidocaine 0.02% significantly reduced 5-HT-induced PE by 35% (AUC, 0.390 ± 0.073; P = 0.05), and further decreases of 60% (AUC, 0.237 ± 0.060; P < 0.01) and 100% (AUC, 0.017 ± 0.002; P < 0.001) were obtained by perfusing larger concentrations of lidocaine (0.1% and 0.2%, respectively). Intraarticular bupivacaine also inhibited 5-HT-induced PE in a dose-dependent manner (Fig. 2B). Although 0.005% bupivacaine did not effectively reduce PE (AUC, 0.520 ± 0.112), bupivacaine 0.025% produced a 60% reduction in 5-HT-induced PE (AUC, 0.223 ± 0.044; P < 0.01), and bupivacaine 0.05% resulted in a 95% inhibition of 5-HT-induced PE (AUC, 0.053 ± 0.019; P < 0.001).

Increasing concentrations of intraarticular lidocaine also dose-dependently inhibited mustard oil-induced PE (Fig. 3A). However, larger lidocaine concentrations were necessary than those required to inhibit 5-HT-induced PE. Whereas lidocaine 0.1% had no significant effect on mustard oil-induced PE (AUC, 0.488 ± 0.096), a fourfold larger concentration of lidocaine (0.4%) was required to significantly reduce mustard oil-induced PE by approximately 60% (AUC, 0.247 ± 0.049; P < 0.05). Lidocaine 2% was required to completely inhibit mustard oil-induced PE to baseline levels (AUC, 0.020 ± 0.006; P < 0.001). Similarly, larger concentrations of intraarticular bupivacaine were needed to dose-dependently inhibit mustard oil-induced PE (Fig. 3B), compared with those required to inhibit 5-HT-induced PE. Bupivacaine 0.05% had no effect on mustard oil-induced PE (AUC, 0.662 ± 0.076), but increasing the bupivacaine concentration to 0.1% resulted in an 80% reduction of PE (AUC, 0.139 + 0.039; P < 0.01). Bupivacaine 0.25% resulted in a 95% inhibition of mustard oil-induced PE (AUC, 0.056 ± 0.017; P < 0.01).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The major finding of this study is that local anesthetics have differing effects on SPGN-mediated (5-HT-induced) versus C fiber-mediated (mustard oil-induced) synovial inflammation. Whereas 2% lidocaine or 0.25% bupivacaine (common clinical concentrations) were required to reduce mustard oil-induced PE to baseline levels, only 0.2% lidocaine or 0.05% bupivacaine was needed to produce the same effect on 5-HT-induced PE. In fact, there was a 35% reduction of 5-HT-induced PE at a 0.02% lidocaine concentration, which is 50- to 100-fold less than clinically used for axonal-blocking effects. Bupivacaine displayed significant antiinflammatory effects against 5-HT-induced PE at a concentration as low as 0.025%, which is 10- to 20-fold less than clinically used. In contrast, a significant reduction of mustard oil-induced PE was achieved only by much larger concentrations of local anesthetics. Lidocaine did not inhibit mustard oil-induced PE until a concentration of 0.4%, and bupivacaine required a concentration of 0.1%; both concentrations are close to those clinically used for axonal-blocking effects.

It is apparent from these data and previous studies that local anesthetics do not produce antiinflammatory effects simply by blocking the conduction of neuronal terminals. Rather, local anesthetics possess antiinflammatory properties that are relatively selective, resulting in differential effects on various types of inflammation, such as described in this study. For example, bupivacaine has been shown to inhibit prostaglandin E2 receptor functioning in cultured cells (20). This receptor, known as EP1, plays a major role in inflammatory pathways. Local anesthetics also have been shown to inhibit the release of histamine, leukotriene B4, and interleukin-1{alpha} from human inflammatory cells (13,21,22). These mediators are also significant components of the inflammatory cascade. Functioning of inflammatory cells, such as polymorphonuclear granulocyte migration and adhesion, also has been demonstrated to be inhibited by local anesthetics (23).

