䢇

Research Report
Transcutaneous Electrical Nerve
Stimulation for the Management of
Neuropathic Pain: The Effects of
Frequency and Electrode Position on
Prevention of Allodynia in a Rat Model of
Complex Regional Pain Syndrome Type II
Background and Purpose. Complex regional pain syndrome type II
ўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўў

(CPSII) is a painful condition that develops following a nerve injury.

Although transcutaneous electrical nerve stimulation (TENS) relieves
the pain of CPSII, the stimulation parameters that would best prevent
the development of the condition are not known. The purpose of this
study was to compare the ability of several different stimulation
strategies to reduce the development of allodynia. Subjects.
Sprague-Dawley rats were used in the study. Methods. A chronic
constriction injury (CCI) to the right sciatic nerve was used to induce
allodynia. Two groups of CCI rats received high-frequency TENS to the
lumbar paravertebral region with electrodes positioned on the skin
overlying either the right or left paraspinal musculature. Two addi-
tional groups of CCI rats received low-frequency TENS to acupuncture
points in the right or left hind limbs. A fifth group of CCI rats received
no TENS intervention. Thermal and mechanical pain thresholds were
assessed in the right hind paw before and 12 days after the CCI surgery.
The TENS was delivered 1 hour per day beginning on the day of
surgery. Results. Daily high-frequency TENS reduced the development
of mechanical allodynia in CCI rats, and low-frequency TENS reduced
the development of thermal allodynia, but only when TENS was
delivered on the left side. Discussion and Conclusion. The results
indicate that TENS delivered contralateral to a nerve injury best
reduces allodynia development. Comprehensive reduction of allodynia
development would require a combination of high- and low-frequency
TENS intervention. [Somers DL, Clemente FR. Transcutaneous elec-
trical nerve stimulation for the management of neuropathic pain: the
effects of frequency and electrode position on prevention of allodynia
in a rat model of complex regional pain syndrome type II. Phys Ther.
2006;86:698 –709.]

Key Words: Causalgia, Electroacupuncture, Transcutaneous electrical nerve stimulation.

David L Somers, F Richard Clemente

ўўўўўўўўўўўўўў

698 Physical Therapy . Volume 86 . Number 5 . May 2006

C
omplex regional pain syndrome type II (CPSII)1 is
defined by the International Association for the
Study of Pain as a chronic condition that can
develop following a peripheral nerve injury.2
Most frequently, the injury involves the median, ulnar,
sciatic, or tibial nerve, and the condition is characterized
by spontaneous pain in the limb of the damaged nerve.
The pain is described as constant and burning and is
accompanied by a lowering of the pain threshold for
mechanical and thermal stimulation (allodynia). In
addition, painful mechanical and thermal stimulation
are perceived as inordinately painful (hyperalgesia).
These symptoms continue after the initial injury has
healed and may become severe, spreading beyond the
site of initial injury and ultimately reducing the normal
use of the affected extremity.
The pain of CPSII is managed by pharmacological or
nonpharmacological interventions. Pharmacotherapy
includes the use of antidepressants, antiepileptics, and
opioids. Although these treatments are somewhat effec-
tive, they are associated with side effects. Administration
of antidepressants to people with neuropathic pain
improved their symptoms 50% of the time.3 However,
when people with chronic pain of multiple origins were
treated with antidepressant medication, dizziness, seda-
tion, gastrointestinal dysfunction, or dry mouth
occurred in about one third of those subjects.3 Admin-
istration of the antiepileptic drug, gabapentin, to people
with postherpetic neuralgia—a painful condition similar
to CPSII—reduced their perception of pain by 33%.4
Although the magnitude of side effects was relatively low,
27% of the subjects who took gabapentin experienced
somnolence, 24% had dizziness, and 7% had ataxia.
Opioid therapy can likewise reduce the pain of CPSII by
as much as 33%,5 but this form of pharmacotherapy is
associated with constipation, sedation, and physical
dependence.6 – 8
Transcutaneous electrical nerve stimulation (TENS) is a
nonpharmacological intervention that is used to reduce
the pain of CPSII. The modality is delivered to periph-
eral sensory nerves through surface electrodes and is
believed to produce analgesia by both peripheral and
central nervous system mechanisms.9 –11 Like pharmaco-
logical interventions, TENS is somewhat effective at
reducing the pain of CPSII. Application of TENS to
humans with neuropathic pain substantially reduced the
pain in 53% to 81% of those treated.12–14 When TENS is
used to manage the pain of CPSII in animal models of
the syndrome, it also is somewhat effective. Trancutane-
ous electrical nerve stimulation delivered to rats with
CPSII reduced thermal allodynia,15,16 mechanical allo-
dynia,17 and mechanical and heat hyperalgesia.18 In a
fashion reminiscent of humans with CPSII, TENS did
not in all cases reduce the symptoms of neuropathy in
these rats. Accordingly, some rats with CPSII treated
daily with TENS experienced substantial relief of ther-
mal allodynia, whereas other TENS-treated rats did not
experience such relief.15,19
Although TENS and pharmacological intervention are
both variably effective when used to manage the pain of
CPSII, TENS produces none of the side effects associ-
ated with drug therapy. There is a risk of skin irritation
or an allergic reaction from application of electrodes to
the skin, but these problems are relatively rare and are
easily managed by shifting the electrode position.12
Therefore, TENS represents a viable, nonpharmacologi-
cal intervention for the management of CPSII.

