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European Journal of Pain xxx (2008) xxx–xxx
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European Journal of Pain
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Effects of intrathecal lidocaine on hyperalgesia and allodynia following chronic
constriction injury in rats
Jie Tian a,1, Yiwen Gu a,1, Diansan Su a, Yichao Wu b, Xiangrui Wang a,*
a
b
Department of Anesthesiology, Renji Hospital, Medical School of Shanghai Jiaotong University, Shanghai, China
CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA, USA
a r t i c l e
i n f o
Article history:
Received 9 September 2007
Received in revised form 6 March 2008
Accepted 29 March 2008
Available online xxxx
Keywords:
Intrathecal lidocaine
Neuropathic pain
Thermal hyperalgesia
Tactile allodynia
Chronic constriction injury
a b s t r a c t
The present study investigated the effects of different doses of intrathecal lidocaine on established thermal hyperalgesia and tactile allodynia in the chronic constriction injury model of neuropathic pain,
defined the effective drug dose range, the duration of pain-relief effects, and the influence of this treatment on the body and tissues. Male Sprague–Dawley rats were divided into five groups and received
intrathecal saline or lidocaine (2, 6.5, 15, and 35 mg/kg) 7 days after loose sciatic ligation. Respiratory
depression and hemodynamic instability were found to become more severe as doses of lidocaine
increased during intrathecal therapy. Two animals in the group receiving 35 mg/kg lidocaine developed
pulmonary oedema and died. Behavioral tests indicated that 6.5, 15, and 35 mg/kg intrathecal lidocaine
showed different degrees of reversal of thermal hyperalgesia, and lasted for 2–8 days, while 2 mg/kg lidocaine did not. The inhibition of tactile allodynia was only observed in rats receiving 15 and 35 mg/kg lidocaine, and the anti-allodynic effects were identical in these two groups. Histopathologic examinations on
the spinal cords revealed mild changes in rats receiving 2–15 mg/kg lidocaine. However, lesions were
severe after administration of 35 mg/kg lidocaine. These findings indicate that intrathecal lidocaine has
prolonged therapeutic effects on established neuropathic pain. The balance between sympathetic and
parasympathetic nervous activities could be well preserved in most cases, except for 35 mg/kg. Considering the ratio between useful effects and side effects, doses of 15 mg/kg are suitable for intrathecal injection for relief of neuropathic pain.
Ó 2008 European Federation of Chapters of the International Association for the Study of Pain. Published
by Elsevier Ltd. All rights reserved.
1. Introduction
Neuropathic pain is one of the most significant health problems
in the world. Although numerous methods have been applied in
the clinics to treat neuropathic pain, many patients report resistance to the available treatments. And issues such as tolerance to
and physical dependence on analgesics, efficacy of treatment alternatives, and high treatment costs plague both the clinicians and
patients. Studies in the implementation of improved therapies for
neuropathic pain, which consider not only analgesic effects, but
also other benefits (e.g., long-term pain-relief effect, improved
quality of life, low cost-effectiveness) have always generated considerable interest.
The use of systemic lidocaine has been extensively studied for
the treatment of chronic pain in the past years. Now there is accumulating evidence for the efficacy of systemic lidocaine to treat
neuropathic pain in both animal models and in clinical patients
(Mao and Chen, 2000; Smith et al., 2002). However, the effective* Corresponding author. Tel.: +86 2158752345x3198; fax: +86 2150903239.
E-mail address: [email protected] (X. Wang).
1
These authors contributed equally to this work.
ness seems to be dose-related (Kalso, 2005). The doses of systemic
lidocaine that are sufficient to relieve neuropathic pain are often
associated with intolerable side effects, such as dizziness, nausea,
seizures, and significant cardiac system injury, thus precluding a
routine use of this therapy (Martin and Eisenach, 2001). And only
certain types of neuropathic pain behaviors are responsive to systemic lidocaine administration (Sinnott et al., 1999; Mao and Chen,
2000).
