sinnott1999 lidocaína

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Differential efficacy of intravenous lidocaine in alleviating ipsilateral versus
contralateral neuropathic pain in the rat
Catherine J. Sinnott, Joseph M. Garfield, Gary R. Strichartz*
Pain Research Center, Department of Anesthesia Research Laboratories, Harvard Medical School,
Brigham and Women’s Hospital, Boston, MA 02115, USA
Received 24 June 1998; received in revised form 7 October 1998; accepted 2 November 1998
Abstract
In the this study we have investigated the threshold plasma concentration of lidocaine for reversal of mechanical ‘allodynia’ in a
neuropathic pain model in the rat, defined the concentration-dependent limits of that reversal and compared the acute reversal during
intravenous drug infusion with the persistent relief of allodynia assayed 48 h later. Actions of i.v. lidocaine on ipsilateral and contralateral
legs were also assessed. Forty rats were sorted into five groups (n = 7–10) and underwent spinal root (L5–6) ligation to produce allodynia,
as quantified by a lower force of von Frey hairs at the plantar hindpaw required to elicit paw withdrawal (PWT, paw withdrawal threshold).
During surgery, intravenous catheters were placed for programmed lidocaine infusion and in some animals arterial catheters were also
inserted for assaying lidocaine blood levels. PWTs were measured in ipsilateral and contralateral paws before and after ligation and during
infusions which, beginning at 5 days after surgery, were conducted every other day to incrementing levels (1.1–9.7 mg/ml plasma). Ligation
produced allodynia in ipsilateral paws (PWT = 1.22 – 0.42 g ( – SEM)) and in contralateral paws (PWT = 4.99 – 0.61 g), both markedly
lower than pre-operative control values for either paw (11.31 – 0.41 g). The ipsilateral allodynia was partially, but significantly and
permanently reversed (to PWT = 6–8 g) after a lidocaine infusion to 2.1 mg/ml in two separate groups (n = 7, 8). Lower concentrations
resulted in elevation of PWT during infusion but no sustained relief. The elevation of PWT during infusion at this threshold level among
individual animals was positively correlated with the relief measured 48 h later, but higher lidocaine concentrations infused in subsequent
dosings could exact no further sustained relief. The residual PWT level, after reversal by threshold lidocaine and greater, was constant for
each individual rat tested over the next 14 days but varied substantially among individuals; some were restored to pre-operative PWTs and
some were totally unresponsive to drug. Retrospective analysis revealed a significant and unanticipated correlation between the incidence of
low pre-operative PWTs (,10 g) and a lack of sustained reversal of post-operative allodynia by lidocaine. Contralateral allodynia, despite
its acute reversal during infusion to 2.1 mg/ml and higher, was not persistently relieved after infusion of lidocaine to any concentration.
Repeated infusions to subthreshold levels (,2 mg/ml) did not provide persisting relief of allodynia on either side, and infusions of saline
were impotent. These findings show that experimental allodynia results from multiple factors, only some of which are sensitive to lidocaine
treatment, and that prolonged reversal of allodynia is limited in extent and likely influenced by pre-existing factors. Ó 1999 International
Association for the Study of Pain. Published by Elsevier Science B.V.
Keywords: Differential efficacy; Neuropathic pain; Lidocaine
1. Introduction
Peripheral nerve injury often manifests as chronic neuro-
pathic pain. In humans, nerve injury can sometimes result in
a condition known as allodynia, in which subjects perceive a
non-noxious stimulus, such as light touch, to be painful, and
for which standard analgesics are often ineffective. The
administration of intravenous lidocaine has been shown to
provide long-term relief of neuropathic syndromes of vary-
ing etiology. Boas et al. (1982) showed that infusion of
intravenous lidocaine in five patients with clinical neuro-
pathic disorders completely abolished all neuropathic pain
in two of the five patients, and provided sustained reduction
of pain scores in two other patients. Brief injections of
Pain 80 (1999) 521–531
0304-3959/99/$20.00 Ó 1999 International Association for the Study of Pain. Published by Elsevier Science B.V.
PII : S0304-3959(98)00245-0
* Corresponding author. Tel.: +1-617-732-8797 or 732-7802; fax: +1-
617-730-2801; e-mail: gstrichz@zeus.bwh.harvard.edu
intravenous lidocaine have also been shown to relieve
chronic painful diabetic neuropathy for 3 to 21 days
(Kastrup et al., 1987). Intravenous lidocaine also can reduce
pain associated with postherpetic neuralgia (Rowbotham et
al., 1991).
One useful model for peripheral neuropathy in the rat
involves the tight ligation of the L5 and L6 spinal nerves
(Kim and Chung, 1992). After ligation, rats developed a
reduced withdrawal threshold to mechanical stimulation
with von Frey filaments. This behavior suggests that a
usually non-noxious mechanical stimulation is unpleasant
to these rats and it, therefore, seems to parallel the symp-
toms of allodynia. Chaplan et al. (1995) demonstrated that
infusion of intravenous lidocaine results in prolonged alle-
viation of allodynia in spinal nerve-ligated rats. We wished
to establish the concentration-dependence of systemic lido-
caine on the degree of reversal of both ipsilateral and con-
tralateral allodynia in such rats. In particular, we asked
whether higher, sub-convulsive anesthetic concentrations
could completely reverse the neuropathic behavior. Of
further interest was the relationship between the degree of
pain relief during infusion and the persistence of analgesia
afterwards.
