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23

Interventional and Nonpharmacological Therapies


for Neuropathic Pain
Mark S. Wallace, MD

Department of Clinical Anesthesiology, University of California, San Diego, La Jolla, California, USA

Educational Objectives
1. To review the challenges of applying evidence to interventional therapies.
2. To describe current and emerging implantable therapies to treat chronic neuropathic pain.
3. To outline some nonpharmacological therapies to
treat chronic neuropathic pain.

Interventional Therapies
Applying Evidence to Interventional Therapies
In recent years, interventional therapies to treat
chronic pain have come under scrutiny owing to a
lack of evidence supporting efficacy. This has led to
the development of consensus guidelines based on
the evidence as well as on expert consensus [35].
In 1990, the Institute of Medicine defined clinical
guidelines as systematically developed statements
to assist practitioner and patient decisions about
appropriate health care for specific clinical circumstances [18]. In 2011, this definition was revised as
statements that include recommendations intended
to optimize patient care that are informed by a systematic review of evidence and an assessment of the
benefits and harms of alternative care options [20].
The new definition acknowledged that, for many
Pain 2014: Refresher Courses, 15th World Congress on Pain
Srinivasa N. Raja and Claudia L. Sommer, editors
IASP Press, Washington, D.C. 2014

clinical domains, high-quality evidence is lacking or


even nonexistent. Despite such constraints, guideline
developers should still be able to produce trustworthy clinical practice guidelines.
Unlike the case for pharmaceuticals, there are
obvious challenges in applying high levels of evidence
to surgical or minimally invasive procedures. These
challenges include ethical limitations of blinded surgical and sham procedures, prohibitive costs, and the
need to recruit adequate numbers to complete a trial.
In addition, there are wider variations in the denition of successful outcomes. For example, an American Academy of Neurology task force reported on
the ecacy of epidural steroid injections (ESIs). They
reviewed all of the literature on ESIs for lumbar radiculopathy and concluded that there is evidence that
supports pain relief for up to 3 months; however, they
could not recommend the routine use of ESIs for lumbar radiculopathy [2]. This conclusion is contrary to
the general opinion that 3 months of pain relief from
a single ESI is both clinically meaningful and cost-effective. A recent recommendations paper on interventional management of neuropathic pain from the IASP
Special Interest Group on Neuropathic Pain (NeuPSIG) concluded that owing to the paucity of highquality clinical trials, no strong recommendations can
be made. However, on the basis of the available data,
they recommended against using sympathetic blocks
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for postherpetic neuralgia or using radiofrequency lesions for radiculopathy [16].
Interventional treatment guidelines should
serve two purposes: (1) to apply evidence-based medicine to improve patient selection and outcome and (2)
to implement best clinical practices for techniques to
improve outcome and safety. The latter point is important, and often overlooked, because as clinical experience evolves, risks emerge from interventions that have
long been felt to be safe. An example is the transforaminal injection of particulate steroid, in which many reports of serious injury and death are emerging [43].

General Principles of Interventional Therapies


for Neuropathic Pain
The application of interventional therapies for the treatment of neuropathic pain is quite dierent from that for
nociceptive pain. In addition, the application will dier
between noncancer and cancer pain. For example, with
the exception of cryoablation, neuroablative therapies
are rarely used to treat neuropathic pain because an
additional insult/injury to the nervous system carries a
high risk of increasing the pain from a preexisting nervous system injury. An exception to this rule is in the
treatment of terminal cancer pain, given that the pain
relief of the neurolytic procedure will outlast the life of
the patient. In other words, the time it takes for the additional injury from the neurolytic to cause pain is longer than the life of the patient.
The location of interventional therapies in
the pain treatment continuum will depend on the invasiveness of the therapy. Simple treatments such as
epidural steroids (although controversial in the treatment of neuropathic pain) or sympathetic blockade
might be used early on, whereas spinal cord stimulation (SCS) or intrathecal drug delivery systems (IDDS)
would be used only after more conservative therapies
have been tried. However, recent controversy has
emerged with regard to the use of SCS over chronic
opioid therapy for noncancer pain. With the increasing reports on the risks and limited value of opioids in
chronic pain, SCS is being favored as a more conservative and safe therapy.
Although a number of interventional therapies
are used in the management of chronic pain, this chapter will focus on implantable therapies used to treat
neuropathic pain. NeuPSIGs evidence-based guidelines
for other interventional therapies were reviewed recently by Dworkin et al. [16].

Mark S. Wallace

Neural Stimulation
Electrical Basics
An understanding of basic electrical physics is critical for the application of SCS clinically. Ohms law is
as follows: Voltage (V) = Current (I) Resistance (R).
We can control V and I, but not R. Patient factors that
aect R include cerebrospinal uid (CSF) depth, uids
(CSF, blood, injectates), dural thickness, epidural fat,
and scar tissue. There are currently three systems on
the market, with the main dierences based on Ohms
law: (1) single-source voltage-controlled, (2) singlesource current-controlled, and (3) multisource current
controlled. Although there are signicant technologies
behind these three systems, there are no controlled
studies comparing ecacy. The stimulation pulse is the
energy applied to the nerve and is characterized by the
strength (amplitude) and duration (pulse width). Four
parameters are controlled: (1) electrode polarity, (2)
amplitude, (3) pulse width, and (4) frequency.

