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Anesth Analg 2001;93:466-471
© 2001 International Anesthesia Research Society

REGIONAL ANESTHESIA

Topical Application of Acidic Bupivacaine to the Lumbar Ganglion Induces Mechanical Hyperalgesia in the Rat

Jun-Ming Zhang, MS, MD*, Yuko Homma, MD*, William E. Ackerman, MD{dagger}, and Sorin J. Brull, MD*

*Department of Anesthesiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and {dagger}Integrative Pain Medicine of Arkansas, Little Rock, Arkansas

Address correspondence and reprint requests to Jun-Ming Zhang, MS, MD, Department of Anesthesiology, Slot 515, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR 72205. Address e-mail to ZhangJunming{at}uams.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
To investigate the neurologic mechanisms of acidic local anesthetic-induced low back pain in humans, we administered bupivacaine and buffered saline at acidic or alkalinized pH at the L5 dorsal root ganglion (DRG) of rats via a hole drilled through the transverse process covering the DRG. Behavioral changes were tested before and after bupivacaine or saline administration. Results indicate that acute single-dose infusion of the DRG with bupivacaine (0.5%) at acidic pH (5.5) induced ipsilateral mechanical hyperalgesia that lasted for 7 days. Acute infusion of alkalinized bupivacaine (pH 7.2), however, caused only minor hyperalgesia that lasted <3 days. Similar results were obtained when bupivacaine was replaced with saline. Alternatively, chronic delivery of acidic saline to the DRG via a subcutaneously implanted osmotic pump resulted in a significant decrease in the withdrawal threshold on the ipsilateral hind paw that lasted for 10 days. In rats receiving chronic treatment of the DRG with alkalinized saline, mechanical hyperalgesia lasted for only 3 days. The results demonstrated that acidic bupivacaine deposited at the DRG causes pain and hyperalgesia when the effects of the local anesthetic have dissipated. These findings may explain the limited therapeutic effects of some acidic local anesthetics used for management of cancer-related and chronic back pain.

IMPLICATIONS: Acidic bupivacaine administered at the L5 lumbar ganglion causes pain and hypersensitivity of the hind paw in the rat. These findings may explain the limited therapeutic effects of some acidic local anesthetics used for treatment of cancer-related and chronic back pain.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Intraspinal analgesia by means of local anesthetics (e.g., bupivacaine) has been used to manage cancer pain as well as acute and chronic back pain (1–3). Therapies for the treatment of such chronic pain conditions involve the administration of local anesthetics either intrathecally or epidurally to nerves or nerve roots. If the acidity of the local anesthetic solution were responsible for the induction of persistent pain, this mechanism would help to explain the variable effects of such therapy, because dorsal root ganglia are fully exposed to local anesthetics during intrathecal or epidural administration.

Severe back pain has been experienced by a group of patients receiving epidural anesthesia with certain local anesthetics (e.g., chloroprocaine) (4). A significant association was also found between the development of long-term backache and epidural anesthesia for labor analgesia (5). The mechanisms responsible for the development of backache after epidural anesthesia are unknown. Although the preservative disodium EDTA may be an important factor, the acidic pH of a local anesthetic may also contribute to the generation of this problem. This hypothesis is supported by the finding that acidic local anesthetic-induced cutaneous burning pain can be dramatically reduced by alkalinization of the local anesthetic before its infiltration in humans (6).

Dorsal root ganglion (DRG) neurons, which normally convey information from peripheral sensory receptors to the central nervous system, may become an important source of ectopic discharge or pain after an injury of the peripheral nerve or the ganglion itself (7–11). Extracellular environment acidification produces nociceptor excitation in rat skin and burning pain in humans (12–14), and it induces prolonged membrane depolarization accompanied, occasionally, by the generation of action potential discharges that are similar to the capsaicin-induced excitatory effects (15,16). In addition, rapid acidification of the extracellular fluid can increase the open probability of capsaicin gated ion channels and facilitate the inward current evoked by capsaicin in DRG cells (17,18). Acidic local anesthetics may cause pain by directly activating nociceptive sensory neurons.