DL Somers, PT, PhD, is Associate Professor, Department of Physical Therapy, Duquesne University, 113 Health Sciences Bldg, Pittsburgh, PA
15282-0011 (USA) (somers@duq.edu). Address all correspondence to Dr Somers.

FR Clemente, PT, PhD, is Associate Professor and Chair, Department of Physical Therapy, Duquesne University.

Both authors provided concept/idea/research design, writing, data collection and analysis, and project management. Dr Somers provided fund
procurement. Dr Clemente provided consultation (including review of manuscript before submission). The authors thank Jeremy W Snodgrass,
Christopher M Bailey, Kelli D Marlow, Michelle L Gregg, and Mary Przybysz for data collection. They also acknowledge Leesa M DiBartola, RobRoy
L Martin, Mary T Marchetti, and Christopher R Carcia for consultation (including review of manuscript before submission). The authors
acknowledge the Empi Corporation for donating the transcutaneous electrical nerve stimulation units used in the study.

This study was approved by the Institutional Animal Care and Use Committee of Duquesne University.

This project was funded by the National Institutes of Health (1 R15 NS/OD 36315– 01). It also was funded, in part, under a grant with the
Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analyses, interpretations, or conclusions.

The data in this article were presented at the annual meeting of the Society for Neuroscience; November 14, 2005; Washington, DC.

This article was received June 9, 2005, and was accepted December 5, 2005.

