Analgesic and anti-inflammatory effects of lignocaine–prilocaine J. L. P , T. C

British Journal of Anaesthesia 1996; 76: 806–810
Analgesic and anti-inflammatory effects of lignocaine–prilocaine
(EMLA) cream in human burn injury
J. L. PEDERSEN, T. CALLESEN, S. MØINICHE AND H. KEHLET
Summary
Pain relief may be improved by reducing
sensitization of nociceptive pathways caused by
tissue injury. Such a reduction depends mainly on
inhibition of local inflammatory changes and the
relation between duration of nociceptive block and
nociceptive input. In this study we examined if
prolonged topical treatment with local anaesthetics
could reduce late hyperalgesia and local inflammation after burn injury in healthy volunteers. The
effects of EMLA treatment for 8 h after burn on
hyperalgesia, inflammation and wound healing
were compared with the contralateral placebotreated leg for 48 h after bilateral burn injuries
(15 25 mm, 49 ⬚C for 5 min) in a double-blind,
randomized study in 12 healthy volunteers. Wound
healing was studied 1 and 2 weeks after injury.
Neither mechanical nor thermal primary hyperalgesia were affected significantly by prolonged
EMLA treatment. Secondary hyperalgesia and skin
erythema were also not changed. Seven of 12
placebo-treated legs developed blisters, in contrast
with four of 12 EMLA-treated legs. Wound healing
showed no apparent differences. Our data suggest
that prolonged, topical treatment with local anaesthetics did not reduce local inflammation and late
hyperalgesia. (Br. J. Anaesth. 1996; 76: 806–810)
Key words
Burns. Anaesthetics local, EMLA. Pain, mechanism.
Injury causes inflammation and may lead to prolonged sensitization of nociceptive pathways. Primary and secondary hyperalgesia are well established
aspects of this process. Hyperalgesia describes the
phenomenon of increased pain intensity in response
to normally painful stimuli [1], primary hyperalgesia
refers to the changes in sensation within the injury,
while secondary hyperalgesia refers to sensory
changes in the undamaged tissue surrounding the
injury. Several inflammatory mediators promote
hyperalgesia by sensitization of nociceptors [2].
Many in vitro and animal studies have shown antiinflammatory effects of local anaesthetics and these
effects may potentiate the analgesic effect of these
agents. The anti-inflammatory effects may impair
the host defence, but may also improve conditions
with destructive inflammation. In contrast, there are
only few human reports on the anti-inflammatory
effects of local anaesthetics and we have shown
previously that brief (3.5 h) topical treatment with
local anaesthetics before and after injury did not
significantly affect inflammation after burn [3]. The
aim of the study was therefore to examine if
prolonged and intense treatment with lignocaine–
prilocaine cream (EMLA) could reduce late hyperalgesia and other markers of local inflammation after
burn injury in healthy volunteers. The treatment
was initiated after the burn, as this mimics the
clinical situation.
Subjects and methods
We studied 12 healthy volunteers, aged 22–47 yr (all
male), after obtaining informed consent and approval
from the local Ethics Committee and the Danish
National Health Board. Subjects were not medically
knowledgeable and were not aware of the purpose of
the study.
Baseline measurements, which included assessment of skin colour, mechanical pain detection
threshold (MPDT) and heat pain detection threshold
(HPDT), were performed on the medial calf in both
legs. After obtaining baseline measurements, thermal
injury was induced on each leg. All measurements,
that is skin erythema, blister formation, MPDT,
secondary hyperalgesia and HPDT, were made in
this order, 16, 20, 24 and 48 h after the injuries.
Immediately after the injury, EMLA or placebo was
applied, double-blind and randomized, to the skin
and covered under occlusive dressing for 8 h after
the injury. Experiments were performed in a quiet
room, temperature 20–22 ⬚C, with subjects in a
relaxed and reclined position. Subjects were
instructed to keep their eyes closed during all
measurements so that they had no impression of the
results of the measurements.
EMLA TREATMENT
EMLA cream 2 g (2.5 % prilocaine and 2.5 %
lignocaine eutectic mixture, Astra, Södertälje,
Sweden) or placebo (Astra; Södertälje, Sweden) was
applied in a double-blind, randomized manner to the
skin and covered under occlusive dressing
(Tegaderm, 3M Health Care Ltd, Leicestershire,
UK) for 8 h after the injury. The cream was renewed
JURI L. PEDERSEN, MD, TORBEN CALLESEN, MD, HENRIK KEHLET,
MD, PHD (Department of Surgical Gastroenterology); STEEN
MØINICHE, MD (Department of Anaesthesiology); Hvidovre
Hospital, University of Copenhagen, Kettegaard Allé 30, 2650
Hvidovre, Denmark. Accepted for publication: January 24, 1996.
