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Anesth Analg 2008; 107:1587-1591
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e31818200aa
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ANESTHETIC PHARMACOLOGY

Low-Dose Systemic Bupivacaine Prevents the Development of Allodynia After Thoracotomy in Rats

Jin Woo Shin, MD, PhD{dagger}, Carlo Pancaro, MD*, Chi Fei Wang, PhD*, and Peter Gerner, MD*

From the *Pain Research Center, Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; and {ddagger}Department of Anesthesiology and Pain Medicine, College of Medicine, University of Ulsan, Asan Medical Center, Seoul, South Korea.

Address correspondence and reprint requests to Dr. Pancaro, Department of Anesthesiology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115. Address e-mail to carlopancaro{at}hotmail.com.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: Chronic pain after thoracotomy has been recently reproduced in a rat model that allows investigation of the effect of drugs that might reduce the incidence of allodynia after thoracotomy. Previous studies suggest that intrathecal or systemic morphine, clonidine, neostigmine, and gabapentin reduce the incidence of allodynia in the rat postthoracotomy pain model. Our purpose was to test whether intercostal and systemic injection of bupivacaine prevented the development of allodynia in an animal model of chronic intercostal neuropathic pain.

METHODS: Male Sprague-Dawley rats were anesthetized and the right 4th and 5th ribs surgically exposed. The pleura were opened and the ribs were retracted for 1 h. Intercostal or systemic bupivacaine 1 mg (0.2 mL at 0.5%) was injected before and after surgery, or before surgery; a control group underwent rib retraction and did not receive any drug. Rats were tested for mechanical allodynia at a predetermined area around the incision site during the 3 wk after surgery.

RESULTS: Allodynia developed in 43% of the animals that did not receive bupivacaine (control group); in contrast, allodynia developed in only 6%, 12%, and 12% of those animals that received intercostal bupivacaine before surgery, after surgery, or systemically before surgery, respectively.

DISCUSSION: Previous studies suggest that allodynia after rib retraction can be prevented by opioids, {alpha}2-adrenergic agonists, neostigmine, and gabapentin. The current results suggest that bupivacaine is effective in preventing mechanical allodynia, whether given by intercostal injection before or after surgery, or systemically before surgery.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Lung cancer is the leading cause of cancer death in the United States,1 and patients who have a relatively positive prognosis are usually candidates for surgery that most commonly involves either thoracotomy or video-assisted thoracoscopic surgery. Chronic pain after thoracotomy was first reported in 1944 by a United States army physician, who noted "chronic intercostal pain" in men who underwent a thoracotomy because of a chest trauma during the Second World War. Chronic postthoracotomy pain (CPTP) is defined as "pain that recurs or persists along a thoracotomy incision at least 2 mo after the surgical procedure."2 CPTP is typically described as a continuous dysesthesia with burning and aching in the general area of the surgical incision. It affects up to 55% of patients followed for more than 1 yr, representing one of the most commonly reported complications after thoracic surgery.3

No preoperative risk factors have been identified in patients who developed pain after thoracotomy, whereas a number of intra- and postoperative variables have been found to affect the etiology and management of CPTP.4 Chest wall resection and pleurectomy seem to increase the likelihood of chronic pain when compared to pulmonary resection alone.5 In contrast, the muscle-sparing thoracotomy approach6 and the use of video-assisted thoracoscopic surgery7 may decrease the incidence of chronic pain and disability when compared to conventional thoracotomy, although the difference disappears 1 yr after the procedure. Likewise, the combined use of intra- and postoperative epidural analgesia was found to dramatically decrease the incidence of pain at 6 mo.8

The etiology of CPTP has not been clearly determined, though clinical and bench research studies suggest that functional impairment and anatomical damage of the intercostal nerves are leading factors in the development of this pain syndrome: Rogers et al. have shown that rib retraction alone causes 50% conduction block in the intercostal nerves on both sides of the retractor in almost every patient who underwent thoracotomy9; Buvanendran et al. developed a postthoracotomy pain model in which nearly 50% of the animals developed allodynia, and all showed extensive axon loss in the intercostal nerves of the retracted ribs.10