2. Methods
Male Sprague–Dawley rats (Taconic Farms, German-
town, NY), initially weighing 150–200 g, were used in
this study. All were housed individually in plastic cages
with soft bedding under a non-inverted 12:12 h light–dark
cycle and fed rat chow ad libitum. All experimental proce-
dures, including surgical preparation and behavioral testing,
were approved by the Harvard Medical Area Standing Com-
mittee on Animals.
2.1. Surgical preparation
2.1.1. Anesthesia and peri-operative management
Animals were anesthetized with pentobarbital sodium
using an intraperitoneal dose of 50 mg/kg. Following the
onset of surgical anesthesia, animals were placed prone
with care to prevent airway obstruction. Upon completion
of surgery, animals were placed back in their individual
cages and allowed to recover.
2.1.2. Surgical procedures
Surgical preparation consisted of either of two proce-
dures: L5–L6 ligation or the sham preparation. For the
two procedures we followed the protocol of Kim and
Chung (1992), with the exception that a 6-0 silk suture
was used for nerve ligation, as opposed to the 3-0 silk suture
originally described. A 2 cm paraspinal incision was made
at the level L4–S2 to a depth of 3 cm (or at the level of the
underlying transverse processes). Enough paraspinous mus-
cle was removed to completely expose the L6 transverse
process, which was then removed with microrongeurs,
exposing the L5 and L6 nerves. Each nerve segment was
isolated and tightly ligated using one silk suture.
2.1.3. External jugular vein cannulation
Under general anesthesia with the animals supine, the left
anterior neck area was shaved and a vertical para-tracheal
incision made over the clavicle down to fascia. The external
jugular vein was identified and two loose 3-0 silk suture ties
were placed loosely around the vein. The more cephalad
ligature was tied tightly and traction applied to the vein.
A small incision was then made in the vein wall and a
polyethylene catheter (PE-50), 12 cm in length, previously
filled with heparinized saline (100 U/ml; Heparin Sodium
Injection, Elkins-Sinn, Cherry Hill, NJ) was inserted and
advanced 2 cm toward the heart. With thecatheter in
place, as verified by venous blood upon aspiration, the sec-
ond tie was tightened securely and a hemostat applied to the
catheter 2–3 cm beyond the incision, leaving 6–8 cm of free
tubing. We then inserted the free end of the cannula through
a 17-gauge needle with the hub removed. The cannula was a
tight fit, wedging into the proximal end of the needle. Grasp-
ing the needle, the catheter tubing was tunneled subcuta-
neously to the midline in the posterior cervical area at about
the level of the ears, exiting the skin at this point. The needle
was then removed and the catheter cut so that approximately
4.0 cm protruded. The free end was then heated with a
match until it melted, allowed to cool slightly and com-
pressed with the jaws of a hemostat to seal it. The anterior
neck incision was closed with wound clips and the animal
allowed to recover.
2.1.4. Carotid artery cannulation
Under general anesthesia, the anterior midline area of the
neck was shaved and a 3 cm vertical incision was made
directly overlying the trachea. The right carotid sheath,
lying posterolateral to the trachea was identified and the
internal carotid artery dissected free. The method of cannu-
lating and tunneling was identical to that described above
for the external jugular vein, except that the arterial cannula
exited 3–4 mm caudal to the jugular cannula. Both jugular
and carotid artery cannulae were flushed daily with hepar-
inized saline.
2.2. Behavioral testing
2.2.1. Experimental design
The overall study incorporated two components: (1) the
evolution and maintenance of allodynia following L5–6
nerve ligation (2) a concentration-dependent study of the
effects of intravenous lidocaine on allodynia. Assessment
of allodynia was performed on an initial group of eight rats
(group 1) 1 day prior to surgery and each day afterward for
10 days. Study of the concentration-dependent effects of
lidocaine involved four additional groups (groups 2, 3, 4
and 5), each with n = 7–10 animals. Two additional groups
522 C.J. Sinnott et al. / Pain 80 (1999) 521–531
(groups 6 and 7) were studied to determine the control
effects of sham surgery and infusion of saline.
2.2.2. Sham control
A group of five rats (group 6) had sham surgery (as
described by Kim and Chung, 1992), as described above
but without nerve ligation, including implantation of jugular
venous cannulae to insure that the ensuing allodynia
resulted from nerve ligation and not from inflammation
due to the invasive nature of the surgery. PWTs were mea-
sured 1 day prior to surgery and on post-operative days 5, 7,
9, 11 and 13, identical to the testing regime for that of the
experimental groups receiving systemic lidocaine (groups 2,
3, 4 and 5).