Correspondence to J.L.P.
Effect of EMLA in human burns
3 and 5.5 h after initial application, and re-covered.
Subjects were instructed to avoid physical activities
that could displace the thick cream layer from the
injury. The burns were performed in the afternoon
and the cream was removed 8 h later (late evening).
Subjects attended next morning for the first measurement, 16 h after the injury.
THERMAL INJURY
Thermal injuries were produced on the medial
surface of the right and left calf with a 1525-mm
Peltier thermode (Thermotest, Somedic A/B,
Stockholm, Sweden). The thermode (49 ⬚C) was
applied to the skin for 5 min under standardized
pressure (34 mm Hg), causing first- and superficial
second-degree burn injuries [4, 5]. The burn caused
immediate intense stinging pain, which was followed
by a moderate burning pain with a more diffuse
quality during the remainder of the stimulation
period. Spontaneous pain after the injury has not
been observed in the model.
PRIMARY HYPERALGESIA
Mechanical pain detection threshold (MPDT)
within the injured area was determined by pinprick
with nine progressively rigid von Frey hairs
(Somedic A/B, Stockholm, Sweden). We examined
the force produced by each hair by pressing it against
a balance and measured the weight it produced when
it was slightly flexed. We confirmed that the steps
from 1 to 9 represented logarithmic increases in force
(hair no. 1 : 3 mN, 2 : 9 mN, 3 : 11 mN, 4 :
18 mN, 5 : 29 mN, 6 : 49 mN, 7 : 98 mN, 8 :
98 mN, 9 : 175 mN). MPDT was defined as the
lowest force (pinprick) which produced a definite
sensation of pain or discomfort. Pinprick was
performed with each hair from the thinnest, 8–10
times in the area of the injury, until some of the 8–10
stimulations were reported to be painful or unpleasant. The number of the hair producing pain was
recorded and the procedure was repeated three times
at each measurement point. The median of three
threshold measurements was reported as the MPDT.
If hair No. 9 did not produce any pain or discomfort,
we assigned this observation the value 10.
Thermal thresholds were determined with the
computerized
Thermotest
(Somedic
A/B,
Stockholm, Sweden) in the area of the injury. Heat
pain detection threshold (HPDT) was the lowest
temperature perceived as painful. Subjects were
instructed to press a button as soon as the specified
sensation was reached. Thermal thresholds were
determined from a baseline of 32 ⬚C with a rate of
change of 1 ⬚C s91. The upper cut-off limit was
52 ⬚C. HPDT was calculated as the average of three
measurements, with intervals of 9 s between each
stimulation.
SECONDARY HYPERALGESIA
The area of mechanical hyperalgesia that developed
around the burn injury was assessed with von Frey
hair No. 9 (175 mN). In most cases pinprick with
807
this hair is a painful or unpleasant stimulus in
distinct spots of the skin, although it is not
universally painful. Thus areas of hyperalgesia were
measured, not areas of allodynia. Borders of hyperalgesia were determined by stimulating along eight
radial linear paths arranged from the centre of
injury. Stimulation along each path began well
outside the hyperalgesic area where slight or no pain
was perceived and continued slowly towards the
centre of the burn injury until the subject reported a
definite change in sensation, most often to a more
intense pricking with a burning after-sensation. This
point was marked and the eight marks were later
traced onto a clear acetate sheet. The area of
secondary hyperalgesia was calculated from the eight
marks using a vector algorithm.
INFLAMMATION
In order to estimate the severity of inflammation, the
intensity of erythema inside the injury was assessed
with a hand-held skin reflectance spectrophotometer
(Dermaspectrometer, Cortex Technology, Hadsund,
Denmark) [6, 7]. The spectrophotometer provided a
skin erythema index based on the absorption characteristics of green and red light in the skin. Measurements were performed in six spots within the burn
injury. All values were recorded and the mean
calculated. The development of blisters was recorded
as present or absent. Healing of the burns was
documented using a questionnaire, 1 and 2 weeks
after the injury.
STATISTICAL ANALYSIS
Distribution of data was evaluated with the Shapiro
Wilk test [8]. Primary mechanical hyperalgesia and
secondary hyperalgesia in EMLA- and placebotreated legs were evaluated at separate times with
multiple Wilcoxon tests for paired observation with
Bonferroni correction and area under the curves
(AUC) for the whole observation period with
Student’s t test for differences in a paired design
[9]. Evaluation of primary thermal hyperalgesia and
erythema was based on AUC values but analysed
also using parametric two-way analysis of variance
(ANOVA) for repeated measurements [8]. Minimal
differences between treatments detectable in the
present study with a power of 90 % and a type I error
of 5 % were evaluated with Student’s t test for
differences in a paired design [8]. P 0.05 was
considered statistically significant.
