Transcutaneous Electrical Nerve Stimulation for the Management of by cmz65105

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									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
                                 (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




 698                                                            Physical Therapy . Volume 86 . Number 5 . May 2006
C
          omplex regional pain syndrome type II (CPSII)1 is                  associated with constipation, sedation, and physical
          defined by the International Association for the                   dependence.6 – 8
          Study of Pain as a chronic condition that can
          develop following a peripheral nerve injury.2                      Transcutaneous electrical nerve stimulation (TENS) is a
Most frequently, the injury involves the median, ulnar,                      nonpharmacological intervention that is used to reduce
sciatic, or tibial nerve, and the condition is characterized                 the pain of CPSII. The modality is delivered to periph-
by spontaneous pain in the limb of the damaged nerve.                        eral sensory nerves through surface electrodes and is
The pain is described as constant and burning and is                         believed to produce analgesia by both peripheral and
accompanied by a lowering of the pain threshold for                          central nervous system mechanisms.9 –11 Like pharmaco-
mechanical and thermal stimulation (allodynia). In                           logical interventions, TENS is somewhat effective at
addition, painful mechanical and thermal stimulation                         reducing the pain of CPSII. Application of TENS to
are perceived as inordinately painful (hyperalgesia).                        humans with neuropathic pain substantially reduced the
These symptoms continue after the initial injury has                         pain in 53% to 81% of those treated.12–14 When TENS is
healed and may become severe, spreading beyond the                           used to manage the pain of CPSII in animal models of
site of initial injury and ultimately reducing the normal                    the syndrome, it also is somewhat effective. Trancutane-
use of the affected extremity.                                               ous electrical nerve stimulation delivered to rats with
                                                                             CPSII reduced thermal allodynia,15,16 mechanical allo-
The pain of CPSII is managed by pharmacological or                           dynia,17 and mechanical and heat hyperalgesia.18 In a
nonpharmacological interventions. Pharmacotherapy                            fashion reminiscent of humans with CPSII, TENS did
includes the use of antidepressants, antiepileptics, and                     not in all cases reduce the symptoms of neuropathy in
opioids. Although these treatments are somewhat effec-                       these rats. Accordingly, some rats with CPSII treated
tive, they are associated with side effects. Administration                  daily with TENS experienced substantial relief of ther-
of antidepressants to people with neuropathic pain                           mal allodynia, whereas other TENS-treated rats did not
improved their symptoms 50% of the time.3 However,                           experience such relief.15,19
when people with chronic pain of multiple origins were
treated with antidepressant medication, dizziness, seda-                     Although TENS and pharmacological intervention are
tion, gastrointestinal dysfunction, or dry mouth                             both variably effective when used to manage the pain of
occurred in about one third of those subjects.3 Admin-                       CPSII, TENS produces none of the side effects associ-
istration of the antiepileptic drug, gabapentin, to people                   ated with drug therapy. There is a risk of skin irritation
with postherpetic neuralgia—a painful condition similar                      or an allergic reaction from application of electrodes to
to CPSII—reduced their perception of pain by 33%.4                           the skin, but these problems are relatively rare and are
Although the magnitude of side effects was relatively low,                   easily managed by shifting the electrode position.12
27% of the subjects who took gabapentin experienced                          Therefore, TENS represents a viable, nonpharmacologi-
somnolence, 24% had dizziness, and 7% had ataxia.                            cal intervention for the management of CPSII.
Opioid therapy can likewise reduce the pain of CPSII by
as much as 33%,5 but this form of pharmacotherapy is




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            other frequency of stimulation. It is also conceivable,
to best relieve neuropathic pain. Transcutaneous electri-      that high- and low-frequency TENS may differentially
cal nerve stimulation may be applied at high frequency         alter individual painful symptoms associated with the
(80 –110 Hz) or low frequency (2–10 Hz),20,21 but it is        syndrome. Therefore, one purpose for the present study
unknown which of these frequencies will best prevent or        was to directly compare the ability of high- and low-
alleviate the pain of CPSII. Electrodes to deliver TENS        frequency TENS to prevent the development of the
may be positioned on skin located ipsilateral or               painful symptoms of CPSII.