2.2.3. Evolution and maintenance of allodynia
To measure PWTs, Group 1 (n = 8) animals were placed
on a wire mesh platform (0.5 cm mesh) and covered by a
transparent box to limit straying. von Frey filaments (Stoelt-
ing, Wood Dale, IL) were applied orthogonally to the mid-
plantar region of the ipsilateral and contralateral hindpaw
with enough force to cause buckling of the filament. A
modification of the ‘up-down’ method of Dixon (1980)
was used to determine the filament value at which foot with-
drawal would occur 50% of the time, as previously used by
Chaplan et al. (1994). Thresholds were obtained in less than
2 min according to the following protocol: filaments were
applied in order of increasing thickness until withdrawal of
the foot occurred. The filament just thinner than the one
evoking a withdrawal response was then applied. If no with-
drawal occurred, the filament just thicker than the one evok-
ing foot withdrawal was applied. If withdrawal occurred at
the lower filament value, the process was repeated until an
oscillatory pattern of response-no response resulted. The
force in g required to elicit paw withdrawal was calculated
by applying the 50% response algorithm of Dixon (1980) to
these data and recorded as the paw withdrawal threshold
(PWT). Ipsilateral and contralateral PWTs were measured
1 day prior to surgery and each day following for 7 days and
then again 10 days after surgery.
2.2.4. Concentration-dependent effects of lidocaine
Groups 2, 3, 4 and 5 (n = 7–10) were used in this com-
ponent of the study. Control values for PWT were measured
1 day prior to surgery, and the operative procedure consisted
of left L5–6 spinal nerve ligation along with external jugu-
lar vein cannulation. On day 5, each animal in groups 2 and
3 (n = 8 and 7, respectively) received a single 30 min infu-
sion of lidocaine delivered by a Harvard Model 22 infusion
pump controlled by the Stanpump Ò software, which
resulted in a steady-state plasma concentration of 1.1 mg/
ml. A steady-state plasma level was attained in less than 10
min (see Section 3) and the infusion continued for an addi-
tional 20 min. PWTs were obtained 5 min after starting the
infusion and repeated at 5 min intervals for a total of six
determinations over each pseudo-steady-state period. The
infusion was then discontinued and the animal placed
back in its cage. Forty-eight hours after this first infusion,
PWTs were measured, followed by the second infusion
resulting in a lidocaine plasma concentration of 1.6 mg/
ml. PWTs were determined as for the first concentration.
Three additional 30 min infusions to concentrations of 2.1,
2.6 and 3.0 mg/ml plasma, were studied at 2 day intervals in
the same manner as were the first two. The final infusion
(3.3 mg/ml) was on day 13 and testing was completed on
post-operative day 15. Animals in group 3 received an
additional infusion resulting in a plasma concentration of
4.0 mg/ml, 17 days after surgery. PWTs of animals in both
group 2 and 3 were measured again on day 25. Group 4
animals (n = 10) were studied to confirm whether or not
further relief of allodynia could be achieved with even
higher but still sub-convulsive concentrations of lidocaine.
Each animal received three infusions on post-operative
days 5, 7 and 9 corresponding to plasma lidocaine concen-
trations of 2.6, 5.0 and 9.7 mg/ml. Infusion times for 5.0 and
9.7 mg/ml concentrations were 60 and 90 min, respectively,
due to the time necessary for the infusion pump to achieve
such high plasma concentrations. Group 5 (n = 7) animals
were studied to determine the effects of repeated infusions
at a ‘subthreshold’ concentration (1.6 mg/ml) followed by a
single threshold infusion (2.1 mg/ml). These animals were
also used to study the effects of systemic lidocaine on con-
tralateral allodynia. Ipsilateral and contralateral PWTs
were measured 1 day prior to surgery, and the operative
procedure again consisted of left L5–6 spinal nerve ligation
along with external jugular vein cannulation. On day 5,
these animals received a 30 min computer-controlled infu-
sion of lidocaine, resulting in a ‘subthreshold’ concentra-
tion of 1.6 mg/ml. This concentration was chosen since it
was below the threshold at which sustained relief of allo-
dynia was achieved in groups 2 and 3 (Section 3). As
described previously, ipsilateral and contralateral PWTs
were obtained 5 min after starting the infusion and repeated
at 5 min intervals for a total of six pseudo-steady-state
determinations. The infusion was then discontinued and
the animal placed back in its cage. Forty-eight hours after
this first infusion, i.e on post-operative day 7, PWTs were
determined and the second infusion begun. PWTs during
the infusion were determined as for the first concentration.
This sequence was repeated on day 9, resulting in a total of
three successive infusions to a plasma concentration of 1.6
mg/ml. On day 11, a 30 min infusion to a plasma concentra-
tion of 2.1 mg/ml plasma was administered and ispilateral
and contralateal PWTs measured on days 13, 19 and 21.
This concentration was chosen because it was the lowest
that produced asustained relief of ipsilateral allodynia in
groups 2, 3 and 4 (Section 3).
2.2.5. Saline infusion control
Animals in group 7 (n = 5) with left L5–L6 spinal nerve
ligation and implantation of jugular venous cannulae were
studied to determine the effect of an intravenous infusion of
523C.J. Sinnott et al. / Pain 80 (1999) 521–531
an inert solution on the PWT. Testing was identical to that
of the lidocaine infusion groups except that an infusion of
saline (0.9% NaCl, Abbott Laboratories, Chicago, IL) was
administered instead of lidocaine at the same rate as that for
each of the five target plasma concentrations.