Results
The area of hyperalgesia surrounding the injury was
not significantly altered by EMLA treatment compared with placebo (fig. 1 A). The effect of EMLA was
evaluated at all times (16 h, P : 0.68; 20 h, P :
0.37; 24 h, P : 0.14; and 48 h, P : 0.07; Wilcoxon
test). The level of significance was reduced to 1 % in
these comparisons with Bonferroni correction, because of the multiple comparisons. The area under
the curve (AUC) for hyperalgesia was applied as a
808
British Journal of Anaesthesia
Figure 1 A: Secondary hyperalgesia, that is area of hyperalgesia to von Frey pinprick (175 mN) outside the
injury, after burn injury in healthy volunteers treated with EMLA (. . . .) or placebo (——). Time 0 h :
measurements before thermal injury. Values are medians. Comparison of AUC values revealed no significant
difference between secondary hyperalgesia in EMLA- vs placebo-treated legs (P : 0.18; Student’s paired t test,
n : 12). B: Primary mechanical hyperalgesia, that is mechanical pain detection threshold to von Frey pinprick, in
the area of the burn injury. Values are medians. Comparison of AUC values revealed no significant difference
between primary mechanical hyperalgesia in EMLA- (. . . .) vs placebo- (——) treated legs (P : 0.19; Student’s
paired t test, n : 12). Von Frey hair no. (1–10) represents a rank scale, where 1 indicates a force of about 3 mN
and 9 about 175 mN, whereas 10 indicates that 175 mN did not produce pain or discomfort. The steps from 1 to
9 are logarithmic increases in force (see text). C: Primary thermal hyperalgesia, that is heat pain detection
threshold (HPDT) in the area of the burn injury. Values are means. Comparison revealed no significant difference
between primary thermal hyperalgesia in EMLA (. . . .)- vs placebo (——)-treated legs (P : 0.61; parametric twoway analysis of variance for repeated measurements, n : 12). D: Skin erythema, that is the intensity of erythema
inside the burn injury assessed with a hand-held skin reflectance spectrophotometer. Values are means.
Comparison revealed no significant difference between erythema in EMLA (. . . .)- vs placebo (——)-treated legs
(P : 0.34; parametric two-way analysis of variance for repeated measurements, n : 12).
Table 1 Positive answers out of 12, in a questionnaire (yes/no)
completed by the 12 subjects
Changes in injury
Placebo
(1 week)
EMLA
(1 week)
Placebo EMLA
(2 weeks) (2 weeks)
Tenderness
Irritated by touch
Itch
Any colour change
Crusts
Blister
Skin erythema
1
2
3
7
3
2
6
0
0
2
9
3
2
6
0
0
3
6
3
1
4
0
0
1
5
1
0
0
summary measure of the total hyperalgesic response.
AUC for secondary hyperalgesia after EMLA treatment was not significantly different from that after
placebo (P : 0.18; Student’s paired t test).
The effect of EMLA on primary mechanical
hyperalgesia (fig. 1 B) was analysed in the same way
and there was no significant differences between
EMLA and placebo (0 h, P : 0.20; 16 h, P : 0.28;
20 h, P : 0.29; 24 h, P : 1.00; and 48 h, P : 0.25;
Wilcoxon test). Comparison of AUC values confirmed this finding (P : 0.19; Student’s paired t
test).
Data for primary thermal hyperalgesia (fig. 1 C)
and skin erythema index (fig. 1 D) were analysed with
both AUC summaries and parametric two-way
ANOVA for repeated measurements. There were no
significant differences between EMLA and placebo
with both methods (primary thermal hyperalgesia:
AUC, P : 0.80 and ANOVA, P : 0.61; and ery-
Table 2 Minimum differences between treatments detectable
with a power of 90 % (type II error of 10 %) and a type I error
of 5 %. Differences are presented as the weighted mean for the
observation period (AUC divided by 48 h)
Secondary
hyperalgesia
(cm2)
Primary
mechanical
hyperalgesia
(von Frey No.)
Primary
thermal
hyperalgesia
(°C)
Erythema
index
(arb. unit)
13
0.9
2.4
1.3
thema: AUC, P : 0.54 and ANOVA, P : 0.34).
Seven of 12 placebo-treated legs developed blisters
in contrast with four of 12 EMLA-treated legs. With
binomial data (yes/no), these small numbers precluded a sensible statistical analysis. There were no
apparent differences in wound healing between
EMLA and placebo treatment (table 1).
Minimal differences between treatments detectable in this study, with a power of 90 % and a type I
error of 5 %, are presented in table 2. Differences are
presented as the weighted mean for the observation
period (AUC divided by 48 h).