We hypothesized that bupivacaine at an acidic pH, when applied directly to the DRG, would induce pain and hyperalgesia by activating the nociceptive neurons similar to that induced peripherally (6). Our hypothesis is based on previous observations of Bromage et al. (19), who observed that some patients who received epidural bupivacaine at an acidified pH of 3 complained of back and leg pain, whereas those patients who received bupivacaine at a pH of 6 had no complaints of pain. Experiments were undertaken that used a newly developed animal model in our laboratory in which local anesthetic or buffered saline at different pH were delivered locally to the lumbar ganglion in vivo to investigate the role of pH on cutaneous mechanical and thermal sensitivity. Understanding the mechanisms of acidic local anesthetic-induced hyperalgesia may provide an insight into the development of chronic pain syndromes (such as back pain) and may guide and facilitate more effective therapy.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
A total of 39 male Sprague-Dawley rats weighing 200–250 g were used in all experiments. Bupivacaine (0.5%) or HEPES-buffered saline (containing, in mM: 140 NaCl, 3 KCl, 25 glucose, 1 CaCl2, 1 MgCl2, and 10 HEPES) at acidic pH (5.5, experimental) or alkalinized pH (7.2, control) was delivered locally to the L5 DRG in vivo by using procedures as described in detail below. Each of 39 rats received one of the six treatments listed in Table 1. The experimental protocol was reviewed and approved by the Institutional Animal Care and Use Committee.


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  		Table 1. Numbers of Rats Used in Different Types of Treatments
 
Acute Topical Application of Local Anesthetics/Saline to the DRG In Vivo
The rats were anesthetized with pentobarbital (40 mg/kg, intraperitoneally). With the rat in the prone position, a midline surgical incision was made at the L4 to L6 spinal level. After separation of the right paraspinal muscles from the vertebrae, the L5 spinal nerve that courses through the intervertebral foramen was identified, and a small hole (diameter, 0.49 mm) was drilled through the transverse process over the DRG. The drill bit had a predetermined and limited length to prevent it from injuring the underlying ganglion. The location of the hole was determined according to the course of the L5 spinal nerve and was approximately 2 mm off the inferior edge of the transverse process (Fig. 1A). A 25-gauge needle (diameter, 0.5 mm) that was cut short before the surgery to a length less than the thickness of the transverse process (approximately 2 mm) was forced into the hole in close proximity to the DRG, but without contacting the ganglion. Then, 50 µL saline or bupivacaine was slowly injected into the hole through the inserted needle via a microsyringe. The needle with attached syringe was left in place for at least 3 min after the end of the injection to ensure complete delivery of the solutions and avoid possible extravasation outside the DRG site.



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  		Figure 1. Schematic drawing of the intended relationships between the positions of the drilled orifice, the dorsal root ganglion, and lumbar vertebrae. The orifice was located along the course of L5 spinal nerve and was approximately 2 mm off the inferior edge of the transverse process covering the ganglion. A, a 2-mm-length needle was inserted into the hole for acute drug delivery. B, an L-shaped catheter was inserted into the hole with its output exposed to the ganglion. The other end of the catheter was connected to an osmotic minipump, which had been prefilled with buffered saline at different pH, and was implanted subcutaneously.

 
Surgical Procedure for Chronic Drug Delivery: Implantation of Osmotic Pump
After a hole was drilled according to the procedure described previously, a piece of L-shaped, stainless steel catheter (diameter, 0.5 mm; length, 1.5–2 mm), instead of a needle, was inserted into the hole in close proximity to, but without contacting, the ganglion. The steel catheter was attached to an osmotic minipump (ALZET; Alza Corp., Mountain View, CA) via a piece of fine silicon tubing (Fig. 1B). The minipump was implanted subcutaneously and secured by suturing to the spinal ligaments. Implanted pumps had a volume of 200 µL, capable of delivering solutions at a rate of 1 µL/h for seven consecutive days. The implanted pump was filled with the buffered saline at the predetermined pH. The tube leading from the pump was filled with the same solution as the pump solution. The surgical incision was closed in layers, and Augmentin (7.52 g to 500 mL drinking water, amoxicillin/clavulanate potassium; SmithKline Beecham, Philadelphia, PA) was given to all rats daily for at least 3 days after the operation.

Behavioral Testing Procedure
The testing procedure has been described in detail in previous publications (20,21). In this study, rats were inspected and tested every other day for 5 days before surgery (three testing sessions) and every other day for 14 days after surgery (seven testing sessions) for a total of 10 testing sessions.