Physical Therapy . Volume 86 . Number 5 . May 2006 Somers and Clemente . 699

There is no consensus on how TENS should be applied
to best relieve neuropathic pain. Transcutaneous electri-
cal nerve stimulation may be applied at high frequency
(80 –110 Hz) or low frequency (2–10 Hz),20,21 but it is
unknown which of these frequencies will best prevent or
alleviate the pain of CPSII. Electrodes to deliver TENS
may be positioned on skin located ipsilateral or
contralateral to a nerve injury,22 but it also is unknown
which of these locations would best prevent or reduce
neuropathic pain. Although the effects of frequency and
electrode positioning on CPSII-like pain has not been
examined, there are reasons to suspect that these param-
eters may influence treatment effectiveness.
High-frequency (80 –110 Hz) and low-frequency (2–10 Hz)
TENS20,21 differ in their ability to relieve pain and in the
central nervous system alterations they produce. Thirty
minutes of high-frequency TENS applied to the upper
extremity in humans who were healthy produced an
increase in the mechanical pain threshold when assessed
in the ipsilateral hand.23 Low-frequency TENS applied to
the same location, however, failed to increase mechani-
cal pain threshold in the hand.20 Differences in effec-
tiveness between high- and low-frequency TENS also are
present when these 2 options for stimulation are com-
pared in animal models of pain. Inflammation produced
by injection of 3% carrageenan into the rat hind paw
induces thermal and mechanical allodynia in the
injected paw. When high-frequency TENS is applied
directly to the inflamed hind paw, thermal and mechan-
ical allodynia are reduced, but neither symptom is
relieved when low-frequency TENS is applied to the
identical sites.24
The central nervous system alterations believed to
underlie high- and low-frequency TENS-induced pain
relief are also distinct. Although both frequencies of
stimulation are effective at reducing secondary allodynia
(an allodynia that develops in a region or body segment
other than the area of original injury) in the hind paws
of rats following experimentally induced knee inflamma-
tion, the neurotransmitters involved in producing this
reduction are somewhat different for the 2 frequencies.
High-frequency TENS relieves secondary allodynia via
muscarinic25 and ␮ opioid26 receptor-dependent mech-
anisms, and low-frequency TENS relieves secondary allo-
dynia via serotonin,27 muscarinic,25 and ␦ opioid26
receptor-dependent mechanisms. In addition, recent
evidence indicates that high- and low-frequency TENS
may produce distinct cortical activation patterns when
producing analgesia.28
Because high- and low-frequency TENS differ in their
mechanism of action and in their ability to relieve pain,
it is conceivable that perhaps one frequency of TENS will
relieve the painful symptoms of CPSII better than the
700 . Somers and Clemente
ўўўўўўўўўўўўўўўўўўўўўў
other frequency of stimulation. It is also conceivable,
that high- and low-frequency TENS may differentially
alter individual painful symptoms associated with the
syndrome. Therefore, one purpose for the present study
was to directly compare the ability of high- and low-
frequency TENS to prevent the development of the
painful symptoms of CPSII.
The effectiveness of TENS when delivered ipsilateral or
contralateral to a CPSII-inducing nerve injury has not
been directly compared. However, in TENS-treated rats
with CPSII, we recently discovered a relationship
between spinal cord neurotransmitter content and
mechanical allodynia,29 suggesting that the location of
stimulation is an important treatment parameter. In that
study, high-frequency TENS was applied to the right side
of rats with a right-sided chronic constriction injury
(CCI) to the sciatic nerve, and the content of pain-
related neurotransmitters30,31 was evaluated bilaterally in
the dorsal horns of the spinal cord. Following daily
TENS treatment, mechanical allodynia in the right hind
paw was reduced in some rats but not in others, and a
strong relationship developed between the magnitude of
allodynia present and the neurotransmitter content in
the spinal cord. As the dorsal horn content of glutamate
and glycine increased within the right side of the spinal
cord and decreased within the left side, mechanical
allodynia decreased. A similar relationship was not
present in untreated CPSII rats. These results indicate
that both sides of the spinal cord are important to
TENS-induced pain relief, even when CPSII is present
unilaterally. Moreover, because the TENS-induced rela-
tionship between mechanical allodynia and spinal cord
neurotransmitter content is strikingly different between
the 2 sides of the spinal cord, we suspect that contra-
lateral and ipsilateral TENS treatment could differ sub-
stantially from each other in the pain relief they pro-
duce. Therefore, a second purpose for the present study
was to directly compare the ability of TENS to prevent or
reduce the painful symptoms of CPSII when it is deliv-
ered ipsilateral or contralateral to a nerve injury.
Method
Subjects
The study was performed on rats because we would
ultimately like to make firm recommendations about
what treatment strategies might be used with a person
who first complains of CPSII-like symptoms. In rat mod-
els, the onset of symptoms is predictable and relatively