contralateral to a nerve injury,22 but it also is unknown
which of these locations would best prevent or reduce          The effectiveness of TENS when delivered ipsilateral or
neuropathic pain. Although the effects of frequency and        contralateral to a CPSII-inducing nerve injury has not
electrode positioning on CPSII-like pain has not been          been directly compared. However, in TENS-treated rats
examined, there are reasons to suspect that these param-       with CPSII, we recently discovered a relationship
eters may influence treatment effectiveness.                   between spinal cord neurotransmitter content and
                                                               mechanical allodynia,29 suggesting that the location of
High-frequency (80 –110 Hz) and low-frequency (2–10 Hz)        stimulation is an important treatment parameter. In that
TENS20,21 differ in their ability to relieve pain and in the   study, high-frequency TENS was applied to the right side
central nervous system alterations they produce. Thirty        of rats with a right-sided chronic constriction injury
minutes of high-frequency TENS applied to the upper            (CCI) to the sciatic nerve, and the content of pain-
extremity in humans who were healthy produced an               related neurotransmitters30,31 was evaluated bilaterally in
increase in the mechanical pain threshold when assessed        the dorsal horns of the spinal cord. Following daily
in the ipsilateral hand.23 Low-frequency TENS applied to       TENS treatment, mechanical allodynia in the right hind
the same location, however, failed to increase mechani-        paw was reduced in some rats but not in others, and a
cal pain threshold in the hand.20 Differences in effec-        strong relationship developed between the magnitude of
tiveness between high- and low-frequency TENS also are         allodynia present and the neurotransmitter content in
present when these 2 options for stimulation are com-          the spinal cord. As the dorsal horn content of glutamate
pared in animal models of pain. Inflammation produced          and glycine increased within the right side of the spinal
by injection of 3% carrageenan into the rat hind paw           cord and decreased within the left side, mechanical
induces thermal and mechanical allodynia in the                allodynia decreased. A similar relationship was not
injected paw. When high-frequency TENS is applied              present in untreated CPSII rats. These results indicate
directly to the inflamed hind paw, thermal and mechan-         that both sides of the spinal cord are important to
ical allodynia are reduced, but neither symptom is             TENS-induced pain relief, even when CPSII is present
relieved when low-frequency TENS is applied to the             unilaterally. Moreover, because the TENS-induced rela-
identical sites.24                                             tionship between mechanical allodynia and spinal cord
                                                               neurotransmitter content is strikingly different between
The central nervous system alterations believed to             the 2 sides of the spinal cord, we suspect that contra-
underlie high- and low-frequency TENS-induced pain             lateral and ipsilateral TENS treatment could differ sub-
relief are also distinct. Although both frequencies of         stantially from each other in the pain relief they pro-
stimulation are effective at reducing secondary allodynia      duce. Therefore, a second purpose for the present study
(an allodynia that develops in a region or body segment        was to directly compare the ability of TENS to prevent or
other than the area of original injury) in the hind paws       reduce the painful symptoms of CPSII when it is deliv-
of rats following experimentally induced knee inflamma-        ered ipsilateral or contralateral to a nerve injury.
tion, the neurotransmitters involved in producing this
reduction are somewhat different for the 2 frequencies.        Method
High-frequency TENS relieves secondary allodynia via
muscarinic25 and opioid26 receptor-dependent mech-             Subjects
anisms, and low-frequency TENS relieves secondary allo-        The study was performed on rats because we would
dynia via serotonin,27 muscarinic,25 and         opioid26      ultimately like to make firm recommendations about
receptor-dependent mechanisms. In addition, recent             what treatment strategies might be used with a person
evidence indicates that high- and low-frequency TENS           who first complains of CPSII-like symptoms. In rat mod-
may produce distinct cortical activation patterns when         els, the onset of symptoms is predictable and relatively
producing analgesia.28                                         rapid. Moreover, the nerve injury producing the symp-
                                                               toms is controlled. In humans, symptoms develop more
Because high- and low-frequency TENS differ in their           slowly, and the precipitating nerve injury is variable.