Local anesthetics have been injected systemically or close to the nerve to treat chronic neuropathic pain in humans.11,12 We hypothesized that bupivacaine injected close to the intercostal nerve prevents the development of allodynia in the postthoracotomy pain animal model, assessed by mechanical threshold testing with von Frey filaments in a 3-wk time frame. In addition, we hypothesized that bupivacaine injected systemically prevents the development of mechanical allodynia in the same animal model.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
After obtaining approval from the Harvard Medical Area Standing Committee on Animals (Boston, MA), 64 male rats (Harlan Sprague-Dawley) weighing 280–340 g at the time of surgery were studied. Animals were purchased from Charles River Laboratory (Wilmington, MA) and kept in the animal housing facilities at Brigham and Women’s Hospital, with controlled relative humidity (20%–30%), at room temperature (24°C), and under a 12–12 h light-dark cycle, with free access to food and water. Rats were handled before the procedure to familiarize them with the experimental environment and to minimize stress-induced analgesia.

Surgical Procedures
Rats were briefly anesthetized with sevoflurane (1%–2% in oxygen) before receiving intraperitoneal xylazine (1.5 mg/Kg) and ketamine (4 mg/Kg). Animals were then tracheally intubated (16-gauge, 51-mm Teflon IV catheter; Terumo Medical, Somerset, NJ) and connected to a ventilator (model 683: Harvard Instruments, Holliston, MA) for the entire duration of the surgical procedure. A 3-cm incision was made in the skin of the right lateral chest wall between the 4th and 5th ribs. The deep and superficial muscles covering the ribs were retracted to expose the intercostal muscle. A 1.5-cm incision was made in the intercostal muscle and pleura above the 5th rib. The blunt tines of a small self-retaining retractor (model SU-3146; Mueller, McGaw Park, IL) were coated with lubricant (Surgilube) and placed under the 4th and 5th ribs. The retractor was opened to its third position, producing a rib separation of 8 mm, and was left in place for 60 min, as previously described.10 After the retraction period, the retractor was returned to the closed position and removed. Both 4th and 5th ribs were approximated and ligated tightly using 3-0 chromic gut sutures. Air was aspirated from the pleural cavity with a 5-mL syringe attached to the tubing to restore normal intrapleural pressure. The superficial muscle covering the ribs was then apposed with 3-0 chromic gut sutures, and the skin was closed with 3-0 nylon sutures. The animals were allowed to recover, and the endotracheal catheter was removed once spontaneous breathing was re-established.

Experimental Protocol
Animals had intercostal injection before or after surgery, or intraperitoneal injection before surgery of bupivacaine 1 mg (n = 16 per group). Behavioral testing was always performed between 9 and 12 am at the following time points: 1 day before and 1, 3, 6, 9, 12, 15, 18, and 21 days after surgery. For testing, rats were placed in individual semi-open plastic boxes, which allowed access to their chest wall, and were allowed to explore and groom until they settled. A series of calibrated von Frey filaments (Stoelting CO, Wood Dale, IL) with bending forces ranging from 0.2 to 15.1 g were applied perpendicularly to the dorsal skin surface (corresponding to the estimated T4–5 dermatomes, i.e., <2 cm from the incision) of the chest wall around the incision site with enough force to bend the filament for 6 s. Escape behavior or scratching of the dorsal right upper back skin by the hindpaw within 6 s of the application of a filament were considered positive responses.10 In the absence of a response, the filament of next greater force was applied. In the presence of a response, the filament of next lower force was applied. The tactile stimulus producing a 50% likelihood of withdrawal was determined using the up–down method, as previously described.13 Each trial was repeated twice at approximately 2-minute intervals, and the mean value was used as the withdrawal threshold. Mechanical allodynia was defined as at least a 20% decrease from the baseline in withdrawal threshold at any time during the experiment, and its persistence at day 21 after the injury was considered the outcome variable. In order to exclude any bupivacaine effect on the central nervous system, rats were closely observed for any abnormal signs such as sedation, altered grooming patterns, and exploratory behaviors throughout the experiment.

Drugs
Bupivacaine 0.2 mL (Hospira, Lake Forest, IL, 5 mg/mL) at a concentration of 0.5% (1 mg) was administered by intraperitoneal or intercostal injection.

Statistical Analysis
Data are presented as mean ± sem. Behavioral analysis comparisons were performed using Kruskal-Wallis followed by Dunn’s test. P < 0.05 was considered statistically significant.


   RESULTS
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 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Withdrawal threshold was 14.98 ± 0.1 g in animals before thoracotomy.