As described previously, the rat was placed in a Plexiglas box with a mesh floor through which von Frey filaments could be applied to the paws. Testing began after 15 min of acclimatization. Each filament was applied to six different spots on the ventral surface of the paw. The duration of each stimulus was 1 s, and the interstimulus interval was approximately 10–15 s. The filaments were applied in order of their bending forces (20, 40, 60, 80, and 120 mN), with a given filament delivered to each spot alternatively from one paw to the other, in sequence, from the first to the sixth spot. The withdrawal threshold, defined as the force associated with a 50% response of foot withdrawal, was calculated by fitting the force-response data to the Hill equation by use of a curve-fitting program, Microcal Origin 6.0 (Microcal Software, Inc., Northampton, MA) (21). A difference score was computed by subtracting the withdrawal threshold of the control side from that of the ipsilateral side. Negative scores indicate a lower threshold on the ipsilateral side. The mean withdrawal thresholds (baseline) of both hind paws before surgery were obtained from an average of three testing sessions.

Rats were placed in a clear plastic cage on an elevated floor of window glass. A radiant heat source beneath the glass floor was aimed at the plantar surface of the hind paw. Stimulus onset activated a timer that was controlled by a photocell positioned to receive light reflected from the hind paw. When the hind paw exhibited a withdrawal response, the paw movement interrupted the photocell’s light and automatically stopped the timer. The hind paws were tested alternately, with 5-min intervals between consecutive tests. Five latency measurements were obtained for each hind paw in each test session. The five latencies per side were averaged, and a difference score was computed by subtracting the average latency of the control side from the average latency of the ipsilateral side. Negative scores indicate a lower threshold on the ipsilateral side.

Preparation of Bupivacaine at Alkalinized pH
Bupivacaine (0.5%) (Abbott Laboratories, North Chicago, IL) at a pH of 5.5 and 7.2 was freshly prepared immediately before the surgery. Adjusting the pH for bupivacaine was accomplished by adding 8.4% sodium bicarbonate to the solution, as described previously (22). The solution was then filtered through a 0.22-µm Millipore (Pall Corp., Ann Arbor, MI) and stored temporally in sterile vials.

Statistical Analysis
Data are expressed as mean and SEM. Differences in withdrawal thresholds over time were tested by using one-way repeated-measures analysis of variance (RM ANOVA) followed by all pairwise comparisons. Differences in withdrawal thresholds between before surgery and a specific day after surgery were tested by using a paired t-test. A two-way RM ANOVA involving the factors treatment (bupivacaine or buffered saline) and postoperative day was used to test the significance of differences in withdrawal thresholds between experimental conditions. A probability of 0.05 was chosen as the criterion for significance.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
In seven rats, after three sessions of behavioral testing, surgery was performed, followed by injection of 50 µL of bupivacaine (pH 5.5) into the hole drilled through the transverse process that covered the DRG. In another seven rats, after the same surgical procedure, the same amount of bupivacaine at pH 7.2 was delivered topically to the DRG. Behavioral testing was performed for 14 days after surgery.

Rats that received a single injection with acidic bupivacaine had gait and hind paw postures that were not different from those of control rats or normal rats. However, tactile stimuli delivered to the ventral surface of the hind paw evoked responses in acidic bupivacaine-treated rats that were distinctly different from those of control rats. Rats often withdraw the hind paw vigorously in response to mechanical poking, accompanied by shaking or licking of the affected paw and by holding it above the floor for at least 10–15 s. This latter behavior was observed rarely in normal rats and only occasionally during the first postoperative day in control rats.

The withdrawal thresholds for the ipsilateral hind paw decreased by 18 mN (1 g = 9.8 mN, P < 0.01, paired t-test) on the first postoperative day in the Acidic Bupivacaine (Experimental) group and by 10 mN (P < 0.01, paired t-test) in the Control group rats. The withdrawal thresholds for contralateral hind paw decreased by 7 mN in the Experimental group and by 2 mN in Control group rats (P < 0.05, paired t-test, from presurgery control values). In rats that received treatment of the ganglion with acidic bupivacaine, hyperalgesia lasted approximately 7 days after surgery (P < 0.01, one-way RM ANOVA) (Fig. 2A). Peak hyperalgesia occurred on approximately the fifth postoperative day. In control rats, however, the withdrawal threshold returned to the presurgical baseline by the third postoperative day (the second testing session after surgery) (P < 0.05, one-way RM ANOVA).