mechanism of action and in their ability to relieve pain,      Therefore, investigating controlled prophylactic treat-
it is conceivable that perhaps one frequency of TENS will      ment in humans would be difficult.
relieve the painful symptoms of CPSII better than the



700 . Somers and Clemente                                                  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        Figure 1.
the right sciatic nerve according to the CCI procedure of       Position of stimulating electrodes for high-frequency transcutaneous
Bennett and Xie.33 The CCI model of CPSII was chosen            electrical nerve stimulation. Electrodes span skin innervated by the
                                                                dorsal rami of spinal nerves L1 through L6. The L1 through L6 segments
because this procedure is well documented and pro-
                                                                of the spinal cord include segments that also innervate the rat hind paw.
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.                                   Thermal pain threshold was assessed by withdraw latency
                                                                (WL) from a radiant heat source as originally described
Mechanical pain threshold was assessed with calibrated          by Hargreaves et al.38 Radiant heat was applied to the
Semmes-Weinstein monofilaments.35,36 The filaments              right and left paws 5 times each with 5 minutes separat-
(0.41, 1.2, 3.63, 8.51, and 15.13 g) were used to give          ing irradiations. The latency to withdraw (in hundredths
graded pressure to the plantar surface of the hind paws.        of a second) was recorded for each irradiation. Twenty
Care was taken to keep the stimulations in the mid-             seconds was the maximum irradiation time. The 5
region of the foot between the toes and the heel because        latency measurements obtained for each paw were aver-
this area is innervated exclusively by the sciatic nerve.37     aged to obtain a mean latency for the right and left paws.
Rats were placed on a metal grid and covered with a             We have found that the intratester reliability of data
plexiglass cover. The lowest-caliber filament (0.41 g) was      obtained with this method is quite good (ICC .83).15
pushed onto the plantar surface of the right hind paw           The same investigator always performs this test.
until the filament bent. This procedure was repeated 5
times with 2 to 3 seconds between pushes. Five minutes          The TENS was applied to rats through self-adhesive
later, the left paw of the same rat was similarly assessed.     surface electrodes (Empi SoftTouch 9000*) using an
Not less than 5 minutes after the left paw was assessed,        Empi Epix XL transcutaneous electrical nerve stimula-
the entire procedure was repeated. In this way, the right       tor.* This device uses a symmetrical, biphasic waveform.
and left paws were pushed by the 0.41-g filament 10             Pulse duration (0 – 400 s) and amplitude (0 – 40 mA)
times, and the number of withdraws was recorded. In             are interlocked and set by a single intensity control. The
ascending order, each filament was so tested until the rat      frequency of stimulation was either 100 Hz or 2 Hz. For
withdrew from all 10 pushes of a single-size filament or        100-Hz stimulation, surface electrode placement was on
the largest-caliber filament was tested.                        the denuded, presumably uninvolved, skin overlying
                                                                either the right (ipsilateral to nerve injury in CCI rats) or
To estimate the force from which the rat withdrew 50%           left (contralateral to nerve injury in CCI rats) paraspinal
of the time, force (in grams) was regressed on withdraw         musculature. Electrodes were cut to 45 mm (length) by
frequency for all 5 filaments using linear regression. The      5 mm (width) and positioned as shown in Figure 1. The
force at which the rat withdrew a paw on 5 of 10 pushes         stimulated skin is innervated by the dorsal rami of
(50% withdraw threshold [WT]) was predicted using the           lumbar spinal cord segments L1 through L6.39 This
regression equation. If the 50% WT so calculated was            placement spans the dermatomes of spinal cord seg-
greater than 15.13 g, the highest-caliber hair used (15.13 g)   ments that also innervate the painful right paw in CCI
was recorded as the gram force. If the rat failed to            rats.37,39 Stimulation was delivered to nonpainful skin
respond to any of the filaments, 15.13 g was recorded as        because this strategy is frequently used clinically to
the 50% WT. We have found that the intratester reliabil-        manage neuropathic pain,13,14 represents an electrode
ity of data obtained with this method is quite good             position that can be used by those who cannot tolerate
(intraclass correlation coefficient [ICC] .98).15 The           TENS directly over the painful skin,40 and was previously
same investigator always performed this test.