Recently, evidence that lidocaine exerts some of its analgesic effects via actions in the spinal cord (Olschewski et al., 1998; Ness,
2000) has led to an interest in intrathecal therapy with this agent
for chronic pain treatment. Several studies have reported that large
doses of intrathecal lidocaine, which will generally lead to total
spinal anesthesia (TSA) in the clinics, produced reduced pain scores
for up to 7 days in patients (Yokoyama et al., 2002). The unexpected long-term pain-relief effect of intrathecal lidocaine has
added a new modality to the treatment regimen for intractable
neuropathic pain. However, a number of issues regarding this
treatment, including the effective, meaningful drug dose range,
the durability of pain-relief effects, and long-term outcomes of
intrathecal anesthetic, remain unclear, because in this kind of clinical study, further investigation is obviously too dangerous and
1090-3801/$34.00 Ó 2008 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejpain.2008.03.013
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unethical. Therefore, there is a need to use animal models of intrathecal lidocaine treatment in the neuropathic states, to broaden
our knowledge of this therapy, and to help to have a rational application, rather than an empirical clinical practice of this treatment.
In the present study, we examined the dose–response and detailed time course of pain-relieving effect of single intrathecally
administered lidocaine in a rat model of neuropathic pain induced
by chronic constriction injury (CCI) of the sciatic nerve, which has
been reported to develop reliable, long-lasting hyperalgesia and
allodynia comparable in character to the clinical syndrome of neuropathic pain (Bennett and Xie, 1988). Histopathologic changes
that intrathecal lidocaine might induce on the spinal cord of these
animals were further evaluated to explore the safety of this
treatment.
2. Methods
Male Sprague–Dawley rats weighing between 250 and 300 g
were used. The rats were fed rat chow with free access to tap water
and housed in temperature- and humidity-controlled animal quarters with 12 h light/dark cycle. All rats were housed for a minimum
of 1 week prior to use. The procedures were approved by the Institutional Animal Care Committee.
2.1. Chronic constriction injury (CCI) surgery
CCI surgery was carried out as described previously (Bennett
and Xie, 1988). Briefly, rats were anesthetized with 10% chloral hydrate (3 ml/kg, i.p.), and a 7-mm segment of the left common sciatic nerve was exposed at the mid-thigh level, proximal to the
sciatic trifurcation. Four 4–0 chromic gut sutures were tired
around the nerve at intervals of 1 mm, and ligatures were tied
loosely enough so that, on visual inspection, blood flow was not
obstructed. The right side of the body was exposed but not ligated.
The surgical incision was completed by closing the muscles and
skin in layers. The CCI surgery day was regarded as post-operative
day (POD) 0.
2.2. Intrathecal catheter implantation
On the fourth day after CCI surgery (POD 4), the rats were anesthetized by intraperitoneal injection of 10% chloral hydrate, and
intrathecal catheters composed of polyethylene (PE-10) tubing
were introduced into the subarachnoid space using a previously
described modification (Størkson et al., 1996) of the method of
Yaksh and Rudy (1976). Catheters were passed through a slit in
the L5-6 interspace, and advanced 2–3 cm into the intrathecal
space so that the tip terminated near the lumbar enlargement.
The right position of the catheters was verified by cautious aspiration of cerebrospinal fluid (CSF). The catheters were then implanted subcutaneously on the back of the rats, and externalized
between the ears for injection. Rats exhibiting any evidence of motor or additional sensory dysfunction were excluded in the further
study 3 days after catheters implantation.
2.3. Intrathecal lidocaine injection
On POD 7, the rats equipped with catheters were anesthetized
under inhalational anesthesia with ether delivered through a facesnout mask. The right jugular vein and caudal artery of the rats
were cannulated with 22-G intravenous catheters (BD AngiocahTM;
Brazil), for administration of vasoconstrictors, and for measurements of mean arterial blood pressure (MAP), respectively. Refitted 16-G intravenous catheters (BD AngiocahTM; Brazil) were
advanced endotracheally for preparation of mechanical
ventilation.
The rats were then randomly divided into five groups (n = 6–10
in each group), and received intrathecal solutions as follows: (1)
control group: 0.5 ml 0.9% saline; (2–5) lidocaine groups: 0.5 ml
of 2, 6.5, 15, or 35 mg/kg lidocaine (pH ranged from 4.48 to
5.38), in group L2, L6.5, L15, or L35, respectively. Lidocaine was supplied as a 2% solution, and diluted in normal saline to 0.5 ml
equally in all the groups, to avoid the influence of different intracranial pressures on the development of pain. Such a volume was
selected because previous studies have shown that a saline injection of 0.5 ml did not induce any brain stem responses (Yamada
et al., 1994, 1997). All the solutions were injected through the
intrathecal catheters with an injection pump (PerfusorÒSpace, B.