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  		Figure 2. Time courses and magnitudes of hyperalgesia measured by the mechanical stimulation-evoked hind paw withdrawal reflex in rats, which underwent different treatments of the L5 lumbar ganglion. Negative difference scores (below the dotted line) indicated a lower nociceptive threshold on the ipsilateral side. *P < 0.01 compared with the presurgery value. Day 0 = average of three testing sessions before surgery. A, acute, topical application of bupivacaine at different pH to the dorsal root ganglion (DRG). B, acute, topical application of buffered saline at different pH to the DRG. C, chronic infusion of the DRG with buffered saline at different pH. Note: some of the SEs are smaller than the size of markers.

 
Cutaneous sensitivity (difference scores between ipsi- and contralateral hind paws) to radiant heat applied to the hind paw did not change significantly in any rats throughout the whole testing period (P < 0.05, one-way RM ANOVA) (Fig. 3A).



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  		Figure 3. Difference scores of foot withdrawal latency before and after acute infusion of the L5 ganglion with bupivacaine or buffered saline at different pH. A, acute, topical application of bupivacaine at different pH to the dorsal root ganglion (DRG). B, acute, topical application of buffered saline at different pH to the DRG. C, chronic infusion of the DRG with buffered saline at different pH.

 
To further examine whether mechanical hyperalgesia developed as a result of the acidic pH and not bupivacaine itself, these experiments were repeated with buffered saline instead of bupivacaine. Thus, six rats (prepared as described previously) received buffered saline at acidic pH, and six rats received the same amount of saline at alkalinized pH. Mechanical hyperalgesia developed as early as the first postoperative day in both groups of rats, but only in the ipsilateral hind paws. On the first postoperative day, the withdrawal thresholds decreased by 45 mN (P < 0.01, paired t-test) and 22 mN (P < 0.01, paired t-test) in those rats treated with acidic saline (Experimental) and alkalinized (Control) saline, respectively. The hyperalgesia lasted more than 14 days in Experimental rats (P < 0.01, one-way RM ANOVA) but was only transient (1 day) in Control rats (P < 0.05, Day 3 to Day 13 after surgery, one-way repeated ANOVA) (Fig. 2B). Compared with Bupivacaine-Treated rats, however, Buffered Saline-Treated rats exhibited more severe hyperalgesia, as indicated by a significantly larger difference score of the ipsilateral and contralateral hind paws within 3 days after surgery (P < 0.01, two-way RM ANOVA). The hyperalgesia also lasted longer in Buffered Saline-Treated rats than Bupivacaine-Treated rats. The latency of the hind paw withdrawal reflex in response to noxious heat was not significantly changed in either group, before or after surgery (Fig. 3B).

To exclude the involvement of acute physical damage to the ganglion during the initial surgery in the etiology of acidic pH-induced long-term cutaneous hyperalgesia and to examine whether chronic acidic exposure of the ganglion will cause any changes in the cutaneous sensitivity, osmotic minipumps containing buffered saline at different pH were implanted subcutaneously in 13 rats (7 with acidic pH, 6 with alkalinized pH).

Behavioral testing results showed that for Acidic Saline-Treated rats, the withdrawal thresholds for the ipsilateral paws decreased significantly after surgery. Preoperative withdrawal thresholds on the ipsilateral hind paw decreased by 18 mN 1 day after surgery (P < 0.01, paired t-test). Postoperative thresholds were lower than preoperative thresholds for 11 postoperative days (P < 0.01, one-way RM ANOVA) (Fig. 2 C). The withdrawal threshold on the contralateral foot also decreased by 14 mN on the first postoperative day (P < 0.01, paired t-test). However, the decreased withdrawal thresholds of the contralateral foot lasted for only 3 days after surgery (P < 0.01, one-way RM ANOVA) (Fig. 2C).