2.2.6. Lidocaine analysis
Spinal nerve ligation along with arterial and venous
cannulation was performed on 19 additional rats to obtain
arterial samples for measurement of plasma concentra-
tions of lidocaine. Two rats received one dosing for
each of the following five target plasma concentrations
(1.0, 1.5, 2.0, 2.5 3.0, 8.0 and 12.0 mg/ml). Once a target
plasma concentration of lidocaine was achieved, one to
three arterial samples (300 ml) were drawn from each rat
30 min after beginning the infusion. The other five rats
were used to measure plasma concentration at 5 min inter-
vals during an infusion to a target of 2.0 mg/ml. Two
arterial samples (30 ml) were drawn at 5 min intervals
for 30 min and sent to the Brigham and Women’s Hospi-
tal Clinical Chemistry Laboratory for measurement of
lidocaine concentration, determined by an immunofluores-
cence assay.
2.3. Data analysis/statistics
Data are expressed as the means – SE. The Friedman test
(SPSSÒ Software) was used to determine overall signifi-
cance for each of the sets of pre-operative and post-opera-
tive PWTs after L5–L6 nerve ligation and after sham
surgery. To evaluate the effects of infusions with lidocaine
or saline, PWTs obtained during infusion and 48 h post-
infusion were compared with the pre-infusion values.
Once overall significance was determined for a response
set, the Wilcoxon test (SPSSÒ Software) was used post
hoc to determine which post-operative responses differed
significantly from the pre-operative control value. All ana-
lyses were performed using SPSSÒ for Windows, Version
6.1.3 (SPSSÒ Software). Results were considered signifi-
cant at P , 0.05.
3. Results
3.1. Evolution and maintenance of bilateral allodynia
Following unilateral spinal nerve ligation, all animals
developed bilateral allodynia. The decrease of PWT in the
contralateral limb was significantly less than that observed
in the ipsilateral limb (Fig. 1). Ipsilateral PWTs were sig-
nificantly reduced from pre-operative values (11.65 – 0.32
g) for the entire evaluation period, reaching a minimum on
day 4 (1.22 – 0.42 g) (P , 0.02). Contralateral PWTs also
reached a minimum on post-operative day 4 (4.99 – 0.61 g
(mean – SE)) from a mean pre-operative value of
(11.31 – 0.41 g) and remained significantly reduced com-
pared with the pre-operative values for the remainder of the
10 day evaluation period (P , 0.02).
3.2. Sham-control
Ipsilateral and contralateral PWTs of the sham-operated
control group (group 6, n = 5) were measured at 5, 7, 9, 11
and 13 days after surgery, consistent with the testing regime
for the four experimental groups receiving intravenous lido-
caine. Mean PWTs for both the ipsilateral and contralateral
limbs were not significantly different from pre-operative
values on any post-operative testing day (data not shown).
3.3. Lidocaine analysis
It is important to show the constancy, as well as to know
the actual concentration of intravenous lidocaine during any
studies of concentration dependent actions. Fig. 2A shows
measured lidocaine concentrations from blood sampled
over 30 min during a 2.0 mg/ml target infusion for a separate
cohort (group 6; n = 5) with L5–L6 nerve ligation. The
values are relatively constant after 10 min and slightly
greater than the target level. Fig. 2B shows ipsilateral
PWTs during this infusion in the same animals. As with
lidocaine concentration, the mean ipsilateral PWT reached
a constant value after 10 min, significantly greater than the
mean pre-infusion value, but still less than the mean pre-
operative value of approximately 12 g. Blood samples
obtained from the other 14 rats used in this portion of the
study showed that the relation between the target lidocaine
concentration and the plasma level that was actually
achieved is near unity (Fig. 3). The points lie around the
Fig. 1. Evolution of ipsilateral and contralateral allodynia to von Frey
filaments after L5–L6 nerve ligation in group 1 animals (n = 8). Paw
withdrawal thresholds (PWT) of both the ipsilateral and the contralateral
limbs were significantly different compared with the pre-operative value
(day 1) by day 2 after surgery. *Indicates significantly different from the
pre-operative value at P , 0.02. **Indicates significantly different from
the pre-operative value at P , 0.03 (Friedman test followed by Wilcoxon
post-hoc test).
524 C.J. Sinnott et al. / Pain 80 (1999) 521–531
line of identity (solid line) and, in general, the average mea-
sured plasma value differs from the targeted value by less
than 20%.
3.4. Concentration-dependent effects of lidocaine
Responses to incrementing concentrations of lidocaine
during a sequence of infusions confirm the threshold nature
of reversal of ipsilateral allodynia reported by Chaplan et al.
(1995) (Fig. 4). In these eight rats (group 2) a modest but
transient elevation of PWT occurred during infusions (filled
squares) to 1.1 and 1.6 mg/ml (P , 0.04 compared with pre-
infusion) on days 5 and 7, respectively, but 48 h after each of
these episodes (open squares) PWTs had returned to the pre-
infusion value. In contrast, infusions to a level of 2.1 mg/ml
(on day 9) significantly reversed ipsilateral allodynia, a pat-
tern that remained 48 h later. Subsequent infusions to higher
lidocaine levels were able to completely alleviate allodynia
during infusion but the persistent effect was no greater than
that after the infusion to 2.1 mg/ml. In a second cohort of
identically treated rats (group 3, n = 7), significant persis-
tent reversal of allodynia occurred after infusions to 2.1 mg/
ml although significant relief during the infusion did not
appear until the next higher level, 2.5 mg/ml, was reached
(data not shown), which itself only added a small additional
prolonged elevation of PWT. The consistent finding from
these two groups was of a threshold lidocaine level of 2.1
mg/ml for irreversible relief of allodynia. Once threshold
was reached, however, further elevation of PWT was incon-
sequential, for plasma lidocaine up to 4.0 mg/ml. We further
pressed the limit by even higher lidocaine infusion levels in
group 4 (n = 10). Nonetheless, these animals did not
achieve more relief of allodynia with infusions to plasma
concentrations up to 9.7 mg/ml (Fig. 5). Lidocaine’s role in
providing sustained relief of allodynia thus shows both a
threshold concentration dependency, as described by Cha-
plan et al. (1995), and a ceiling effect.