Withdrawal threshold started to decrease 15 days after injury in almost half of the animals (7/16 = 43%) that did not receive bupivacaine injections and was significantly decreased by 3 wk after thoracotomy (8.25 ± 1.46 g [P < 0.05]). In almost all animals that underwent intercostal injection of bupivacaine before thoracotomy (15/16 = 94%), after thoracotomy (14/16 = 87%), or that received intraperitoneal injections before the injury (14/16 = 87%), withdrawal thresholds did not change significantly at any time point, even 3 wk after the injury (Fig. 1). Of note, no signs of sedation, difference in grooming patterns, or exploratory behavior were observed at any time during the experiment.


Figure 120
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  		Figure 1. Withdrawal Thresholds. The four different treatment groups underwent baseline behavioral testing one day before the injury. Animals in the control group started to show a progressive decrease in withdrawal thresholds 1 wk after injury; thresholds reached their lowest value after 21 days. All treated groups failed to show any sign of allodynia even 3 wk after the injury. Each data point represents the mean ± se of the mean. *P < 0.05 compared to treatment groups and compared to the baseline in the control group.

 


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study suggests that bupivacaine, injected systemically or intercostally, reduces the development of allodynia in an animal model of persistent postthoracotomy pain. In the current study, 7 of 16 rats (43%) in the no-treatment arm (control group) developed allodynia, a result that replicates the findings of Buvanendran et al. in their persistent postthoracotomy pain model, in which half of the animals developed mechanical allodynia.10 Like other neuropathic animal pain models, in which most myelinated fibers are damaged during the time course of allodynia,14,15 the rib-retraction model is associated with the loss of nearly all myelinated fibers: in animals exhibiting allodynia, there was an extensive Wallerian degeneration 14 days postsurgery; in addition, no remyelination was noted even 2 wk after surgery.10 In the same model, the mechanical allodynia started to appear on day 10 after the injury, a finding replicated in the current study, where the mechanical threshold decreased progressively from day 15 to day 21 after the injury in the animal group that did not receive the drug. Since in the current study behavioral data were consistent with the development of allodynia, we believe that histology examinations would have been helpful but were beyond the scope of the study. In the rib retraction model, cold and mechanical allodynia show a similar timing. In contrast to the original published rib retraction model, in which the authors also observed for cold allodynia, here we tested only for mechanical allodynia, since clinical evidence suggests that the most common reported symptoms in humans after thoracotomy are spontaneous and mechanical-evoked pain.2–4 We chose to test bupivacaine, since patients undergoing thoracic surgery receive local anesthetics in the form of neuraxial or intercostal nerve blocks. In the current study, bupivacaine injected intercostally appears responsible for the decreased incidence of allodynia. However, it remains unclear whether the timing of local anesthetic administration is critical in this animal model, since the incidence of allodynia was similar whether the animals were treated by intercostal injection before or after thoracotomy. These results are in contrast with previous findings that preemptive thoracic epidural analgesia in humans reduces long-term pain after thoracotomy,8,16 and are also in contrast with other studies that found no long-term reduction of pain17; moreover, these results challenge the role of timing of analgesia.18,19

We also wanted to test whether the systemic injection of bupivacaine is effective in the prevention of allodynia. A growing body of evidence supports the role of systemic local anesthetics to prevent neuropathic pain after surgical insult. Clinical trials of patients undergoing prostatectomy or major abdominal surgery have found that systemic administration of local anesthetic decreases pain scores by more than half in the postoperative period, an effect that lasts several days.20 Systemic lidocaine (bolus injection followed by a continuous infusion) decreased postoperative pain and morphine consumption after major abdominal surgery in the 72 h after surgery, with the most prominent effect after 36 h.21 In a randomized, double-blind, active-placebo-controlled, crossover trial, an IV bolus of lidocaine after an IV infusion also showed an analgesic effect on postamputation stump pain.22

In addition, a few studies in healthy volunteers and a study in patients with complex regional pain syndromes receiving systemic lidocaine showed a suppression in capsaicin-induced secondary hyperalgesia by a central mode of action23 and a reduced response to cold stimuli,24 respectively.