                                                                * Empi Inc, 599 Cardigan Rd, St Paul, MN 55126.



Physical Therapy . Volume 86 . Number 5 . May 2006                                                          Somers and Clemente . 701
successful when used to manage lower-extremity neuro-        rats that received high-frequency TENS, including
pathic pain in humans and rats.13,15,40 The intensity of     paraspinal skin preparation and halothane administra-
stimulation was 80% of that needed to produce a visible      tion, except that no TENS was delivered. Paraspinal skin
muscle contraction.                                          preparation, rather than acupuncture point skin prepa-
                                                             ration, was the control condition because this group was
For 2-Hz stimulation, a modified version of the proce-       completed first. We also examined several additional
dure described by Leem et al41 was used. Electrodes were     control rats that had received only halothane anesthesia
cut into 5-mm squares and applied to the denuded skin        and skin preparation to acupuncture points and could
surrounding the knee and leg of either the right or left     see no perceptible difference between paraspinal and
hind limb. The first electrode was applied to the Zusanli    acupuncture point skin preparation. We aborted the
acupuncture point.42 The Zusanli point is located            acupuncture point control condition in order to mini-
between the tibia and fibula about 5 mm lateral to the       mize the use of rats.
anterior tubercle of the tibia just below the knee. The
other electrode was placed at the Sanyinjiao acupunc-        To determine whether TENS administration altered
ture point.43 This point is located 3 mm proximal to the     mechanical or thermal pain threshold, a second group
medial malleolus at the posterior border of the tibia.       of control rats (n 24) received high-frequency TENS to
These sites were chosen because stimulation occurring        the right paraspinal musculature using a schedule anal-
through them previously produced analgesia43,44 and          ogous to that used with rats that received a CCI. To
reduced mechanical allodynia in a rat model of CPSII.45      minimize the use of rats, data from this second group
The intensity of stimulation was 3 times that necessary to   were used for 2 purposes. Mechanical and thermal pain
produce visible muscle contraction in the tibialis ante-     thresholds assessed in the right hind paw were used to
rior muscle of the leg.46                                    determine the effects of high-frequency TENS when
                                                             delivered ipsilateral to the assessed extremity. Mechani-
The TENS was delivered daily and commenced on the            cal and thermal pain thresholds assessed in the left hind
day of surgery while the rats were still under the influ-    paw were used to determine the effects of high-
ence of sodium pentobarbital for both 100-Hz and 2-Hz        frequency TENS when delivered contralateral to the
stimulation. On subsequent days, TENS was adminis-           assessed extremity. A similar strategy was used with the
tered to rats while they were lightly anesthetized with      third group of control rats (n 12) to determine
halothane (4%, maintained at 0.2%– 0.5%).                    whether low-frequency TENS administration altered
                                                             mechanical or thermal pain threshold.
Design
Five groups of rats received a CCI to the right sciatic      All rats were assessed once for mechanical and thermal
nerve. The first group of CCI rats (n 23) received           pain thresholds 3 days after their arrival. A second
high-frequency TENS through stimulating electrodes           baseline measurement was taken 1 day after the first, and
positioned on skin overlying the right paraspinal muscu-     the 2 measurements were averaged to give a single
lature (ipsilateral to nerve injury). The second group of    baseline pain threshold for each assessment. All rats
CCI rats (n 15) received high-frequency TENS through         were subsequently assessed 12 days after surgery or on
stimulating electrodes positioned over the left paraspi-     the analogous day if no CCI surgery occurred. We have
nal musculature (contralateral to nerve injury). The         previously found that thermal and mechanical allodynia
third group of CCI rats (n 23) received low-frequency        reach a maximum intensity by 12 days after a CCI.15 The
TENS through stimulating electrodes positioned over          postsurgery assessment was performed at least 12 hours
acupuncture points in the right hind limb, and the           after the final TENS treatment or halothane anesthesia.