Among individual rats in a group there was widespread
variability in the degree of persistent relief. The sustained
responses of each rat in group 2, 48 h after each lidocaine
infusion at the indicated plasma concentrations, are shown
in Fig. 6. Three of the eight animals (rats 2, 4 and 5) showed
complete relief of allodynia as evidenced by the return to
pre-operative PWT, three obtained partial relief (rats 3, 6
and 7), and two showed no relief at all (rats 1 and 8).
3.5. Correlation between acute transient relief and
sustained relief
Fig. 7 compares PWT values during a 2.1 mg/ml infusion
of lidocaine with PWT values 48 h later for all fifteen rats in
groups 2 and 3. Three of the 15 rats achieved sustained relief
of allodynia to pre-operative levels and, tellingly, all three
were also fullyrelieved during infusion. The correlation
Fig. 2. (A) Actual measured plasma lidocaine concentration during a 30
min 2.0 mg/ml target infusion (n = 5). (B) Shows ipsilateral paw with-
drawal thresholds (PWT) during this infusion, measured over 1–2 min
periods beginning at the indicated time.
Fig. 3. Actual measured plasma lidocaine concentration versus target
plasma concentration. Linear regression for data shows m = 0.954
(– 0.022); b = 0.163 ( – 0.108); R = 0.994; SD = 0.336; P , 0.001.
525C.J. Sinnott et al. / Pain 80 (1999) 521–531
between peri- and post-infusion values was strong and there
was a highly significant probability at this threshold con-
centration that the degree of relief during infusion antici-
pated the relief that persevered afterwards.
3.6. Pre-operative behavior and responsiveness to
lidocaine
A sub-population of the 15 rats in groups 2 and 3 had
unusually low PWTs before surgery, on what would become
the ipsilateral leg; whereas the majority of 11 animals all
had PWTs of approximately 12 g (11.95 – 0.02 g (mean –
SEM), these four had values below 10 g (7.42 – 1.03 g).
Two of these four also had abnormally low ‘contralateral’
PWTs before surgery; 4.34 and 2.81 g. It is noteworthy that
these four rats were also the ones minimally relieved by
lidocaine infusions, at concentrations well above the thresh-
olds for reversing the other animals. When the maximum
PWT achieved after all lidocaine infusions is graphed
against the pre-operative PWT values (Fig. 8), this anom-
alous distribution is apparent. Animals with low pre-opera-
tive PWTs (,10 g) were correlated with the resistance to
reversal of allodynia by lidocaine (PWT , 4 g). Significant
dependence between these two variables was tested through
Spearman’s rank correlation coefficients for pre-operative
PWT and maximum post-operative PWT after lidocaine
infusion; a significant (P = 0.004) but rather weak linear
correlation (correlation coefficient = 0.695) exists between
these two variables. Analysis by a 2 · 2 contingency test led
to rejection of the hypothesis of independence between
these two variables at P , 0.05 level: Fisher’s Exact Test,
P-value = 0.026. Interestingly, despite the absence, in these
four rats, of sustained recovery after lidocaine infusion,
their withdrawal thresholds were still elevated during the
infusion, often to the pre-operative level of the other 11
rats (i.e. 12 g).
3.7. Effects of repeated dosing to sub-threshold infusion
levels
Ipsilateral PWTs in Group 5; (n = 7), measured during
three sequential infusions to the same plasma concentration
of 1.6 mg/ml were significantly different from pre-infusion
values (P , 0.02), and did not differ significantly from
each other (Fig. 9). The PWT values 48 h after each infusion
were not significantly different from the pre-infusion value
on day 5, thus demonstrating that repeated lidocaine infu-
sions at identical sub-threshold concentrations do not com-
bine to relieve allodynia, despite the fact that the summed
dose from these three infusions equals that from the incre-
menting infusions that let to persistent relief in groups 2 and
3. A subsequent infusion of rats in this group at a target
plasma concentration of 2.1 mg/ml produced complete relief
of allodynia during infusion, and the mean PWTs measured
Fig. 4. The effects of successive intravenous lidocaine infusions at increas-
ing plasma concentrations on ipsilateral allodynia in group 2 (n = 8).
Beginning on post-operative day 5, five infusions were administered at
48 h intervals which correspond to plasma concentrations of 1.1 (day 5),
1.6 (day 7), 2.1 (day 9), 2.6 (day 11) and 3.0 (day 13) mg/ml. Filled circle
indicates mean pre-operative paw withdrawal threshold (PWT). Open
squares indicate mean PWT 5 min before lidocaine infusion. Filled squares
indicate mean PWT at the end of the infusion. *Indicates significantly
different from pre-infusion PWT value on day 5 at P , 0.02. **Indicates
significantly different from pre-infusion PWT on this day at P , 0.02
(Friedman test followed by Wilcoxon post-hoc test).