Hyperexcitability after a peripheral nerve injury is considered to be a principal feature of the underlying pathophysiology associated with neuropathic pain, and continuing activity in nociceptors has been shown to be necessary for the maintenance of allodynia in humans.25 An abnormal repetitive firing characterizes the injury of primary nerve afferents, where there is an accumulation and increased membrane density of sodium channels at focal sites of injury.26,27 The resultant membrane remodeling contributes to a lower threshold for action potential generation at these sites and, consequently, triggers ectopic impulse generation.28,29 Further, sodium channel blockade with subanesthetic doses of local anesthetic drugs suppresses ectopic electrogenesis and may account for the analgesic and antihyperalgesic effects of these drugs.30

Bupivacaine is a very potent local anesthetic with sodium channel blockade properties; at extremely low concentrations it is nearly 8 times more potent than lidocaine as a blocker of Na+ channels in the open-channel state.31 Since no signs of sedation, difference in grooming patterns, or exploratory behavior were observed in the animals at any time during the current experiment, the likelihood of systemic toxicity in our study is trivial. As we previously have shown, the IV bupivacaine dose that can result in systemic toxicity in Sprague-Dawley male rats is 22.7 ± 7 mg/kg32; this dose is circa 7 times larger than the intercostal or intraperitoneal dose used in the current study (between 2.9 and 3.5 mg/Kg), meaning that in the Sprague-Dawley rat, low-dose bupivacaine has a high therapeutic index for the prevention of neuropathic pain after thoracotomy. In healthy volunteers, intercostal bupivacaine doses similar to those used in the current study (2–3 mg/Kg), failed to elicit any systemic signs or symptoms of local anesthetic toxicity and were associated with a low maximum plasma concentration of bupivacaine (0.9 ± 0.2 µg/mL).33 Though it is difficult to extrapolate human data to animal models, our data combined with those available currently in the literature might encourage further investigations for the prevention of chronic pain in humans undergoing thoracotomy.

Systemic antiinflammatory action could have been responsible for the antiallodynic effect of bupivacaine in the current experiment. After peripheral nerve injury, the site of damage is typified by the activation of resident immune cells and recruitment and proliferation of nonneuronal elements like neutrophils; a number of factors can be released (e.g., interleukin 1β) that initiate and maintain sensory abnormalities after injury.34 It has been shown that local anesthetics at very low concentrations inhibit neutrophil priming without interfering with their activation, thereby preventing their hyperactivation.35 In addition, in an in vitro cell culture model, the interleukin 1β release was attenuated by lidocaine (0.05%–0.5%) and bupivacaine (0.00125%–0.125%) incubated for 24 h with lipopolysaccharide-stimulated human leukocytes.36

Similar to high-dose steroids, which have been proven to contribute to analgesia,37 local anesthetics prevent the release of cytokines,38 and bupivacaine has been shown to cause antiinflammatory effects.35,39 Hence, IV administration of local anesthetics provides pain relief that greatly exceeds the duration of action of the drug itself, probably by preventing inflammatory responses to tissue injury. A growing body of evidence suggests that N-methyl-d-aspartate (NMDA) receptors play an important role in secondary hyperalgesia and in chronic pain syndromes.40 Also, local anesthetics concentration-dependently and reversibly inhibit glutamate/glycine-induced NMDA receptor channel (NR1A/2A) activation.41 Concentrations of local anesthetic that significantly inhibit NMDA receptor channel activation are within the range found in blood during epidural analgesia.42 In the current study, the action of bupivacaine can be explained by a systemic sodium channel blockade, antiinflammatory activity, NMDA receptor blockade, or a combination of all these effects. The fact that our subjects did not differ significantly in their withdrawal thresholds according to who received intercostal or intraperitoneal injections could be because the intercostal route entails significant systemic absorption that may be responsible for bupivacaine’s systemic effects.

In summary, in a rib retraction model of chronic neuropathic pain, our data suggest that systemic or intercostal low-dose bupivacaine prevents allodynia after thoracotomy.

Due to the relatively low dosage necessary to achieve a significant treatment effect, bupivacaine seems to have a relatively high therapeutic ratio in this setting. Therefore, we think that a systemic one-time dose before surgery might be useful as a pre-or postoperative intercostal block, for both postoperative analgesia and prevention of neuropathic pain. Human studies are needed to validate our results and for potential prevention of CPTP in clinical practice.


   Footnotes
 
Accepted for publication April 2, 2008.

Supported by NIH grant GM 64051 to PG (Bethesda, MD).


   REFERENCES
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 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2008 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press