Braun, Germany) at a constant rate of 0.10 ml/min. Ether inhalation was stopped immediately after onset of intrathecal injection.
At the end of each injection, the intrathecal catheter was flushed
with 15 ll of 0.9% saline solution for the dead space of the catheter.
Rectal temperature was monitored and maintained within 0.5 °C
throughout the procedure by means of a heat pad.
Respiration of the rats was observed carefully once intrathecal
injection had begun. The rats were mechanically ventilated (Rat
Ventilator, RSP1002, Kent Scientific Inc., USA) with an oxygen/air
mixture immediately at the sight of irregular respiration. Onset
time of mechanical ventilation was recorded. MAP was continuously monitored during intrathecal lidocaine therapy. A hypotension episode was defined as a drop in pressure to less than 30%
from the baseline value, and was treated by continuous intravenous administration of dopamine at an initial rate of
100 lg kg 1 min 1. The rate of administration was decreased by
20 lg kg 1 min 1 from its current level (80, 60, 40, 20, and
0 lg kg 1 min 1), when blood pressure returned to normal range
and remained stable for at least 5 min. In the case that the administration rate was kept at 100 lg kg 1 min 1 for more than 5 min,
Voluven (HAES-steril 130/0.4, 6%, Fresenius Kabi, Germany), which
is a clinically commonly used colloidal fluid, would be infused continuously using a B. Braun injection pump at a rate of 0.2 ml/min,
and was stopped when the rate of dopamine decreased. The total
doses of dopamine and Voluven administration were recorded.
The total duration time was comprised between the beginning of
injection and complete recovery from the block, which was defined
as comeback of spontaneous ventilation and free movement of
hind limbs without any limitation.
The wounds of the animals were closed with suture after recovery. They were then housed in groups of 2 or 3 in clear plastic cages
with solid floors covered with 3–6 cm of soft bedding, and fed with
free access to food and water.
2.4. Behavioral tests
Yiwen Gu, who was blinded to the animal groups, performed
the behavioral tests. The thermal hind paw withdrawal latency
and Von Frey withdrawal threshold of all animals was obtained 3
days prior to CCI surgery (pre-lesion baseline, PRE), on POD 1,
POD 3, POD 6, and each day after intrathecal lidocaine therapy
(post-therapeutic day [PTD] 1, PTD 2, PTD 3, . . .) until PTD 10, as
the pilot study showed that the values returned to pre-therapeutic
levels in all the groups on PTD 10. Those responding abnormal at
baseline values were excluded from the beginning.
2.4.1. Thermal paw withdrawal latency
Thermal hyperalgesia was assessed with a test apparatus consisting of a movable radiant heat source and a controller (BME410A, Institute of Biomedical Engineering, CAMS) as previously described (Villetti et al., 2003). The rat was placed on a smooth glass
surface in a box measuring 17 22 14 cm. The temperature of
the glass surface was maintained at 25 ± 1 °C. The radiant heat
source under the glass floor was positioned directly under the
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desired hind paw, and the controller detected the paw withdrawal
latency (PWL) in 0.1-s steps, and switched off the heat source when
the animal withdrew its hind paw. The intensity of the heat stimulus was maintained constant throughout all experiments, and
was pre-calibrated to give a baseline PWL of approximately 10–
15 s in control rats. Cut-off latency was set at 30 s to prevent tissue
damage of the plantar zone. Thermal stimulus was delivered five
times to each hind paw at 10-min intervals. The five responses
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 ligated side.
2.4.2. Von Frey withdrawal threshold
The pressure algometer was used to test mechanical threshold
as performed by Tabo et al. (1999). Rats were placed on a metal
mesh cage, which allowed access to the paws. A set of Von Frey filaments was applied, in ascending order, to the mid-plantar left
hind paws. Each filament was delivered five times at approximately 5-s intervals; if the rat did not withdraw the paw, a filament with the next higher bending force was similarly delivered.
The procedure was continued until application of the filament elicited a paw withdrawal on each of the five applications. The procedure was repeated two times, and the average force was taken as
threshold.