Polarity
For current to ow and nerve depolarization to occur,
there must be at least one negative (cathode) and one
positive (anode) electrode. Depolarization occurs under the cathode. An increased ratio of anodes to cathodes will increase the charge density under the cathode.
A decreased ratio of anodes to cathodes will reduce
the charge density under the cathode. This ratio controls the shape and density of the electrical eld, which
in turn will determine the nerve bers in the spinal
cord that are activated. More closely spaced electrodes
will penetrate the current with more focus and depth,
whereas more widely spaced electrodes will spread the
current more widely and supercially. Multiple electrodes placed cephalad/caudad and medial/lateral over
the spinal cord can be used to steer the current.

Amplitude
Dened as the strength of the stimulus measured in
volts or milliamps, amplitude is the primary control
over the intensity of the stimulus sensation. The higher
the amplitude, the greater the size of the electrical eld,
resulting in the depolarization of nerves over a larger
area. Higher amplitudes can result in painful sensations.

Pulse Width
Dened as the duration of the stimulation pulse, pulse
width is typically measured in microseconds. Greater
pulse width will cause the stimulation to stay on longer,

Interventional and Nondrug Neuropathic Pain Therapies

249

resulting in depolarization of bers with higher thresholds (sequential recruitment). Adjustment in pulse
width can activate bers that normally would require
higher amplitudes, resulting in painful stimulation.
Pulse width can be used in conjunction with amplitude adjustment to control the intensity of the stimulation pulse.

are from single sites, and there is a need for multicenter


randomized controlled trials with larger numbers. An
attempt was made to perform such a trial. However
after over 2 years, the study was prematurely terminated due to diculties in enrolling subjects. This failure
stresses the challenges of performing high-quality studies on interventional therapies to treat pain.

Frequency

Burst Stimulation

Frequency is dened as the number of stimulation pulses delivered per second. Higher frequency increases the
number of action potentials delivered by the nerve up
to a point at which conduction block can occur. Changes in frequency result in changes in sensation. Low frequency results in a pulsing sensation, and high frequency results in a utter sensation. Higher frequencies will
increase the rate of battery depletion.

Burst spinal cord stimulation is an emerging technique that uses multiple bursts of stimulation that are
paresthesia free. Traditional stimulation consists of a
single higher-amplitude waveform. Burst stimulation
uses multiple smaller-amplitude, higher-pulse-width
waveforms in the same frequency range as traditional stimulation parameters. For example, a traditional
waveform is 5 mA, 200 s, and 40 Hz. A similar burst
stimulation waveform is ve 1-mA, 1000- s bursts
within a 40-Hz frequency. A typical burst stimulation parameter is ve 1-s bursts separated by 1-s
intervals in a 10-s period, which results in a paresthesia-free stimulation. The lateral thalamic cells re
in a tonic pattern, and medial thalamic cells re in
a burst pattern. Therefore, the theory behind burst
stimulation is that the medial thalamic cells are activated, resulting in a dissociation from the pain. These
observations have been conrmed with studies showing that burst stimulation produces signicantly more
alpha activity in the dorsal anterior cingulate cortex
(the medial pain system), which controls the aective/attentional component of the pain experience
[15,22,25,34]. De Ridder et al. showed a statistically
signicant benet of burst stimulation versus tonic
for the general pain visual analogue scale. There was
also a signicant benet of burst stimulation versus
tonic stimulation with respect to attention to pain and
attention to changes in pain. Further studies are currently in progress [14,15].

Spinal Cord Stimulation


Conventional Paresthesia Stimulation
Spinal cord stimulation (SCS) is indicated for the treatment of neuropathic pain. Neuropathic pain that is
continuous and unchanging responds the best. SCS
is not indicated for activity-related non-neuropathic
pain. The goal of SCS is to apply sucient electrical
current over the dorsal columns to result in paresthesias that overlap the painful area while minimizing
paresthesias in extraneous areas. The most common
indication is failed back surgery syndrome with leg
pain. Less common indications are peripheral nerve
injury, complex regional pain syndrome (CRPS), and
painful peripheral neuropathy [27]. In these three latter syndromes, overlapping paresthesias can be challenging, and it is more common for patients to report
pain in spite of overlapping stimulation. The mechanism of action is thought to be based on the gate control theory of pain by selectively depolarizing largeber aerents in the dorsal column, thus closing the
gate to small-ber aerents that transmit pain into the
spinal cord [37]. Animal studies also suggest that SCS
may alter neurotransmitter release in the sympathetic
nervous system and in GABAergic interneurons of the
spinal cord. CSF concentrations of glutamate, glycine,
and serotonin are aected by SCS. SCS does not appear
to alter the -opioid receptor system [32].
The cost-eectiveness of SCS versus reoperation or versus conventional medical management for
failed back surgery syndrome has been shown in randomized controlled trials [28,38]. However, these trials