Discussion
We examined if prolonged and intensive topical
treatment with local anaesthetics reduced late hyperalgesia, blister formation or erythema after thermal
injury in healthy volunteers in a double-blind,
randomized study. We found that the local anaesthetics neither reduced local inflammation and late
Effect of EMLA in human burns
hyperalgesia nor produced apparent changes in
wound healing, although the sample size does not
exclude minor differences. This result may seem
surprising, considering the known anti-inflammatory
effects of local anaesthetics. Several in vitro studies
have demonstrated reduced production of free
oxygen radicals from polymorphonuclear leucocytes
after treatment with local anaesthetics [10–14], and
reduced adherence and migration of leucocytes have
been documented in different in vivo models [15–18].
Furthermore, local anaesthetics inhibit movement of
leucocytes and phagocytosis in vitro [14, 19–21].
Local anaesthetics have also been shown to reduce
albumin extravasation in rats after burn injury and
chemical peritonitis [22, 23] and to modify the
inflammatory response to experimental colitis [24]
and irradiation [25].
Local anaesthetics may alter release of inflammatory mediators, for example histamine release
from mast cells in vitro [26], leukotriene B-4 and
interleukin-1 release from polymorphonuclear
granulocytes and mononuclear cells in vitro, respectively [27]. The flare reaction induced by trauma
and injection of inflammatory mediators is
diminished by local anaesthetics, in contrast with the
weal and local red reaction [28–30]. Thus local
anaesthetics block axon reflexes and sensory
functions of nociceptors. Inhibition of axon reflexes
reduces local, indirect release of inflammatory neuropeptides, but the clinical importance of diminished
neurogenic inflammation is unclear. It is not known
if the local effector function of directly stimulated
nociceptors is affected by local anaesthetics [31].
Furthermore, local anaesthetics have been shown to
inhibit substance P receptor binding [32]. Thus
several anti-inflammatory effects of local anaesthetics
have been demonstrated in vitro and in animal
models, but evidence of effects in human studies is,
to our knowledge, restricted to one uncontrolled
study and one case report, where lignocaine
improved ulcerative proctitis and severe interstitial
cystitis, respectively [33, 34]. Topical lignocaine has
been tested several times in asthmatic subjects with
conflicting, but mainly negative results [35–37].
Topical lignocaine had no effects on allergeninduced nasal secretion, blood flow or obstruction, in
allergic individuals [38]. We have shown earlier that
short-lived topical application, or subcutaneous
infiltration with local anaesthetics, did not affect
inflammation after burn [3]. This study, with
prolonged and intensive treatment, supports this
conclusion. Our findings, and the lack of other
clinical evidence, may therefore question the relevance of the anti-inflammatory effects of local
anaesthetics.
There may be different explanations for our
results. First, the response involves several inflammatory mediators and cell types, which may not be
affected by local anaesthetics. Second, the timing of
the treatment (before compared with after injury)
may be important in modulating inflammatory
responses, as early mediators release cascades of
secondary mediators. In this study we preferred
treatment after injury, as this mimics most clinical
situations, while treatment was initiated before
809
injury in our first study [3]. Apparently, this did not
affect the results. Third, the effects of prolonged
topical treatment were either too transient or incapable of altering the course of the inflammatory
response. Although the analgesic effects did not last
into the observation period (16–48 h after injury), we
do not question the effectiveness of EMLA cream in
pain relief, but effects on hyperalgesia should not be
expected for prolonged periods (more than 8 h) after
removal of the cream. The potential reduction of
leukotriene B-4, interleukin-1, histamine, free oxygen radicals and activated leucocytes by local
anaesthetics [27] should attenuate sensitization of
nociceptors in the injury, but removal of EMLA
cream 8 h before the first measurements may have
returned the process to its natural course. Fourth, we
studied only 12 subjects and we may have missed
some real differences. The minimal differences
between treatments detectable in this study, with a
power of 90 %, are shown in table 2.
The consequences for wound healing after treatment with local anaesthetics are controversial. The
synthesis of collagen and glycosaminoglycans by
fibroblasts in vitro is reduced by local anaesthetics
[39], as is the tensile strength of skin wounds in rats
[40]. Other studies [41], including our own, have
been unable to demonstrate adverse clinical effects
on host defences and wound healing, but our study
is less specific in this respect than the first mentioned
studies, and prolonged use of local anaesthetics may
threaten tissue defences.
Acknowledgements
The study was supported by grants from the John and Birte
Meyer Foundation, the P. A. Messerschmidt and Wife’s Fund,
Fonden til Laegevidenskabens Fremme and Astra Pain Control,
Södertälje, Sweden.
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