2.5. Histopathologic study
In another set of experiments, animals underwent the same
treatments. The set of rats was killed immediately after recovery
from intrathecal lidocaine therapy (POD 7 or PTD 0), for histopathologic examination of the spinal cord (lumbar enlargement).
Rats were killed with a chloral hydrate overdose. Hearts were
perfused in situ with 0.9% saline (37 °C) followed by 4%
paraformaldehyde, first at 37 °C, then at 4 °C. The lumbar spinal
cord, including both the anterior and posterior roots, was
sampled by laminectomy. All specimens were stored in 4% paraformaldehyde (4 °C) until histopathologic examination. Spinal
cords were embedded in paraffin, and then cut with a microtome in 6-lm section slices. Examinations were performed on
6 hematoxylin- and eosin-stained slices in each segment under
an Olympus B40 microscope. A neuropathologist, who was
blinded to intrathecal administration, examined the morphologic
pathology.
2.6. Statistics
All data were expressed as mean ± SEM. The mean values after
nerve injury or after intrathecal therapy vs. pre-lesion baseline values (within group), and a control mean vs. each group mean at
each time point (between group) comparisons were done by repeated measures analysis of variance, and post hoc Student–Newman–Keuls test. P < 0.05 was considered significant.
3. Results
3.1. General observations
After CCI surgery, the rats developed neuropathic pain syndrome as previously described by Bennett and Xie (1988). Unusual
gait and posture of the rats could be seen as early as on the first day
after surgery (POD 1). In general, the affected toes, which are normally spread and apart while walking or standing, became together and slightly ventroflexed, with the corresponding hind
paws everted, and placed clumsily while walking. The rats were often seen to raise the affected hind paws from the floor and hold
them in a protected position. Licks of the affected paws were frequently seen.
18.6% (8 of 43) rats were excluded from the study after intrathecal catheter implantation due to traumatic hind limb palsy caused
by catheterization (n = 6), or insufficient fixation (n = 2).
After recovery from intrathecal solutions injections, the unusual appearance of the affected hind paws was retained in all
the rats. However, raising and licks of the paws were rarely seen
in groups L15 and L35, which were still frequent in control group
and the groups receiving lower doses of lidocaine. Besides the
same posture and different action above, all the animals were
in good health, and the behavior was generally normal. No
palsy or additional sensory dysfunction was encountered. The
fur of all rats was sleek and well groomed. There was no significant difference among the weights of the five groups (data not
shown).
3.2. Systemic effects of intrathecal lidocaine
Two rats in group L35 died during recovery from intrathecal
lidocaine therapy. Frothy and pink sputum was seen in the dying
rats. Post-mortem dissection revealed extensive pulmonary oedema upon gross examination. A total of 33 rats were analyzed by
behavioral tests. The number of rats in each group was as follows:
control group, n = 6; group L2, n = 6; group L6.5, n = 6; group L15,
n = 8; group L35, n = 7.
In all groups, a total volume of 0.5 ml liquid was injected
through the catheter over 5 min. The saline injection failed to induce any significant changes in respiration, or in hemodynamics
(Table 1, Fig. 1). With the lowest dose (2 mg/kg) of lidocaine, no
rats presented respiratory inhibition, while mechanical ventilation
was needed in five of six rats in group L6.5, and all the animals in
groups L15 and L35 (Table 1). Significant hypotension was observed
soon after lidocaine injection (Fig. 1). Dopamine administration
was required in all the rats with 6.5 mg/kg or higher doses of lidocaine, while only in two-thirds of rats receiving 2 mg/kg lidocaine.
The dose of dopamine ranged from 0.31 to 1.94 mg, with the volume of Voluven infusion ranging from 0 to 2.06 ml (Table 1). Complete recovery of intrathecal anesthesia was observed in all rats in
control group, group L2, L6.5, and L15, but only in 77.8% rats in group
Table 1
Systemic effects of intrathecal saline or 2–35 mg/kg lidocaine in rats (mean ± SEM)
Group
Onset time (min)
Dopamine (mg)
Voluven (ml)
Total time (min)
Control (n = 6)
L2 (n = 6)
L6.5 (n = 6)
L15 (n = 8)
L35 (n = 7)
na
na
3.60 ± 0.62 (n = 5)
1.59 ± 0.21
1.01 ± 0.17
0
0.31 ± 0.10
0.61 ± 0.13
0.93 ± 0.06
1.94 ± 0.14
0
0
0.50 ± 0.22
1.13 ± 0.08
2.06 ± 0.12
13.83 ± 0.70
32.67 ± 0.84
40.50 ± 4.98
76.25 ± 4.40
94.29 ± 11.79
na = not applicable.