fourth group of CCI rats (n 12) received low-frequency       The final TENS treatment occurred 11 days after the
TENS through the same acupuncture points in the left         surgery. Following the last assessment on day 12, the
hind limb. The TENS was delivered to these 4 groups for      sciatic nerve of all CCI rats was re-examined to deter-
90 minutes commencing immediately after the CCI              mine the integrity of the lesion. If 1 or more of the 4
surgery and then daily for 60 minutes for the next 11        ligatures was untied, the rat was eliminated from
days. The fifth group of CCI rats (n 28) was treated         consideration. Three rats were dropped from the
exactly like the rats that received TENS, including          study for this reason, and are not included in the
halothane administration, except that no TENS was            numbers above.
administered.
                                                             Data Analysis
Three groups of rats did not receive a CCI and were used     Percentages of change from baseline for mechanical and
as controls. To determine whether mechanical or ther-        thermal pain thresholds were calculated for the right
mal pain threshold changed over time, a group of rats        hind paw of each rat using the following formulas:
(naive; n 20) was included that was treated exactly like



702 . Somers and Clemente                                                Physical Therapy . Volume 86 . Number 5 . May 2006
              Mechanical pain threshold                       their mechanical pain threshold of 8%. This reduction
                                                              was significantly less than that observed in untreated CCI
  [(Right 50% WT 12 day         Right 50% WT baseline)/       rats (41%), but was not significantly different from that
                                                              observed in naive control rats.
             Right 50% WT baseline]          100
                                                              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-
               Thermal pain threshold                         enced a mean reduction from baseline in thermal pain
                                                              threshold of 25%, whereas naive control rats experi-
       [(Right WL 12 day        Right WL baseline)/           enced a mean decrease of only 10%. Daily high- or
                                                              low-frequency TENS delivered ipsilateral to the nerve
                Right WL baseline]        100                 injury did not prevent this CCI-induced lowering of the
                                                              thermal pain threshold. However, daily TENS delivered
For the control groups (no CCI) that received TENS,           contralateral to the nerve injury blocked the CCI-induced
calculations also were performed for the left hind paw of     lowering of thermal pain threshold, but only when the
individual rats. These values were considered the per-        treatment was delivered at low frequency (Fig. 2B). Rats
centage of change from baseline contralateral to the          that received low-frequency TENS contralateral to the
TENS stimulation. In all cases, the more negative the         nerve injury experienced a mean reduction from base-
percentage of change from baseline, the lower the pain        line in their thermal pain threshold of 13%. This reduc-
threshold on the final assessment.                            tion was significantly less than that observed in untreated
                                                              CCI rats (25%), but not was significantly different from
For each data group, a mean percentage of change from         that observed in naive control rats.
baseline for mechanical pain threshold was calculated.
Mean values of the groups were then compared with 2           Daily high- or low-frequency TENS delivered to rats
one-way analyses of variance (ANOVAs). The first              without a CCI did not alter mechanical pain threshold
ANOVA was used to compare the mean percentages of             from that observed in naive control rats at 12 days
change in mechanical pain threshold among all 4               (Fig. 3A). This finding was true regardless of whether
groups of TENS-treated CCI rats, untreated CCI rats,          measurements were taken ipsilateral or contralateral to
and naive control rats. The second ANOVA was used to          the side of TENS treatment. Daily high-frequency TENS
compare the mean percentages of change in mechanical          delivered to rats without a CCI likewise did not alter
pain threshold among all 4 groups of data from rats           thermal pain threshold from that observed in naive
treated only with TENS and naive control rats. When           control rats (Fig. 3B). However, low-frequency TENS
ANOVAs indicated that the mean percentages of change          delivered to rats without a CCI significantly increased
in mechanical pain threshold were different among the         the thermal pain threshold from that observed in naive
groups, pair-wise comparisons were performed with a           control rats (Fig. 3B).