rapid. Moreover, the nerve injury producing the symp-
toms is controlled. In humans, symptoms develop more
slowly, and the precipitating nerve injury is variable.
Therefore, investigating controlled prophylactic treat-
ment in humans would be difficult.
Physical Therapy . Volume 86 . Number 5 . May 2006
One hundred fifty-seven male Sprague-Dawley rats
(170 –200 g) were used for the experiments. The rats
were housed in a controlled environment on a 12-hour
light-dark cycle with unlimited access to food and water.
All experiments were carefully conducted according to
the ethical guidelines for the use of experimental pain in
conscious animals put forth by the International Associ-
ation for the Study of Pain.32
Procedure
To produce CPSII, the rats were deeply anesthetized
with sodium pentobarbital (50 mg/kg) via intraperito-
neal injection. Four chromic gut sutures were applied to
the right sciatic nerve according to the CCI procedure of
Bennett and Xie.33 The CCI model of CPSII was chosen
because this procedure is well documented and pro-
duces symptoms that are quite similar to those seen in
people with CPSII.33,34 At the conclusion of an experi-
ment, the sciatic nerve was re-exposed and the integrity
of the sutures was confirmed.
Mechanical pain threshold was assessed with calibrated
Semmes-Weinstein monofilaments.35,36 The filaments
(0.41, 1.2, 3.63, 8.51, and 15.13 g) were used to give
graded pressure to the plantar surface of the hind paws.
Care was taken to keep the stimulations in the mid-
region of the foot between the toes and the heel because
this area is innervated exclusively by the sciatic nerve.37
Rats were placed on a metal grid and covered with a
plexiglass cover. The lowest-caliber filament (0.41 g) was
pushed onto the plantar surface of the right hind paw
until the filament bent. This procedure was repeated 5
times with 2 to 3 seconds between pushes. Five minutes
later, the left paw of the same rat was similarly assessed.
Not less than 5 minutes after the left paw was assessed,
the entire procedure was repeated. In this way, the right
and left paws were pushed by the 0.41-g filament 10
times, and the number of withdraws was recorded. In
ascending order, each filament was so tested until the rat
withdrew from all 10 pushes of a single-size filament or
the largest-caliber filament was tested.
To estimate the force from which the rat withdrew 50%
of the time, force (in grams) was regressed on withdraw
frequency for all 5 filaments using linear regression. The
force at which the rat withdrew a paw on 5 of 10 pushes
(50% withdraw threshold [WT]) was predicted using the
regression equation. If the 50% WT so calculated was
greater than 15.13 g, the highest-caliber hair used (15.13 g)
was recorded as the gram force. If the rat failed to
respond to any of the filaments, 15.13 g was recorded as
the 50% WT. We have found that the intratester reliabil-
ity of data obtained with this method is quite good
(intraclass correlation coefficient [ICC]⫽.98).15 The
same investigator always performed this test.
Physical Therapy . Volume 86 . Number 5 . May 2006
Figure 1.
Position of stimulating electrodes for high-frequency transcutaneous
electrical nerve stimulation. Electrodes span skin innervated by the
dorsal rami of spinal nerves L1 through L6. The L1 through L6 segments
of the spinal cord include segments that also innervate the rat hind paw.
Thermal pain threshold was assessed by withdraw latency
(WL) from a radiant heat source as originally described
by Hargreaves et al.38 Radiant heat was applied to the
right and left paws 5 times each with 5 minutes separat-
ing irradiations. The latency to withdraw (in hundredths
of a second) was recorded for each irradiation. Twenty
seconds was the maximum irradiation time. The 5
latency measurements obtained for each paw were aver-
aged to obtain a mean latency for the right and left paws.
We have found that the intratester reliability of data
obtained with this method is quite good (ICC⫽.83).15
The same investigator always performs this test.
The TENS was applied to rats through self-adhesive
surface electrodes (Empi SoftTouch 9000*) using an
Empi Epix XL transcutaneous electrical nerve stimula-
tor.* This device uses a symmetrical, biphasic waveform.
Pulse duration (0 – 400 ␮s) and amplitude (0 – 40 mA)
are interlocked and set by a single intensity control. The
frequency of stimulation was either 100 Hz or 2 Hz. For
100-Hz stimulation, surface electrode placement was on
the denuded, presumably uninvolved, skin overlying
either the right (ipsilateral to nerve injury in CCI rats) or
left (contralateral to nerve injury in CCI rats) paraspinal
musculature. Electrodes were cut to 45 mm (length) by
5 mm (width) and positioned as shown in Figure 1. The
stimulated skin is innervated by the dorsal rami of
lumbar spinal cord segments L1 through L6.39 This
placement spans the dermatomes of spinal cord seg-
ments that also innervate the painful right paw in CCI
rats.37,39 Stimulation was delivered to nonpainful skin
because this strategy is frequently used clinically to
manage neuropathic pain,13,14 represents an electrode
position that can be used by those who cannot tolerate
TENS directly over the painful skin,40 and was previously
* Empi Inc, 599 Cardigan Rd, St Paul, MN 55126.
Somers and Clemente . 701