Onset time = Onset time of mechanical ventilation; dopamine was used to treat drop in mean arterial pressure; Voluven treatment was used if blood pressure remained low
after dopamine administration at highest level for more than 5 min; total time = from beginning of saline/lidocaine injection until complete recovery from the block.
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Fig. 1. Variations of mean arterial blood pressure in rats receiving saline or 2–35 mg/kg lidocaine during intrathecal therapy. Significant hypotension occurred immediately
with intrathecal lidocaine, and required the use of dopamine in some groups (see text). *Indicates significantly different from control saline group at the same time at P < 0.05.
Mean values are shown, n = 6–8 in each group.
Fig. 2. Effects of intrathecal lidocaine on established thermal hyperalgesia caused by chronic constriction injury (CCI). Scores are expressed as the mean of difference between
ipsilateral and contralateral paw withdrawal latency (PWL). The PWL was markedly reduced on the ligated side since post-operative day (POD) 1 after CCI surgery, yielding
negative mean difference scores. The difference enlarged on POD 6. Single intrathecal injection of 6.5–35 mg/kg lidocaine significantly reversed the thermal hyperalgesia from
post-therapeutic day (PTD) 1. The difference scores were turned to positive values in rats receiving 15 and 35 mg/kg lidocaine. The anti-hyperalgesic effects remained for 2, 8,
and 8 days by 6.5, 15, and 35 mg/kg lidocaine, respectively. *Indicates significantly different from control saline group on the same day at P < 0.05. Mean values are shown,
n = 6–8 in each group.
L35, taking from 13.83 to 94.29 min (Table 1). As the intrathecal
drug dose increased, the doses of dopamine and Voluven administration also increased, and the total duration time became
prolonged.
At the end of intrathecal infusion in each group, the extent of
anesthesia level was determined by a skin clamp applied progressively cephalad until a response was elicited. No response was
encountered throughout the body in animals given 15 and
35 mg/kg lidocaine. The rats in the two groups were found unconscious, and dilation of pupils was observed. The level of sensory
block extended to the fore limb in groups L6.5, to the hind limb
in groups L2, and no block was revealed in control group.
3.3. Behavioral tests
3.3.1. Thermal paw withdrawal latency
The difference latency scores between the left side and the right
side of normal animals clustered around zero, as shown in Fig. 2.
The PWL was markedly reduced on the ligated side starting on
POD 1 after CCI surgery, yielding negative mean difference scores.
The difference enlarged on POD 6, and the scores remained stable
around 7 s during the following days in control group. No significant difference was found between group L2 and control group on
all the days. In contrast, infusion of 6.5, 15 and 35 mg/kg lidocaine
significantly reversed the thermal hyperalgesia beginning the first
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day after intrathecal therapy (PTD 1). The elevation of PWL on the
ligated side in group L6.5 was modest, and the difference between
the left side and the right side returned to the pre-therapeutic value 3 days after injection. Higher doses of 15 and 35 mg/kg lidocaine were able to turn the difference scores to positive values.
In other words, the PWL on the ligated side was even longer than
the normal side after treatment in these two groups. Lidocaine
(15 mg/kg) continued to elevate the PWL of the ligated side above
that of the normal side for 4 days, and the reversal of hyperalgesia
remained for 8 days. The therapeutic effect was even greater in rats
receiving 35 mg/kg lidocaine, with the PWL of the ligated side
above that of the normal side for 7 days. But the persistent effect
was no greater in group L35 than group L15.
3.3.2. Von Frey withdrawal threshold
There was no significant difference in Von Frey withdrawal
threshold among any of the tested groups at pre-lesion baseline.
CCI surgery was found to significantly lower the threshold on the
ligated side (Fig. 3), indicating that tactile allodynia had developed.