Fig. 5. The effect of lidocaine infusions at higher subconvulsive plasma
concentrations on paw withdrawal thresholds (PWT) in group 4 animals
(n = 10). Three successive infusions corresponding to plasma concentra-
tions of 2.6 (day 5), 4.9 (day 7) and 9.7 (day 9) mg/ml were administered.
*Indicates significantly different from pre-infusion PWTs on day 5 at
P , 0.02 (Friedman test followed by Wilcoxon post-hoc test).
526 C.J. Sinnott et al. / Pain 80 (1999) 521–531
2, 7 and 14 days after this last infusion remained constant
and significantly different from the mean pre-infusion value
on day 5 (P , 0.03).
3.8. Lack of sustained recovery for contralateral allodynia
Lidocaine did not permanently relieve contralateral allo-
dynia in group 5 animals (Fig. 10). Although a 2.1 mg/ml
infusion returned the mean contralateral PWT to the pre-
operative value during infusion (P , 0.02 compared with
the pre-infusion values), forty-eight hours later the contral-
Fig. 6. Paw withdrawal thresholds (PWT) of individual rats in group 3,
(n = 8), 5 min before each of the five successive lidocaine infusions (as
indicated by an arrow) which correspond to plasma concentrations of 1.1
(day 5), 1.6 (day 7), 2.1 (day 9), 2.6 (day 11) and 3.0 (day 13) mg/ml.
Fig. 7. Paw withdrawal thresholds (PWT) of individual animals in groups 2
and 3 during a 2.1 mg/ml lidocaine infusion versus PWTs 48 h later (n =
15). R = 0.873; SD = 2.104; P , 0.0001.
Fig. 8. PWTs 48 h after administering final lidocaine infusion versus pre-
operative PWTs in groups 2 and 3 animals (n = 15).
Fig. 9. The effect of successive infusions at a sub-thresholds plasma con-
centration (1.6 mg/ml) on ipsilateral PWTs in group 5 animals (n = 7).
Three infusions corresponding to a plasma concentration of 1.6 mg/ml were
administered on post-operative days 5, 7 and 9. An infusion corresponding
to a ‘threshold’ plasma concentration of 2.1 mg/ml was administered on
day 11. *Indicates significantly different compared with the mean pre-
infusion PWT on this day at P , 0.02. **Indicates significantly different
compared with the mean pre-infusion PWT on day 5 at P , 0.03 (Fried-
man test followed by Wilcoxon test post-hoc).
527C.J. Sinnott et al. / Pain 80 (1999) 521–531
ateral PWT had fallen back to the pre-infusion level. Lido-
caine at 10 mg/ml also sustained relief of contralateral allo-
dynia during infusion, but had no persistent effect.
3.9. Saline infusions control
In a group of five rats (group 7) PWTs were obtained
during and after infusion of 0.9% NaCl (Abbott Labora-
tories, Chicago, IL) at rates equivalent to those used for
the five target plasma lidocaine levels. Mean ipsilateral
and contralateral PWTs measured during saline infusion
and 48 h, thereafter, were not significantly different from
the mean pre-infusion allodynic PWTs showing that saline
provided no relief.
4. Discussion
The results of this study show that experimental allodynia
in the spinal nerve ligation model is partially relieved by i.v.
lidocaine. The concentration dependence of this relief
demonstrates a ‘threshold’ value of about 2 mg/ml and a
distinctly limited ‘ceiling’ effect’ meaning that higher lido-
caine concentrations do not result in any greater sustained
relief. Although there is wide variability in the persistent
alleviation of allodynia among individual animals, this
persistent relief is strongly correlated with the degree of
reversal that occurs during infusion at the threshold con-
centration. In addition, a substantial population (4/
15 = 27%) of animals with unusually low pre-operative
PWTs (below 10 g, a value 3–4 SEs below the mean for
the rest of the population) demonstrates no prolonged rever-
sal by lidocaine despite showing a strong transient reversal
during infusion.Finally, contralateral allodynia is also
acutely reversed during lidocaine infusion, but shows no
persistent relief after infusion.
Together these observations suggest that separate patho-
physiological mechanisms, with differing pharmacologies,
may account for different aspects of neuropathic pain in this
spinal nerve ligation model. For acute suppression of allo-
dynia the threshold for acute reversal is about 2 mg lido-
caine/ml (cf. Figs. 4 and 5) and, as noted above, efficacy for
transient reversal is 100%, i.e. all rats show normal pre-
operative PWTs during infusion to a high enough level of
lidocaine. This plasma threshold lidocaine level (2 mg/ml) is
equivalent to 8.5 mM free lidocaine and any mechanism for
acute reversal must have a similar concentration depen-
dence. A sustained recovery from allodynia also occurs at
this same lidocaine level in some rats, regardless of the
extent of that recovery. This suggests that a common target
of lidocaine is critical for both the acute and sustained ther-
apeutic responses; the permanence of reversal is a reflection
of the drug’s ability to elicit long lasting effects, but not of
its apparent activity at the common primary target.
Others have reported similar concentration requirements
for acute reversal of neuropathic pain during drug adminis-
tration in animals and humans. Using the identical rat model
and infusion pump program, Chaplan et al. (1995) reported
a threshold for sustained recovery of 1.2–1.5 mg lidocaine/
ml. Bolus injections of local anesthetics can transiently
reverse nerve firings in experimental neuropathies, e.g.
from neuromas (Chabal et al., 1989, Devor et al., 1992),
but in those studies blood levels were not controlled and
sustained reversal was not assayed. Nonetheless, different
sites of ectopic activity were differentially sensitive to lido-
caine; that recorded from DRG was halved by doses of ca.