successful when used to manage lower-extremity neuro-
pathic pain in humans and rats.13,15,40 The intensity of
stimulation was 80% of that needed to produce a visible
muscle contraction.
For 2-Hz stimulation, a modified version of the proce-
dure described by Leem et al41 was used. Electrodes were
cut into 5-mm squares and applied to the denuded skin
surrounding the knee and leg of either the right or left
hind limb. The first electrode was applied to the Zusanli
acupuncture point.42 The Zusanli point is located
between the tibia and fibula about 5 mm lateral to the
anterior tubercle of the tibia just below the knee. The
other electrode was placed at the Sanyinjiao acupunc-
ture point.43 This point is located 3 mm proximal to the
medial malleolus at the posterior border of the tibia.
These sites were chosen because stimulation occurring
through them previously produced analgesia43,44 and
reduced mechanical allodynia in a rat model of CPSII.45
The intensity of stimulation was 3 times that necessary to
produce visible muscle contraction in the tibialis ante-
rior muscle of the leg.46
The TENS was delivered daily and commenced on the
day of surgery while the rats were still under the influ-
ence of sodium pentobarbital for both 100-Hz and 2-Hz
stimulation. On subsequent days, TENS was adminis-
tered to rats while they were lightly anesthetized with
halothane (4%, maintained at 0.2%– 0.5%).
Design
Five groups of rats received a CCI to the right sciatic
nerve. The first group of CCI rats (n⫽23) received
high-frequency TENS through stimulating electrodes
positioned on skin overlying the right paraspinal muscu-
lature (ipsilateral to nerve injury). The second group of
CCI rats (n⫽15) received high-frequency TENS through
stimulating electrodes positioned over the left paraspi-
nal musculature (contralateral to nerve injury). The
third group of CCI rats (n⫽23) received low-frequency
TENS through stimulating electrodes positioned over
acupuncture points in the right hind limb, and the
fourth group of CCI rats (n⫽12) received low-frequency
TENS through the same acupuncture points in the left
hind limb. The TENS was delivered to these 4 groups for
90 minutes commencing immediately after the CCI
surgery and then daily for 60 minutes for the next 11
days. The fifth group of CCI rats (n⫽28) was treated
exactly like the rats that received TENS, including
halothane administration, except that no TENS was
administered.
Three groups of rats did not receive a CCI and were used
as controls. To determine whether mechanical or ther-
mal pain threshold changed over time, a group of rats
(naive; n⫽20) was included that was treated exactly like
702 . Somers and Clemente
ўўўўўўўўўўўўўўўўўўўўўў
rats that received high-frequency TENS, including
paraspinal skin preparation and halothane administra-
tion, except that no TENS was delivered. Paraspinal skin
preparation, rather than acupuncture point skin prepa-
ration, was the control condition because this group was
completed first. We also examined several additional
control rats that had received only halothane anesthesia
and skin preparation to acupuncture points and could
see no perceptible difference between paraspinal and
acupuncture point skin preparation. We aborted the
acupuncture point control condition in order to mini-
mize the use of rats.
To determine whether TENS administration altered
mechanical or thermal pain threshold, a second group
of control rats (n⫽24) received high-frequency TENS to
the right paraspinal musculature using a schedule anal-
ogous to that used with rats that received a CCI. To
minimize the use of rats, data from this second group
were used for 2 purposes. Mechanical and thermal pain
thresholds assessed in the right hind paw were used to
determine the effects of high-frequency TENS when
delivered ipsilateral to the assessed extremity. Mechani-
cal and thermal pain thresholds assessed in the left hind
paw were used to determine the effects of high-
frequency TENS when delivered contralateral to the
assessed extremity. A similar strategy was used with the
third group of control rats (n⫽12) to determine
whether low-frequency TENS administration altered
mechanical or thermal pain threshold.
All rats were assessed once for mechanical and thermal
pain thresholds 3 days after their arrival. A second
baseline measurement was taken 1 day after the first, and
the 2 measurements were averaged to give a single
baseline pain threshold for each assessment. All rats
were subsequently assessed 12 days after surgery or on
the analogous day if no CCI surgery occurred. We have
previously found that thermal and mechanical allodynia
reach a maximum intensity by 12 days after a CCI.15 The
postsurgery assessment was performed at least 12 hours
after the final TENS treatment or halothane anesthesia.
The final TENS treatment occurred 11 days after the
surgery. Following the last assessment on day 12, the
sciatic nerve of all CCI rats was re-examined to deter-
mine the integrity of the lesion. If 1 or more of the 4
ligatures was untied, the rat was eliminated from
consideration. Three rats were dropped from the
study for this reason, and are not included in the
numbers above.
Data Analysis
Percentages of change from baseline for mechanical and
thermal pain thresholds were calculated for the right
hind paw of each rat using the following formulas:
Physical Therapy . Volume 86 . Number 5 . May 2006
 Mechanical pain threshold ⫽
[(Right 50% WT 12 day ⫺ Right 50% WT baseline)/
Right 50% WT baseline] ⫻ 100
Thermal pain threshold ⫽
[(Right WL 12 day ⫺ Right WL baseline)/
Right WL baseline] ⫻ 100
For the control groups (no CCI) that received TENS,
calculations also were performed for the left hind paw of
individual rats. These values were considered the per-
centage of change from baseline contralateral to the
TENS stimulation. In all cases, the more negative the
percentage of change from baseline, the lower the pain
threshold on the final assessment.
For each data group, a mean percentage of change from
baseline for mechanical pain threshold was calculated.
Mean values of the groups were then compared with 2
one-way analyses of variance (ANOVAs). The first
ANOVA was used to compare the mean percentages of
change in mechanical pain threshold among all 4
groups of TENS-treated CCI rats, untreated CCI rats,
and naive control rats. The second ANOVA was used to
compare the mean percentages of change in mechanical
pain threshold among all 4 groups of data from rats
treated only with TENS and naive control rats. When
ANOVAs indicated that the mean percentages of change
in mechanical pain threshold were different among the
groups, pair-wise comparisons were performed with a
Tukey test. This analysis procedure was repeated for the
mean percentages of change in thermal pain threshold.
The alpha level was .05 for all statistics.