The mechanical withdrawal threshold was acutely elevated from
6.70 ± 1.17 and 5.44 ± 0.47 g before therapy to 17.79 ± 3.46 and
16.86 ± 2.28 g on PTD1 for groups L15 and L35, respectively, significantly above the pre-therapeutic levels. Infusion of saline or 2 and
6.5 mg/kg lidocaine, however, did not change the mechanical
threshold. The anti-allodynic effects in groups L15 and L35 peaked
on PTD 2 and 3, respectively, and both remained for 8 days. Statistical examination revealed no significant difference between these
two groups on all the days. The mechanical withdrawal threshold
values in the rats receiving 2 and 6.5 mg/kg intrathecal lidocaine
were not different from saline-infused animals throughout the
same period.
3.4. Histopathologic study
No specific histopathologic changes were seen in the spinal
cords in rats receiving saline, as shown in Fig. 4A. In contrast,
intrathecal lidocaine caused different degrees of lesions in the
treated rats.
5
In rats receiving 2 mg/kg lidocaine, mild infiltration of inflammatory cells and endoneuronal oedema were found in spinal cord.
The lesions were limited to the posterior root and posterior horn.
Other areas, such as the anterior horn, were intact. In groups L6.5
and L15, histopathologic changes were similar to those observed
in L2 group (data not shown for groups L2 and L6.5, representative
picture of group L15 was shown in Fig. 4B). However, rats receiving
35 mg/kg lidocaine presented more prominent lesions in the spinal
cords. In addition to inflammation and oedema, severe neurotoxicity, such as destruction of myelin sheaths and axonal structures
was frequently seen (Fig. 4C). The lesions were no longer restricted,
extending to the anterior horn. In some cases in group L35, red
blood cell infiltration was also found in the posterior root. Table
2 shows the incidence of the lesions with each drug dose.
4. Discussion
The present study investigated effects of different doses of single intrathecal lidocaine on established thermal hyperalgesia and
tactile allodynia caused by chronic constriction injury. In addition
to 2, 6.5, 15, and 35 mg/kg, we also studied several doses in between, including 4, 10, and 25 mg/kg. The results showed that
the anti-hyperalgesic effect of 4 mg/kg lidocaine was between that
of 2 and 6.5 mg/kg, 10 mg/kg between that of 6.5 and 15 mg/kg,
and 25 mg/kg between that of 15 and 35 mg/kg, whereas the
anti-allodynic effect of 4, 10, and 25 mg/kg was identical to that
of 2, 6.5, and 15 mg/kg, respectively (data not shown). These results, together with the present findings, indicate that certain
doses of single intrathecal lidocaine can produce long-term alleviation of established thermal hyperalgesia and tactile allodynia. But
the effects of lidocaine on the two kinds of pain do not appear to
share a common pattern. The degree and persistence of the antihyperalgesic effect is related to the dose of intrathecally administered lidocaine, and the doses of approximately 6.5 mg/kg and
higher are effective for reversal of hyperalgesia. Meanwhile, the
anti-allodynic effect of the drug demonstrates a ‘‘threshold” value
of about 15 mg/kg, and a ‘‘ceiling effect”, as 25 and 35 mg/kg lidocaine exerts no greater magnitude and durability of anti-allodynic
Fig. 3. Effects of intrathecal lidocaine on established tactile allodynia caused by chronic constriction injury (CCI). The Von Frey withdrawal threshold on the ligated side was
significantly decreased after CCI surgery. While the threshold was not changed by intrathecal saline or 2 and 6.5 mg/kg lidocaine, it was significantly elevated after injection
of 15 and 35 mg/kg lidocaine. The value returned to the level identical to control group both on post-therapeutic day (PTD) 8 in the two groups. Statistical examination
revealed no significant difference between 15 and 35 mg/kg groups on all the days. *Indicates significantly different from control saline group on the same day at P < 0.05.
Mean values are shown, n = 6–8 in each group. POD = post-operative day.
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Fig. 4. Representative pictures of hematoxylin- and eosin-stained slides in the spinal cords of rats receiving intrathecal saline or lidocaine (original magnification 100). (A)
No specific lesion was observed in the spinal cord after 0.5 ml intrathecal saline. (B) Mild infiltration of inflammatory cells and endoneuronal oedema could be seen in the
posterior root and posterior horn of the spinal cord after 15 mg/kg intrathecal lidocaine. (C) The lesions in the spinal cord after 35 mg/kg intrathecal lidocaine were extensive.