SPGN-mediated PE is a rather complex process that requires the involvement of many SPGN co-transmitters, such as prostaglandin E2 (24). The potent antiinflammatory effects of lidocaine and bupivacaine on SPGN-mediated PE in this study may have been due, in part, to a direct inhibitory effect on synovial EP1 receptors. C fiber-mediated PE results from the activation of C-fiber terminals with subsequent release of substance P and other neuropeptides, which act directly on vessels to produce PE (25,26). It is possible that local anesthetics do not interfere with this neuropeptide pathway of neurogenic inflammation until the concentrations of the local anesthetics are large enough to inhibit electrical activation of the C-fiber terminal and, thereby, inhibit the local release of neuropeptides.

The clinical concentrations of local anesthetics often used in local postoperative wound irrigation, although large enough to inhibit both components of neurogenic inflammation, have been shown to be both neurotoxic and myotoxic, especially during continuous administration. Specifically, lidocaine at concentrations as small as 1% has well documented neurotoxic effects in rat sciatic nerve (7), frog sciatic nerve (5), and crayfish giant axon (6). Bupivacaine myotoxicity was clearly apparent within three hours in rat paraspinous muscles with bupivacaine concentrations of 5–10 mM (approximately 0.25%) (4). This toxicity included severe injury to plasma membrane, sarcoplasmic reticulum, and mitochondria. Recently, bupivacaine toxicity was demonstrated to be mediated by mitochondrial depolarization in highly oxidative muscles, such as the soleus (8). All these studies demonstrated toxicity within three hours or less, suggesting that the time frame for toxicity development in these studies is clinically relevant to postoperative irrigation of wounds.

This study demonstrates that it is possible to use much smaller concentrations of local anesthetics than are currently used in postoperative wound irrigation and maintain an antiinflammatory effect. Because local anesthetics at small concentrations have only selective effects on inflammatory pathways, a solution combining local anesthetics with other analgesic or antiinflammatory drugs may be optimal to maximize efficacy while decreasing potential toxicity.