Compared with rats with acute treatment, chronic treatment of the DRG with acidic-buffered saline produced ipsilateral hyperalgesia that was lower in magnitude for the first 3 days after surgery. The hyperalgesia on the contralateral hind paws, however, was more severe in rats with chronic acidic treatment than rats with acute treatment of the ganglion (P < 0.05, two-way RM ANOVA). There was no significant change in foot withdrawal latency to noxious heat before and after surgery in Acidic Saline-Treated rats or Alkalinized Saline-Treated rats (Fig. 3C).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study suggests that bupivacaine induced behavioral changes as a result of its acidic pH. Alkalinization of local anesthetics can significantly shorten the onset time of sensory anesthesia (22). On the basis of our results, the longer sensory onset time of regular, nonalkalinized bupivacaine may be attributed to its activation of nociceptive nerve endings when delivered intradermally or to the excitation of the cell bodies of nociceptors during epidural anesthesia. Thus, the expected local anesthetic effects of bupivacaine may have been markedly diminished when used at an acidic pH.

Results from this study are supported by early clinical findings that bupivacaine at an acidic pH, such as procaine (4), causes back pain in humans when administered epidurally (19). In that study, the authors found that large doses (>=40 mL) of acidic chloroprocaine containing EDTA resulted in an increased incidence of deep burning lumbar back pain. However, we believe that when acidic local anesthetics are used to treat intractable cancer pain or chronic back pain, pain evoked by acidic pH may often be covered by or mixed with the existing pain.

We also demonstrated that acidic saline induced more severe hyperalgesia when delivered acutely with a larger volume (50 µL) than when delivered chronically with a relatively smaller volume (1 µL/h for seven days), suggesting that the volume of the local anesthetic used to perfuse the ganglion also contributed to the development of cutaneous hyperalgesia. These results agree with clinical observations that procaine-induced back pain in humans is related to the volume of local anesthetics used (4).

In this study, because bupivacaine was delivered locally to the DRG, we have demonstrated, for the first time with an animal model, that acidic local anesthetic-induced low back pain during epidural anesthesia may have resulted from its activation of nociceptive DRG neurons. It is possible that a large concentration of protons in the acidic bupivacaine solution activated nociceptive DRG neurons, altered membrane properties of the DRG, and induced abnormal spontaneous neural activity (15,16). The effect of the protons may last beyond the duration of anesthesia and may eventually induce "central sensitization" of the spinal neurons (23,24). Once established, the central sensitization of the dorsal horn neurons will last for a long time and will be independent of the input from the periphery (e.g., firing from the DRG neurons) (23). This may explain why acidic local anesthetic-induced pain and hyperalgesia persisted after the effects of the local anesthetic dissipated. Acidic bupivacaine (given acutely) produced hyperalgesia that was lower in magnitude and shorter in duration than acidic saline, suggesting that a bupivacaine-induced anesthetic effect may have partially offset its hyperalgesic effect.

A possible limitation of this study is that we have not investigated the chronic effect of acidic and alkalinized bupivacaine on the development of hyperalgesia. A major reason was that bupivacaine at a pH of 7.2 became crystallized (precipitation) within several hours of preparation. However, in a previous study, we found that chronic infusion of the DRG with lidocaine at a pH of 6.2 reduced mechanical hyperalgesia and allodynia caused by a chronic compression of the lumbar ganglion (21).

It is conceivable that the debris resulting from drilling the hole through the transverse process may have contributed to the development of mechanical hyperalgesia. In this study, we did not use a group of rats with sham surgery because we believe that the effect of drilling the hole, if present, is minor because results from the control rats showed only transient hyperalgesia after surgery.

Rats with the chronic delivery of buffered saline at alkalinized pH to the DRG developed ipsilateral hyperalgesia that was more severe than in rats with acute treatment; this suggests that the chronic delivery system itself may cause minor, transient irritation of the ganglion. However, this minor effect does not influence our results significantly: buffered saline at acidic pH produces more severe hyperalgesia when delivered acutely or chronically to the DRG than normal pH saline.

In summary, the results of this study demonstrated the feasibility of local irrigation of DRG, in vivo, without causing mechanical damage to the ganglion. It also demonstrated that local perfusion of the lumbar ganglion with acidic bupivacaine (or buffered saline) induced unilateral hyperalgesia, which can be prevented by prealkalinization of the solutions to a normal pH of 7.2. Local anesthetic alkalinization before epidural anesthesia may improve its therapeutic effects on the treatment of cancer-related pain and may decrease the incidence of chronic pain syndromes such as chronic back pain or sciatica.


   Acknowledgments
 
Supported by the National Institute of Neurological Disorders and Stroke Grant R1NS39568A (J-MZ and SJB) and by the University of Arkansas for Medical Sciences Intramural Grant Program.


   References
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 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 2, 2001.




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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 2001 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press