Tukey test. This analysis procedure was repeated for the
mean percentages of change in thermal pain threshold.         Discussion
The alpha level was .05 for all statistics.
                                                              The Response of CCI Rats to Daily TENS Is Also Likely to
Results                                                       Be the Response of Humans Developing CPSII
Rats with a CCI had a significant lowering of mechanical      We have shown that the development of mechanical and
pain threshold at 12 days postsurgery when compared           thermal allodynia is reduced in CCI rats by daily appli-
with naive control rats (Fig. 2A). The CCI rats experi-       cation of TENS, but only when the treatment is delivered
enced a mean reduction from baseline in mechanical            contralateral to the nerve injury. Mechanical allodynia is
pain threshold of 41%, and naive control rats experi-         best prevented by high-frequency TENS delivered to the
enced a mean increase from baseline in mechanical pain        skin overlying the paraspinal musculature and thermal
threshold of 11%. Daily high- or low-frequency TENS           allodynia is best prevented by low-frequency TENS
delivered ipsilateral to the nerve injury failed to prevent   applied to acupuncture points. Although it cannot be
this CCI-induced lowering of the mechanical pain              said with certainty that the response of CCI rats to TENS
threshold. However, daily TENS delivered contralateral to     intervention would also be the response of humans with
the nerve injury blocked the CCI-induced lowering of          CPSII, there are several reasons to believe that this would
mechanical pain threshold, but only when the treatment        be the case.
was delivered at high frequency (Fig. 2A). Rats that
received high-frequency TENS contralateral to the nerve       The mechanism of nerve injury, occurrence of symp-
injury experienced a mean reduction from baseline in          toms, and mechanism of pain development are similar



Physical Therapy . Volume 86 . Number 5 . May 2006                                               Somers and Clemente . 703
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; P .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; P .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          frequency TENS was delivered to skin overlying the
reduced perception of pain. It is not just painful stimu-      paraspinal musculature, whereas low-frequency TENS
lation to the contralateral hind paw that is capable of this   was delivered to acupuncture points. Thus, it is possible
modulatory effect on dorsal horn neurons of the nerve-         that frequency was not the sole factor that determined
injured side. A subcutaneous injection of lidocaine into       whether mechanical or thermal allodynia was reduced.
the nonpainful hind paw of CCI rats suppressed sponta-         Nevertheless, there is evidence indicating that frequency
neous and pain-induced hyperactivity in wide dynamic           of stimulation is a factor that may determine TENS
range neurons of the nerve-injured side.62 This is true        effectiveness. For example, when high- and low-
even though there is no evidence suggesting that               frequency TENS are delivered to the same acupuncture
contralateral peripheral nerves are hyperactive in ani-        point in the lower extremity of humans who are healthy,
mals or humans with unilateral CPSII.                          only low-frequency TENS can produce analgesia in the
                                                               ipsilateral hand.20,23 Moreover, the nervous system
Although the present research did not investigate activ-       response to high- and low-frequency TENS delivered
ity of wide dynamic range neurons, it is possible that         through the same electrode positions is somewhat
daily TENS delivered contralateral to a nerve injury is        unique. When humans who are healthy receive high- or
better able to reduce allodynia because this mode of           low-frequency TENS through electrodes identically posi-
delivery suppresses pain-mediating neurons on the side         tioned on the hand or leg, high-frequency TENS
of nerve injury. Confirmation of this notion awaits            increases the cerebrospinal fluid content of dynorphin
further research, but the present data adds to an emerg-       and low-frequency TENS increases the cerebrospinal
ing body of evidence suggesting that contralateral treat-      fluid content of enkephalin.63 Thus, although electrode
ment for unilateral neuropathic pain is a reasonable,          position, in part, may explain why high- and low-
effective treatment option.                                    frequency TENS differentially reduced the development
                                                               of allodynia in the present study, it is likely that fre-
There is a clinical perception that bilateral stimulation      quency, either alone or through an interaction with
may be helpful in managing unilateral painful condi-           electrode position, is also a primary contributing factor.