In addition to massive polynuclear infiltration and oedema, diffuse destruction of myelin sheaths and axon could be seen.
Table 2
Injury scores for spinal cords obtained from rats receiving saline or 2–35 mg/kg
lidocaine during intrathecal therapy (mean ± SEM)
Group
Spinal cord
Control
L2
L6.5
L15
L35
0.22 ± 0.11
0.89 ± 0.06
0.89 ± 0.15
1.11 ± 0.06
2.61 ± 0.15
Injury scores for each animal were based on all slices presented in a cross-section.
Each slice was assigned an injury score of 0–3, where 0 = normal (no lesions),
1 = mild (lesions were rare, seen in occasional fields), 2 = moderate (lesions could be
seen in less than 50% of all fields), and 3 = severe (lesions could be seen in more
than 50% of all fields). The injury score for each animal was then calculated as the
average score of all slices in the segment. n = 3 in each group.
effect than 15 mg/kg lidocaine. Our study also shows that increasing doses of intrathecal drug are associated with increasing severity of respiratory depression and hemodynamic instability.
Especially, the highest dose of intrathecal lidocaine, 35 mg/kg, induces increased mortality, as well as significant spinal lesions, as
revealed by histopathologic examinations.
It is a common practice to develop spinal anesthesia in rats by
intrathecal injection of 2 mg/kg lidocaine (Chaplan et al., 1995).
Yamada et al. demonstrated that the dose of lidocaine required
to cause TSA in rats ranged from 15.0 to 38.1 mg/kg (Yamada
et al., 1997). We therefore tested a dose-range paradigm from 2
to 35 mg/kg in our study, to explore the dose–response of painrelieving effect of intrathecal lidocaine. Subarachnoid anesthetics
are known to block the sympathetic system, but the results from
the current study indicated that the balance between sympathetic
and parasympathetic nervous activities could be well preserved
with the use of vasoconstrictors and breathing machine in most
cases. Only with the highest dose of lidocaine (35 mg/kg), hypotension and respiratory depression could not be corrected in some
rats, and severe lesions in the spinal cords occurred. The more
prominent histopathologic changes observed in group L35 than
other groups might have been the consequence of severe arterial
hypotension-induced decreased spinal cord blood flow, or might
be related to the effects of large amount of vasoconstrictors on
the tissue circulation.
The possible neurotoxicity of intrathecal lidocaine, as demonstrated by histologic evidence in the present study, raises the possibility that lidocaine induced changes in neurologic function
towards stimulation rather than it reversed hyperalgesia and allodynia. In order to discriminate between the effects of intrathecal
lidocaine per se and neurological deficits induced by its toxicity,
we tested the sensory threshold by means of thermal hind paw
withdrawal latency in normal rats before and each day after intrathecal injection of 2–35 mg/kg lidocaine, until the 10th day. Another set of normal rats were sacrificed after recovery from
lidocaine injection, and the spinal cords were prepared for histopathologic examination. The results showed that the morphologic
changes induced by different doses of intrathecal lidocaine in normal rats were similar to the same dose in the neuropathic rats, and
no significant difference in the hind paw withdrawal latency was
observed in all the rats at any time points after receiving lidocaine
injection as compared with their pre-injection baseline (data not
shown). This suggests that intrathecal lidocaine, even at the highest dose given, was not interfering with normal sensorimotor integration. Our results of the pilot study were consistent with the
findings by Takenami et al., who reported normal sensory threshold in the rats that exhibited comparable severe histopathologic lesions in the spinal cord after receiving high doses of intrathecal
Please cite this article in press as: Tian J et al., Effects of intrathecal lidocaine on hyperalgesia and allodynia following chronic ..., Eur J Pain
(2008), doi:10.1016/j.ejpain.2008.03.013
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lidocaine (Takenami et al., 2004). Therefore, the elevation of thermal withdrawal latency and mechanical withdrawal threshold
after intrathecal drug injection in the neuropathic rats in the present study should have been caused by the pain-relieving effect of
lidocaine.