0.5 mg/kg whilst activity from the neuroma required ca. 2
mg/kg (Devor et al., 1992). Using a variation on the techni-
que to induce neuromas, Omana-Zapata et al. (1997) found
that 1 mg/kg lidocaine effectively halved ectopic firing in
both DRG and spontaneously firing dorsal horn (DH) neu-
rons. In contrast, lidocaine was equipotent in suppressing
neuron-induced ectopic activity recorded in DRG and DH
neurons. In rats made neuropathic by chronic nerve con-
striction, systemic bolus lidocaine had stronger, longer last-
ing effects on DH than on DRG neurons (Sotgiu et al.,
1994). Thus, different experimental models may induce
anatomically and biochemically differing pathologies with
correspondingly different pharmacotherapeutics.
Bolus i.v. injections of lidocaine in unoperated rats selec-
tively depressed polysynaptic mediated responses of flexor
motor fibers, with insignificant actions on peripheral
impulse conduction or monosynaptic reflexes (Woolf and
Wiesenfeld-Hallin, 1985). No antinociceptive activity fol-
Fig. 10. The lack of persistent effect of successive infusions at a sub-
thresholds plasma concentration (1.6 mg/ml) on contralateral PWTs in
group 5 (n = 7). Three infusions corresponding to a plasma concentration
of 1.6 mg/ml were administered on post-operative days 5, 7 and 9. An
infusion corresponding to a ‘threshold’ plasma concentration of 2.1 mg/ml
was administered on day 11. *Indicates significantly different compared to
the mean pre-infusion PWT on this day at P , 0.02 (Friedman test fol-
lowed by Wilcoxon test post-hoc).
528 C.J. Sinnott et al. / Pain 80 (1999) 521–531
lowed i.v. lidocaine administration in unoperated rats (Wie-
senfeld-Hallin and Lindblom, 1985), and in the rats used for
neuroma studies (see above) normal impulse conduction
was unaltered by systemic lidocaine (Chabal et al., 1989;
Devor et al., 1992). Thermal hyperalgesia induced by
chronic rat sciatic nerve compression (model of Bennett
and Xie, 1988) was reversed during and for 3 h after an
i.v. lidocaine infusion to 1 mg/ml serum (Abram and
Yaksh, 1994). At a higher intravenous concentration of lido-
caine, 4–6 mg/ml, both the second phase of formalin-evoked
paw lifting (Abram and Yaksh, 1994) and of impulse firing
in peripheral fibers was strongly suppressed (Puig and Sor-
kin, 1996).
The quaternary lidocaine derivative, QX314, given sys-
temically, reduced neuroma-induced ectopic activity in rat
sciatic nerve, activity recorded at the neuroma, at dorsal root
ganglia (DRG) and in dorsal horn (DH) (Omana-Zapata et
al., 1997). Lidocaine also reduced these activities, with a
potency similar to QX314’s for blocking DRG ectopic
impulses but considerably greater for inhibition of such
activity in DH neurons.
One interpretation of this difference is that permanently
charged QX molecules are able to penetrate only poorly into
the CNS and that their systemic effect is largeley restricted
to the peripheral nervous system. Other interpretations
should not be dismissed, however, particularly the possibi-
lity that lidocaine (and QX) may have more than one
mechanism or site of action or that the ionic basis for gen-
erating spontaneous impulse activity differs between per-
ipheral and central neurons.
Many of the aforementioned studies point to a peripheral
site of drug action and a suppression of ectopic or sponta-
neous discharges. Quantifying spontaneous discharges in C-
and Ad-fibers innervating injured, isolated cornea, Tanelian
and MacIver (1991) halved this activity with lidocaine at ca.
6 mg/ml. Electrically stimulated impulses in this preparation
were only abolished by lidocaine concentrations greater
than 250 mg/ml (1 mM), similar to the requirement deter-
mined from in vivo measurements where lidocaine was
superfused around an intact sciatic nerve in a normal rat,
(Huang et al., 1997).
Nevertheless, several electrical responses in spinal cord
are also suppressed by low concentrations of lidocaine. The
slow ventral root potentials recorded from spinal cord iso-
lated from neonatal rat were attenuated by 20–65% during
perfusion by 1–10 mg lidocaine/ml (Jaffe and Rowe, 1995).
Inhibition of spinal cord responses evoked by electrical C-
fiber activation as well as by direct excitation with the glu-
tamate receptor agonists N-methyl-d-aspartate and quisqua-
late, as well as glycine, and by NK1 receptor agonists
(Biella and Sotgiu, 1993a,b; Nagy and Woolf, 1996), are
all consistent with a direct action of lidocaine on DH neu-
rons, although concentrations above 40 mM were required
for these latter effects. Thus, there is experimental animal
evidence in support of both a peripheral and a central site of
action for i.v. lidocaine in relieving neuropathic pain.