tions.22 At least when bilateral stimulation is used to
manage the pain of neuropathy, this perception appears         Why high- and low-frequency TENS prevents mechanical
to have merit. In one published report where this              and thermal allodynia, respectively, is not known. How-
approach was used to treat a woman with unilateral             ever, because the central nervous system mechanisms
painful, diabetic neuropathy, daily TENS was applied           that undergird mechanical and thermal allodynia are
bilaterally in the lumbar paravertebral region.40 The          somewhat distinct, this differential effect is not surpris-
treatment virtually eliminated the neuropathic pain            ing. For example, glutamate neurotransmission is impli-
experienced by the woman in the left lower extremity.          cated in establishing and maintaining the pain of
The present results suggest that when bilateral TENS is        CPSII,64,65 but the glutamate receptors involved in main-
used to manage neuropathic pain, at least in part, it is       taining mechanical and thermal allodynia are at least
producing its beneficial effect through stimulation of         somewhat distinct. In humans with CPSII, pharmacolog-
peripheral nerves located contralateral to the nerve           ical blockade of a binding site on the NMDA glutamate
injury. Although TENS delivered on the side of nerve           receptor reduces indicators of mechanical allodynia, but
injury in CCI rats did not alter allodynia, it is unknown      fails to reduce any measure of thermal allodynia.66
whether this side also contributes to pain relief when         Similarly, pharmacological blockade of a non-NMDA
stimulation is delivered bilaterally. At a minimum, how-       glutamate receptor in neuropathic rats abolishes the
ever, we believe the present results suggest that people       presence of mechanical allodynia, but not thermal allo-
with neuropathic pain should be treated with stimula-          dynia.67 It is possible that these different underlying
tion that in some way includes the side located contra-        mechanisms for the production of mechanical and ther-
lateral to the nerve injury.                                   mal allodynia are best addressed by different frequencies
                                                               of TENS treatment. Confirmation of this notion awaits
The Type of Allodynia Reduced by TENS Is Dependent on          further research.
the Frequency of the Stimulation
When daily TENS was administered contralateral to a            Because high- and low-frequency TENS specifically pre-
nerve injury, it reduced the development of thermal            vent mechanical and thermal allodynia, respectively, it
allodynia, but only when delivered at low frequency. The       seems that a comprehensive clinical strategy would
development of mechanical allodynia, however, was              involve them both. Although a tested strategy for com-
reduced only when daily TENS was delivered at high             bining these 2 frequencies of treatment together has yet
frequency. It appears, then, that the frequency of stim-       to be established, clearly exposing patients in the initial
ulation may determine which form of allodynia is most          stages of CPSII development to both high- and low-
reduced. One caveat to this conclusion is that high-           frequency TENS is warranted. This notion has some



706 . Somers and Clemente                                                  Physical Therapy . Volume 86 . Number 5 . May 2006
precedent. In a recent report,68 people with radiculop-                        5 Rowbotham MC, Twilling L, Davies PS, et al. Oral opioid therapy for
athy were treated with stochastic or conventional (high-                       chronic peripheral and central neuropathic pain. N Engl J Med.
                                                                               2003;348:1223–1232.
frequency) TENS. Stochastic TENS randomly alters the
frequency of stimulus delivery, although the average                           6 Chen HJ, Lamer TJ, Rho RH, et al. Contemporary management of
                                                                               neuropathic pain for the primary care physician. Mayo Clin Proc.
frequency over time remains in the high-frequency
                                                                               2004;79:1533–1545.
range. Patients receiving this multiple-frequency form of
TENS perceived significantly less pain than did their                          7 Gilron I, Bailey JM, Tu DS, et al. Morphine, gabapentin, or their
                                                                               combination for neuropathic pain. N Engl J Med. 2005;352:1324 –1334.
counterparts who received conventional TENS.68 There-
fore, it appears that exposing the nervous system to                           8 Stacey BR. Management of peripheral neuropathic pain. Am J Phys
                                                                               Med Rehabil. 2005;84:S4 –S16.
different frequencies of TENS may promote pain relief.