Results
Rats with a CCI had a significant lowering of mechanical
pain threshold at 12 days postsurgery when compared
with naive control rats (Fig. 2A). The CCI rats experi-
enced a mean reduction from baseline in mechanical
pain threshold of 41%, and naive control rats experi-
enced a mean increase from baseline in mechanical pain
threshold of 11%. Daily high- or low-frequency TENS
delivered ipsilateral to the nerve injury failed to prevent
this CCI-induced lowering of the mechanical pain
threshold. However, daily TENS delivered contralateral to
the nerve injury blocked the CCI-induced lowering of
mechanical pain threshold, but only when the treatment
was delivered at high frequency (Fig. 2A). Rats that
received high-frequency TENS contralateral to the nerve
injury experienced a mean reduction from baseline in
Physical Therapy . Volume 86 . Number 5 . May 2006
their mechanical pain threshold of 8%. This reduction
was significantly less than that observed in untreated CCI
rats (41%), but was not significantly different from that
observed in naive control rats.
Rats with a CCI also had a significant lowering of thermal
pain threshold at 12 days postsurgery when compared
with naive control rats (Fig. 2B). The CCI rats experi-
enced a mean reduction from baseline in thermal pain
threshold of 25%, whereas naive control rats experi-
enced a mean decrease of only 10%. Daily high- or
low-frequency TENS delivered ipsilateral to the nerve
injury did not prevent this CCI-induced lowering of the
thermal pain threshold. However, daily TENS delivered
contralateral to the nerve injury blocked the CCI-induced
lowering of thermal pain threshold, but only when the
treatment was delivered at low frequency (Fig. 2B). Rats
that received low-frequency TENS contralateral to the
nerve injury experienced a mean reduction from base-
line in their thermal pain threshold of 13%. This reduc-
tion was significantly less than that observed in untreated
CCI rats (25%), but not was significantly different from
that observed in naive control rats.
Daily high- or low-frequency TENS delivered to rats
without a CCI did not alter mechanical pain threshold
from that observed in naive control rats at 12 days
(Fig. 3A). This finding was true regardless of whether
measurements were taken ipsilateral or contralateral to
the side of TENS treatment. Daily high-frequency TENS
delivered to rats without a CCI likewise did not alter
thermal pain threshold from that observed in naive
control rats (Fig. 3B). However, low-frequency TENS
delivered to rats without a CCI significantly increased
the thermal pain threshold from that observed in naive
control rats (Fig. 3B).
Discussion
The Response of CCI Rats to Daily TENS Is Also Likely to
Be the Response of Humans Developing CPSII
We have shown that the development of mechanical and
thermal allodynia is reduced in CCI rats by daily appli-
cation of TENS, but only when the treatment is delivered
contralateral to the nerve injury. Mechanical allodynia is
best prevented by high-frequency TENS delivered to the
skin overlying the paraspinal musculature and thermal
allodynia is best prevented by low-frequency TENS
applied to acupuncture points. Although it cannot be
said with certainty that the response of CCI rats to TENS
intervention would also be the response of humans with
CPSII, there are several reasons to believe that this would
be the case.
The mechanism of nerve injury, occurrence of symp-
toms, and mechanism of pain development are similar
Somers and Clemente . 703
 ўўўўўўўўўўўўўўўўўўўўўў
between CCI rats and humans with
CPSII. The nerve injury that precipi-
tates neuropathic pain in CCI rats is
incomplete, affecting some but not all
of the axons passing through the con-
striction.47 A recent meta-analysis of the
literature revealed that a partial nerve
injury also preceded the onset of CPSII
in 92% of the subjects in the literature
reviewed.48 The symptoms that develop
following a partial nerve injury in both
humans with CPSII and CCI rats also
are quite similar. The presence of allo-
dynia, hyperalgesia, and ongoing pain
are experienced by the majority of peo-
ple with CPSII and by CCI rats.48 –50 In
addition, skin temperature within the
affected extremity often is altered in
both humans with chronic regional
pain syndrome (types I and II) and CCI
rats, and in both cases whether the skin
is warmer or colder than normal is
variable.49,50 Not only are the symptoms
and mechanism of nerve injury similar
between CCI rats and humans with
CPSII, the mechanism of pain develop-
ment also appears to be similar. Rats
with a CCI experience an increase in
the dorsal horn content of the excita-
tory neurotransmitters glutamate and
aspartate.19,51 This elevation is believed
to play a role in pain development, and
administration of broad glutamate/
aspartate receptor antagonists block
the development of painful symptoms
in these rats.30 Likewise, administration
of glutamate/aspartate receptor antag-
onists to people with CPSII reduces the
painful symptoms of the syndrome.52
Figure 2.
People with CPSII and CCI rats also are Mean percentage of change from baseline in mechanical and thermal pain thresholds in naive
similar in how they respond to interven- control, chronic constriction injury (CCI), and transcutaneous electrical nerve stimulation
(TENS)-treated CCI rats. Bars represent mean (⫾SEM) percentage of change in mechanical (A)
tions intended to reduce pain. The or thermal (B) pain threshold as assessed by withdraw from calibrated Semmes-Weinstein
same pharmacological agents that are monofilaments (in grams) or from radiant heat (in seconds), respectively. All means are
used to reduce the pain of CPSII in calculated from the right hind paw (nerve-injured hind paw in CCI rats). HFS⫽high-frequency
humans are effective when used to treat TENS, LFS⫽low-frequency TENS, ipsi⫽ipsilateral to the †
nerve injury, contra⫽contralateral to
CCI rats.53 Moreover, the response of the nerve injury. *significant difference from CCI rats; significant difference from naive control
rats (single-factor analysis of variance, Tukey post hoc comparisons; Pⱕ.05).
people with CPSII and CCI rats to
TENS intervention is similar. Both
humans with CPSII and CCI rats have
varied responses to TENS intervention, with the modal- humans, rather than later, may augment the effective-
ity being effective in some cases, but not in others.12–15 In ness of the treatment.54,55 In a similar fashion, TENS
addition, for both people with CPSII and CCI rats, the delivered to CCI rats reduced thermal allodynia when the
timing of TENS intervention appears to be important. treatment commenced immediately after the nerve injury,
Intervention with high-frequency peripheral nerve stim- but not when started 3 days after the nerve injury.15
ulation in the first 2 months after a nerve injury in