To our knowledge, this is the first study to demonstrate the detailed dose–response as well as the magnitude and duration of
pain-relieving effects of intrathecal lidocaine. In a previous study,
Chaplan et al. reported that intrathecal lidocaine failed to attenuate
tactile allodynia following spinal nerve ligation (Chaplan et al.,
1995). Their result was not contrary to our findings, as they used
only 500 lg lidocaine, which equaled approximately 2 mg/kg in
250 g rats. Since no response was elicited by a skin clamp through
out the body in animals receiving 15 and 35 mg/kg lidocaine, suggesting that these doses of drugs also caused TSA in rats in the
present study, our behavioral result is in agreement with the clinical study by Yokoyama et al., who reported sustained analgesic effects of TSA therapy with lidocaine for the relief of neuropathic
pain (Yokoyama et al., 2002). In addition, our results extend this
previous study by showing that lower doses of intrathecal lidocaine, which are not sufficient to cause TSA, also induce long-term
suppression of hyperalgesia, and that the role of intrathecal lidocaine in providing relief of allodynia has a ‘‘ceiling effect”, which
means higher doses of intrathecal lidocaine do not result in any
greater anti-allodynic effects once the dose reaches the TSA level.
Ma et al. (2003) demonstrated in their report, however, that
ongoing allodynia was significantly reversed at 2 h as well as 3
days after intrathecal injection of only 100–300 lg lidocaine in
partial spinal nerve ligation rats. The inconsistency between their
study and ours may be caused by the differences in injury models.
At the same time, it is necessary to point out that examination of
the effects of intrathecal lidocaine was started 24 h after infusion
in the current study. An acute anti-nociceptive effect of lower
doses of intrathecal lidocaine thus can not be excluded based on
the present findings.
The mechanisms by which intrathecal lidocaine reduces thermal hyperalgesia and tactile allodynia are yet to be understood.
While the suppression of spontaneous ectopic discharges on the
peripheral injured nerve is not likely involved, it is more possible
that intrathecal lidocaine exerts its effect through a central suppression effect. Actually, several previous studies have demonstrated a central action of lidocaine. Jaffe et al. found that with
electrophysiological examinations, the electrical responses in
spinal cord were suppressed during perfusion with lidocaine (Jaffe
and Rowe, 1995). Olschewski et al. (1998) showed that lidocaine
inhibited spinal neuron activity, likely by blocking sodium and
potassium currents evoked in dorsal horn neurons. These evidence
support the assumption that the central action plays an important
role in the pain-relieving effects of intrathecal lidocaine. Meanwhile, our findings that the effects of lidocaine on hyperalgesia
and allodynia are different also lead to speculation that the mechanisms of lidocaine on reversal of these two behavioral manifestations are distinct. Actually, the development of thermal
hyperalgesia and tactile allodynia is known to involve separate
pathways (Ossipov et al., 2000). While noxious thermal stimuli is
thought to be mediated through high-threshold, thin unmyelinated primary afferent C-fibers, non-noxious tactile stimulation
is believed to be mediated through large diameter, low threshold
Ab afferent fibers, and processed at supraspinal sites receiving input through the dorsal columns (Yeomans et al., 1996; Ossipov
et al., 1999; Willis et al., 1999). We are currently using this intrathecal lidocaine therapy in neuropathic pain rat model to investigate the actual effective site (spinal cord or supraspinal site, or
both) and means of action of intrathecal lidocaine.
In summary, we have shown that doses of 6.5 mg/kg or 15 mg/
kg and higher intrathecal lidocaine could produce prolonged rever-
7
sal of established hyperalgesia or allodynia, respectively, but severe lesions in the spinal cord will develop after administration
of 35 mg/kg lidocaine. Considering the ratio between useful effects
and side effects, doses of 15 mg/kg are suitable for intrathecal
injection for the relief of neuropathic pain. The mechanisms of action remain to be elucidated. Although extrapolation to clinical
practice must be made with caution, the present finding carries
important fundamental and methodological consideration for the
basic and clinical study of treatment for neuropathic pain. For
the patients who have failed more conservative treatments and
with no surgical treatable pathology, intrathecal lidocaine therapy
can provide an alternative approach to the treatment of their
intractable neuropathic pain.
Declaration of interests
The work was supported by Doctoral Innovation Program Foundation from Medical School of Shanghai Jiaotong University
(BXJ0720), Shanghai, China.
Acknowledgement
We thank Dr. Xu Zhang and Dr. Lan Bao for their contribution to
the design and for showing us the technique of behavioral tests.
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