Our data would support this notion by indicating that                          9 Garrison DW, Foreman RD. Decreased activity of spontaneous and
people who are developing CPSII should be exposed to                           noxiously evoked dorsal horn cells during transcutaneous electrical
                                                                               nerve stimulation (TENS). Pain. 1994;58:309 –315.
both high- and low-frequency stimulation in order to
comprehensively reduce the development of allodynia.                           10 Ignelzi RJ, Nyquist JK. Direct effect of electrical stimulation on
                                                                               peripheral nerve evoked activity: implications in pain relief. J Neurosurg.
                                                                               1976;45:159 –165.
Conclusion
We have shown that early intervention with high- and                           11 Janko M, Trontelj JV. Transcutaneous electrical nerve stimulation: a
                                                                               microneurographic and perceptual study. Pain. 1980;9:219 –230.
low-frequency TENS can reduce the development of
mechanical and thermal allodynia, respectively. There is                       12 Cauthen JC, Renner EJ. Transcutaneous and peripheral nerve
                                                                               stimulation for chronic pain states. Surg Neurol. 1975;4:102–104.
good reason to suspect that what was observed in the CCI
rats of the present study also would be true of humans                         13 Johansson F, Almay BGL, Von Knorring L, Terenius L. Predictors
treated with daily TENS following a nerve injury. The                          for the outcome of treatment with high-frequency transcutaneous
                                                                               electrical nerve stimulation in patients with chronic pain. Pain. 1980;
differential effect of high- and low-frequency TENS on                         9:55– 61.
mechanical and thermal allodynia suggests that both
                                                                               14 Meyler WJ, de Jongste MJL, Rolf CAM. Clinical evaluation of pain
treatment strategies may be necessary in order to com-
                                                                               treatment with electrostimulation: a study on TENS in patients with
prehensively reduce allodynia in humans developing                             different pain syndromes. Clin J Pain. 1994;10:22–27.
CPSII. Moreover, the present data suggest that treatment
                                                                               15 Somers DL, Clemente FR. High-frequency transcutaneous electrical
contralateral to the nerve injury, rather than ipsilateral                     nerve stimulation alters thermal but not mechanical allodynia follow-
to the nerve injury, may be the best strategy for begin-                       ing chronic constriction injury of the rat sciatic nerve. Arch Phys Med
ning treatment with daily TENS. Finally, it is important                       Rehabil. 1998;79:1370 –1376.
to note that based on the present data, our recommen-                          16 Sun RQ, Wang HC, Wan Y, et al. Suppression of neuropathic pain
dations for managing the pain of CPSII are intended                            by peripheral electrical stimulation in rats: mu-opioid receptor and
only as starting points for the use of the modality.                           NMDA receptor implicated. Exp Neurol. 2004;187:23–29.
Because TENS is variable in its ability to relieve multiple                    17 Hwang BG, Min BI, Kim JH, et al. Effects of electroacupuncture on
forms of pain, it is likely that the strategies of stimulation                 the mechanical allodynia in the rat model of neuropathic pain.
described here will be altered once the treatment begins                       Neurosci Lett. 2002;320:49 –52.
in order to maximize its effectiveness. Nevertheless, we                       18 Dai Y, Kondo E, Fukuoka T, et al. The effect of electroacupuncture
believe that the data presented here suggest that both                         on pain behaviors and noxious stimulus-evoked Fos expression in a rat
high- and low-frequency stimulation delivered through                          model of neuropathic pain. J Pain. 2001;2:151–159.
electrodes positioned contralateral to a nerve injury may                      19 Somers DL, Clemente FR. Dorsal horn synaptosomal content of
be the best starting point for TENS treatment of humans                        aspartate, glutamate, glycine and GABA are differentially altered
developing CPSII.                                                              following chronic constriction injury to the rat sciatic nerve. Neurosci
                                                                               Lett. 2002;323:171–174.

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Physical Therapy . Volume 86 . Number 5 . May 2006                                                                 Somers and Clemente . 709

								
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