704 . Somers and Clemente Physical Therapy . Volume 86 . Number 5 . May 2006
 tion on the day of nerve injury is a
reasonable option for people, because
only a small percentage of people with
a nerve injury will ultimately develop
CPSII56 and prophylactic treatment of
them all is untenable. It might be
argued, then, that the results reported
here are irrelevant to people who will
develop CPSII. However, although CCI
rats and humans with CPSII are strik-
ingly similar, one difference between
them is that humans develop symptoms
after a nerve injury often more slowly
than do CCI rats. The onset of measur-
able symptoms in CCI rats occurs
between day 157 and day 7.15,49 Seventy
percent to 90% of humans with CPSII
experience the onset of pain within 1 to
4 weeks after the nerve injury.48 Conse-
quently, there is a window with humans
where symptom development can be
monitored and early intervention can
occur. For this reason, and because of
the similarities between CCI rats and
humans with CPSII, we believe the
results presented here are indeed rele-
vant to the care of humans following a
nerve injury.

TENS Intervention Reduces Allodynia

Only When Delivered Contralateral to a
Nerve Injury
Regardless of the frequency used, daily
TENS intervention reduced allodynia
when applied contralateral, but not
ipsilateral, to a nerve injury. This char-
acteristic of TENS effectiveness appears
to be specific to nerve-injured rats
because unilateral low-frequency TENS
Figure 3. increased thermal pain threshold bilat-
Mean percentage of change from baseline in mechanical and thermal pain thresholds in naive erally in rats that did not have a CCI.
and transcutaneous electrical nerve stimulation (TENS)-treated control rats. Bars represent mean
Why only contralateral delivery of
(⫾SEM) percentage of change in mechanical (A) or thermal (B) pain threshold as assessed by
withdraw from calibrated Semmes-Weinstein monofilaments (in grams) or from radiant heat (in TENS was effective at reducing allo-
seconds), respectively. Means are calculated from the right hind paw in naive control rats. In dynia in CCI rats is not known. How-
TENS-treated control rats, means are calculated relative to the side of stimulation. HFS⫽high- ever, peripheral nerves located
frequency TENS, LFS⫽low-frequency TENS, ipsi⫽ipsilateral to TENS treatment, contralateral to a nerve injury play a
contra⫽contralateral to TENS treatment. †significant difference from naive control rats (single-
unique role in pain modulation within
factor analysis of variance, Tukey post hoc comparisons; Pⱕ.05).
the dorsal horn on the side of nerve
injury. On the nerve-injured side of
CCI rats, wide dynamic range neurons
Because of these broad similarities between humans with in the dorsal horn are responsive to stimulation of the
CPSII and CCI rats, it is likely that the TENS-induced contralateral hind paw.58 When this stimulation is nox-
prevention of allodynia reported here also may occur in ious, spontaneous activity of wide dynamic range neu-
humans with CPSII. Even if this is so, CCI rats in the rons within the dorsal horn on the nerve-injured side is
present study were treated immediately following the reduced.59 Because activity within wide dynamic range
nerve injury. It cannot be expected that TENS interven- neurons is associated with the perception of pain,60,61