Intravenous lidocaine has been shown to relieve neuro-
pathic pain in humans. Boas et al. (1982) analyzed the
responses to lidocaine infusion of five patients suffering
upper extremity unilateral chronic pain. At plasma levels
of 1.5–2 mg lidocaine/ml most of the patients reported sub-
stantial relief of the neuropathic pain. In a study of 13 peo-
ple with neuropathic pain, Ferrante et al. (1996),
administered up to 500 mg of lidocaine intravenously over
60 min and took regular blood samples while scoring pain
by VAS during infusion. They observed a steep dose depen-
dence, with half the patients relieved of their acute pain at
about 30 mg lidocaine as an accumulated dose, yielding a
measured plasma level of 3–4 mg/ml, close to what we
observe for acute reversal of allodynia in rats. However,
persistent relief of pain was not evaluated.
Fifteen patients with diabetic neuropathy denoted by a
variety of objective and subjective symptoms were infused
with lidocaine (5 mg/kg) over 30 min (Kastrup et al., 1987).
Although the objectively measurable signs, such as deficits
in vibratory sensation, were not altered by lidocaine, the
perception of spontaneous neuropathic pain was abolished,
for 3–21 days after infusion.
Pain from identifiableperipheral nerve lesions was tran-
siently relieved by i.v. lidocaine as low as 1.5 mg/kg (Sotgiu
et al., 1994); both the receptive field size and the intensity of
hyperesthetic sensation waned rapidly after injection but
returned to pre-injection values by 35 min.
The development of contralateral signs in the animals of
the present study extends a well-documented finding in
human and experimental animal neuropathy. Loose ligature
of one rat sciatic nerve, resulting in unilateral allodynia and
hyperalgesia, also produced bilaterally enhanced dorsal
horn responses (cord dorsum potentials) to peripheral
nerve stimulation (Colvin et al., 1996). Unilateral nerve
constriction in animals also leads to bilateral elevation of
spinal dynorphin (Draisci et al., 1991; Wagner et al., 1993)
and to an extension of hyperalgesic behavior to the contral-
ateral leg (Attal et al., 1994). After partial sectioning of one
sciatic nerve, rats showed lowered mechanical and thermal
withdrawal thresholds bilaterally (Seltzer et al., 1990). Cen-
tral neuroplasticity is a recognized contributor to neuro-
pathic pain (Coderre et al., 1993) and the possibility of
new functional connections between spinal or more rostral
neurons extending across the midline presents one anatomi-
cal explanation for the appearance of contralateral signs
(Attal et al., 1990; Colvin et al., 1996). Based on the insen-
sitivity to i.v. lidocaine for sustained analgesia, we posit that
the mechanisms of contralateral hyperalgesia differ funda-
mentally from those of the ipsilateral, operated leg.
Are these results consistent with the hypothesis that
Na+ channels are the unique targets for i.v. local anesthetics
in relieving neuropathic pain? Lidocaine blocks Na+ chan-
nels in peripheral and central neurons with a potency that
depends on the state of the nerve membrane; those that have
less negative resting potentials or a pattern of high fre-
quency impulses are more effectively blocked (Strichartz,
529C.J. Sinnott et al. / Pain 80 (1999) 521–531
1973; Hille, 1977; Hondeghem and Katzung, 1977). The
IC50 for lidocaine’s inhibition of sodium current in unsti-
mulated peripheral nerve is about 200 mM (Schwarz et al.,
1977; Roy and Narahashi, 1992; Chernoff and Strichartz,
1990). High frequency stimulation can effectively double
this potency for channel inhibition (Courtney et al., 1978)
and constant depolarization can increase it by 10-fold
(Hille, 1977).
The degree of impulse blockade is not directly propor-
tional to the inhibition of Na channels (Cohen et al., 1981).
This relationship depends on the geometry of the neuron, as
well as the presence of other channels in the membrane
(Raymond et al., 1990; Drachman and Strichartz, 1991),
often requiring a drug to be present at concentrations
three to four times its IC50 for channel inhibition in order
to effect impulse blockade. In a study of lidocaine require-
ments for functional axonal blockade in vivo, Huang et al.,
(1997) reported IC50 values of 200–300 mM for myelinated
Ab- and Ad-fibers and about 800 mM for nociceptive C-
fibers. Similar values have been reported for lidocaine’s
blockade of isolated peripheral nerve fibers (Fink and
Cairns, 1984) and spinal root axons (Jaffe and Rowe,
1995). Relief of neuropathic pain occurs at 0.03–0.05
times these concentrations. At this time we do not know if
the conditions of a ‘neuropathically contributing’ nerve
fiber, such as resting depolarization, enhanced outward
(e.g. K+) currents, or high frequency ectopic discharge, are
together sufficient to potentiate lidocaine to a point where
5–10 mM can block aberrant impulses. Prudence recom-
mends that alternative drug targets also be considered,
including K+ channels open at the resting potential and
known to be very sensitive to lidocaine (Olschewski et al.,
1996) or certain G-protein coupled receptors whose actions
are disrupted by relatively low concentrations of local anes-
thetics (Xiong et al., 1999). Nevertheless, the hypothesis
that Na+ channels are the primary targets of therapeutic
i.v. local anesthetics has not yet been disproven.
Acknowledgements
We thank Dr. Jin-Mo Chung for showing us the technique
of spinal nerve ligation and Dr. Sandra Chaplan for gener-
ously sharing information and the Stanpump Ò software.
Supported by NIH grant GM35647 and funds from the
BWH Anesthesia Foundation.
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