   Acknowledgments
 
Supported by NIH (National Institutes of Health, Bethesda, MD) Grant NS37224 and DFG (Deutsche Forschungsgemeinschaft, Germany) Grant Pi350/1-1.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Pfeiffer U, Dodson ME, Van Mourik G, et al. Wound instillation for postoperative pain relief: a comparison between bupivacaine and saline in patients undergoing aortic surgery. Ann Vasc Surg 1991; 5: 80–4.[Medline]
  2. Majid AA, Hamsah H. Pain control after thoracotomy: an extrapleural tunnel to provide a continuous bupivacaine infusion for intercostal nerve blockade. Chest 1992; 101: 981–4.[Abstract/Free Full Text]
  3. Givens VA, Lipscomb GH, Meyer NL. A randomized trial of postoperative wound irrigation with local anesthetic for pain after cesarean delivery. Am J Obstet Gynecol 2002; 186: 1188–91.[ISI][Medline]
  4. Hall-Craggs EC. Early ultrastructural changes in skeletal muscle exposed to the local anaesthetic bupivacaine (Marcaine). Br J Exp Pathol 1980; 61: 139–49.[ISI][Medline]
  5. Bainton CR, Strichartz GR. Concentration dependence of lidocaine-induced irreversible conduction loss in frog nerve. Anesthesiology 1994; 81: 657–67.[ISI][Medline]
  6. Kanai Y, Katsuki H, Takasaki M. Graded, irreversible changes in crayfish giant axon as manifestations of lidocaine neurotoxicity in vitro. Anesth Analg 1998; 86: 569–73.[Abstract]
  7. Kanai Y, Katsuki H, Takasaki M. Lidocaine disrupts axonal membrane of rat sciatic nerve in vitro. Anesth Analg 2000; 91: 944–8.[Abstract/Free Full Text]
  8. Irwin W, Fontaine E, Agnolucci L, et al. Bupivacaine myotoxicity is mediated by mitochondria. J Biol Chem 2002; 277: 12221–7.[Abstract/Free Full Text]
  9. Hollmann MW, Durieux ME. Local anesthetics and the inflammatory response. Anesthesiology 2000; 93: 858–75.[ISI][Medline]
  10. Rimbäck G, Cassuto J, Wallin G, Westlander G. Inhibition of peritonitis by amide local anesthetics. Anesthesiology 1988; 69: 881–6.[ISI][Medline]
  11. Green PG, Luo J, Heller PH, Levine JD. Further substantiation of a significant role for the sympathetic nervous system in inflammation. Neuroscience 1993; 55: 1037–43.[ISI][Medline]
  12. Dux M, Janscó G, Sann H, Pierau F-K. Inhibition of neurogenic inflammatory response by lidocaine in rat skin. Inflamm Res 1996; 45: 10–3.[ISI][Medline]
  13. Martinsson T, Haegerstrand A, Dalsgaard CJ. Effects of ropivacaine on eicosanoid release from human granulocytes and endothelial cells in vitro. Inflamm Res 1997; 46: 398–403.[ISI][Medline]
  14. Jonsson A, Mattsson U, Tarnow P, et al. Topical local anaesthetics (EMLA) inhibit burn-induced plasma extravasation as measured by digital image colour analysis. Burns 1998; 24: 313–8.[ISI][Medline]
  15. Wong JK, Haas DA, Hu JW. Local anesthesia does not block mustard-oil-induced temporomandibular inflammation. Anesth Analg 2001; 92: 1035–40.[Abstract/Free Full Text]
  16. Sanico AM, Atsuta S, Proud D, Togias A. Plasma extravasation through neuronal stimulation in human nasal mucosa in the setting of allergic rhinitis. J Appl Physiol 1998; 84: 537–43.[Abstract/Free Full Text]
  17. Komorowski RC, Torneck CD, Hu JW. Neurogenic inflammation and tooth pulp innervation pattern in sympathectomized rats. J Endod 1996; 22: 414–7.[ISI][Medline]
  18. Pierce PA, Xie G-X, Peroutka SJ, et al. 5-Hydroxytryptamine-induced synovial plasma extravasation is mediated via 5-hydroxytryptamine2A receptors on sympathetic efferent terminals. J Pharmacol Exp Ther 1995; 275: 502–8.[Abstract/Free Full Text]
  19. Carr J, Wilhelm DL. The evaluation of increased vascular permeability in the skin of guinea pigs. Aust J Exp Biol Med Sci 1964; 42: 511–22.[ISI][Medline]
  20. Honemann CW, Heyse TJ, Mollhoff T, et al. The inhibitory effect of bupivacaine on prostaglandin E(2) (EP(1)) receptor functioning: mechanism of action. Anesth Analg 2001; 93: 628–34.[Abstract/Free Full Text]
  21. Sinclair R, Eriksson AS, Gretzer C, et al. Inhibitory effects of amide local anaesthetics on stimulus-induced human leukocyte metabolic activation, LTB4 release and IL-1 secretion in vitro. Acta Anaesthesiol Scand 1993; 37: 159–65.[ISI][Medline]
  22. Yanagi H, Sankawa H, Saito H, Iikura Y. Effect of lidocaine on histamine release and Ca2+ mobilization from mast cells and basophils. Acta Anaesthesiol Scand 1996; 40: 1138–44.[ISI][Medline]
  23. MacGregor RR, Thorner RE, Wright DM. Lidocaine inhibits granulocyte adherence and prevents granulocyte delivery to inflammatory sites. Blood 1980; 56: 203–9.[Free Full Text]
  24. Green PG, Luo J, Heller P, Levine JD. Modulation of bradykinin-induced plasma extravasation in the rat knee joint by sympathetic co-transmitters. Neuroscience 1993; 52: 451–8.[ISI][Medline]
  25. Lembeck F, Holzer P. Substance P as neurogenic mediator of antidromic vasodilatation and neurogenic plasma extravasation. Naunyn Schmiedebergs Arch Pharmacol 1979; 310: 175–83.[ISI][Medline]
  26. Gamse R, Saria A. Potentiation of tachykinin induced plasma protein extravasation by calcitonin gene-related peptide. Eur J Pharmacol 1985; 114: 61–6.[ISI][Medline]
Accepted for publication January 22, 2003.





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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press