Physical Therapy . Volume 86 . Number 5 . May 2006 Somers and Clemente . 705

this reduction in activity is likely accompanied by a
reduced perception of pain. It is not just painful stimu-
lation to the contralateral hind paw that is capable of this
modulatory effect on dorsal horn neurons of the nerve-
injured side. A subcutaneous injection of lidocaine into
the nonpainful hind paw of CCI rats suppressed sponta-
neous and pain-induced hyperactivity in wide dynamic
range neurons of the nerve-injured side.62 This is true
even though there is no evidence suggesting that
contralateral peripheral nerves are hyperactive in ani-
mals or humans with unilateral CPSII.
Although the present research did not investigate activ-
ity of wide dynamic range neurons, it is possible that
daily TENS delivered contralateral to a nerve injury is
better able to reduce allodynia because this mode of
delivery suppresses pain-mediating neurons on the side
of nerve injury. Confirmation of this notion awaits
further research, but the present data adds to an emerg-
ing body of evidence suggesting that contralateral treat-
ment for unilateral neuropathic pain is a reasonable,
effective treatment option.
There is a clinical perception that bilateral stimulation
may be helpful in managing unilateral painful condi-
tions.22 At least when bilateral stimulation is used to
manage the pain of neuropathy, this perception appears
to have merit. In one published report where this
approach was used to treat a woman with unilateral
painful, diabetic neuropathy, daily TENS was applied
bilaterally in the lumbar paravertebral region.40 The
treatment virtually eliminated the neuropathic pain
experienced by the woman in the left lower extremity.
The present results suggest that when bilateral TENS is
used to manage neuropathic pain, at least in part, it is
producing its beneficial effect through stimulation of
peripheral nerves located contralateral to the nerve
injury. Although TENS delivered on the side of nerve
injury in CCI rats did not alter allodynia, it is unknown
whether this side also contributes to pain relief when
stimulation is delivered bilaterally. At a minimum, how-
ever, we believe the present results suggest that people
with neuropathic pain should be treated with stimula-
tion that in some way includes the side located contra-
lateral to the nerve injury.
The Type of Allodynia Reduced by TENS Is Dependent on
the Frequency of the Stimulation
When daily TENS was administered contralateral to a
nerve injury, it reduced the development of thermal
allodynia, but only when delivered at low frequency. The
development of mechanical allodynia, however, was
reduced only when daily TENS was delivered at high
frequency. It appears, then, that the frequency of stim-
ulation may determine which form of allodynia is most
reduced. One caveat to this conclusion is that high-
706 . Somers and Clemente
ўўўўўўўўўўўўўўўўўўўўўў
frequency TENS was delivered to skin overlying the
paraspinal musculature, whereas low-frequency TENS
was delivered to acupuncture points. Thus, it is possible
that frequency was not the sole factor that determined
whether mechanical or thermal allodynia was reduced.
Nevertheless, there is evidence indicating that frequency
of stimulation is a factor that may determine TENS
effectiveness. For example, when high- and low-
frequency TENS are delivered to the same acupuncture
point in the lower extremity of humans who are healthy,
only low-frequency TENS can produce analgesia in the
ipsilateral hand.20,23 Moreover, the nervous system
response to high- and low-frequency TENS delivered
through the same electrode positions is somewhat
unique. When humans who are healthy receive high- or
low-frequency TENS through electrodes identically posi-
tioned on the hand or leg, high-frequency TENS
increases the cerebrospinal fluid content of dynorphin
and low-frequency TENS increases the cerebrospinal
fluid content of enkephalin.63 Thus, although electrode
position, in part, may explain why high- and low-
frequency TENS differentially reduced the development
of allodynia in the present study, it is likely that fre-
quency, either alone or through an interaction with
electrode position, is also a primary contributing factor.
Why high- and low-frequency TENS prevents mechanical
and thermal allodynia, respectively, is not known. How-
ever, because the central nervous system mechanisms
that undergird mechanical and thermal allodynia are
somewhat distinct, this differential effect is not surpris-
ing. For example, glutamate neurotransmission is impli-
cated in establishing and maintaining the pain of
CPSII,64,65 but the glutamate receptors involved in main-
taining mechanical and thermal allodynia are at least
somewhat distinct. In humans with CPSII, pharmacolog-
ical blockade of a binding site on the NMDA glutamate
receptor reduces indicators of mechanical allodynia, but
fails to reduce any measure of thermal allodynia.66
Similarly, pharmacological blockade of a non-NMDA
glutamate receptor in neuropathic rats abolishes the
presence of mechanical allodynia, but not thermal allo-
dynia.67 It is possible that these different underlying
mechanisms for the production of mechanical and ther-
mal allodynia are best addressed by different frequencies
of TENS treatment. Confirmation of this notion awaits
further research.
Because high- and low-frequency TENS specifically pre-
vent mechanical and thermal allodynia, respectively, it
seems that a comprehensive clinical strategy would
involve them both. Although a tested strategy for com-
bining these 2 frequencies of treatment together has yet
to be established, clearly exposing patients in the initial
stages of CPSII development to both high- and low-
frequency TENS is warranted. This notion has some
Physical Therapy . Volume 86 . Number 5 . May 2006
precedent. In a recent report,68 people with radiculop-
athy were treated with stochastic or conventional (high-
frequency) TENS. Stochastic TENS randomly alters the
frequency of stimulus delivery, although the average
frequency over time remains in the high-frequency
range. Patients receiving this multiple-frequency form of
TENS perceived significantly less pain than did their
counterparts who received conventional TENS.68 There-
fore, it appears that exposing the nervous system to
different frequencies of TENS may promote pain relief.
Our data would support this notion by indicating that
people who are developing CPSII should be exposed to
both high- and low-frequency stimulation in order to
comprehensively reduce the development of allodynia.
Conclusion
We have shown that early intervention with high- and
low-frequency TENS can reduce the development of
mechanical and thermal allodynia, respectively. There is
good reason to suspect that what was observed in the CCI
rats of the present study also would be true of humans
treated with daily TENS following a nerve injury. The
differential effect of high- and low-frequency TENS on
mechanical and thermal allodynia suggests that both
treatment strategies may be necessary in order to com-
prehensively reduce allodynia in humans developing
CPSII. Moreover, the present data suggest that treatment
contralateral to the nerve injury, rather than ipsilateral
to the nerve injury, may be the best strategy for begin-
ning treatment with daily TENS. Finally, it is important
to note that based on the present data, our recommen-
dations for managing the pain of CPSII are intended
only as starting points for the use of the modality.
Because TENS is variable in its ability to relieve multiple
forms of pain, it is likely that the strategies of stimulation
described here will be altered once the treatment begins
in order to maximize its effectiveness. Nevertheless, we
believe that the data presented here suggest that both
high- and low-frequency stimulation delivered through
electrodes positioned contralateral to a nerve injury may
be the best starting point for TENS treatment of humans
developing CPSII.
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Physical Therapy . Volume 86 . Number 5 . May 2006 Somers and Clemente . 709