High-Frequency Stimulation
High-frequency stimulation uses frequencies up to 10
kHz, pulse width up to 1000 ms, and amplitude up to
15 mA, which results in paresthesia-free stimulation.
The exact mechanism of pain relief is unclear, but preclinical studies have shown that a high-frequency alternating-current sinusoidal waveform applied to a nerve
will result in a reversible block of activity [3]. This block
occurs in three phases: an onset response, a period of
asynchronous ring, and a steady state of complete or

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partial block. This technology is currently available in
Europe and Australia, with clinical trials ongoing in the
United States. Due to the high frequencies used, energy
consumption is high, thus requiring a rechargeable battery. This method is used primarily to treat back pain,
with some eect on lower-extremity pain. Intraoperative paresthesia mapping is not necessary, and leads are
placed anatomically over T9 in the midline, thus shortening procedure time. A U.S. pilot study in 24 patients
with back and leg pain demonstrated a signicant reduction in back and leg pain [49]. A European study
conducted in 83 patients with primarily low back pain
was successful in 72 patients. Long-term follow-up to
12 months showed a signicant reduction in both back
and leg pain. There was also a signicant improvement
in the Average Oswestry Disability Index Score. Sleep
disturbance was improved, and patient satisfaction was
high [50]. Perruchoud et al. performed a blinded, shamcontrolled study interspersing high-frequency and
sham stimulation between conventional stimulation periods. They demonstrated no dierence between highfrequency and sham stimulation. However, they placed
the leads for conventional stimulation with frequencies
of 5 kHz [41]. The current system approved in Europe
uses 10 kHz with all leads placed a specic location,
which may explain the results.

Dorsal Root Ganglion Stimulation


The dorsal root ganglion (DRG) has an important role
in the development and maintenance of chronic neuropathic pain. In addition, CRPS, distal leg and foot pain,
inguinal pain, and truncal pain have been dicult areas to target with conventional paresthesia stimulation.
Therefore, the DRG is a reasonable target for stimulation to treat these challenging pain syndromes. The
predictable location of the DRG in the epidural space
and the lack of overlying CSF allows for increased energy eciency and lower energy consumption than
traditional and high-frequency spinal cord stimulation.
Leads are placed into the epidural space and steered
out of the target neural foramen to overlay the DRG.
Advancing the lead into the epidural space creates retaining loops that reduce lead migration. A prospective study was performed in 32 patients with chronic
pain of the limbs and/or trunk. At 6 months after implant, more than half of the participants reported 50%
or greater pain relief, with the proportions experiencing 50% or more reduction in pain specic to back, leg,
and foot regions being 57%, 70% and 89% respectively.

Mark S. Wallace
They concluded that areas hard to treat with SCS (such
as the feet and trunk) may be more amenable to DRG
stimulation [31].

Peripheral Nerve Stimulation


Peripheral nerve stimulation (PNS) was rst used over
40 years ago, but it fell out of favor because of the need
for an invasive cut-down for lead placement [52]. SCS
came into favor owing to its success and the ease of lead
placement. However, with recent advances and new
techniques, there is renewed interest in PNS to treat
chronic neuropathic pain, partly because SCS is not as
eective in the treatment of peripheral nerve injuries.
There are several ongoing clinical trials with DRG stimulation for the treatment of traumatic nerve injury and
CRPS. The mechanism of PNS is unclear, but some suggest that it changes the neurotransmitter milieu of the
peripheral nerve to relieve pain. The classic gate control
theory has also been suggested [6,51].
Indications for PNS include pain in the distribution of an accessible peripheral nerve. The most
common nerves to be treated are the supraorbital, infraorbital, greater occipital, ulnar, median, suprascapular, intercostal, ilioinguinal, iliohypogastric, genitofemoral, lateral femoral cutaneous, saphenous, sciatic,
posterior tibial, supercial peroneal, and sural nerves.
With the use of ultrasound, the percutaneous placement of leads is becoming more common, at least in
trials. The same concepts of electrical physics described
for SCS also apply to PNS [44].
There are few studies on the long-term outcomes of PNS. Deer et al. published a recent study
showing relief from a device that does not require an
implantable pulse generator. They are currently conducting a multicenter trial. Hassenbusch and StantonHicks published a study evaluating PNS for CRPS.
The success rate was more than 60% with devices that
would now be considered antiquated. There are also favorable studies evaluating PNS to treat migraine (with
occipital nerve stimulation), facial pain, and axial spine
pain [8].

Intrathecal Drug Delivery


Intrathecal drug delivery (IDD) is considered an invasive and labor-intensive therapy. Therefore, appropriate patient selection and failure of more conservative
therapies are essential. Indications for IDD include: (1)
somatic/nociceptive pain, (2) neuropathic pain that has

Interventional and Nondrug Neuropathic Pain Therapies


failed to respond to spinal cord stimulation (if indicated), (3) multiple pain sites with truncal/axial pain, and
(4) static or changing pain. Table I summarizes selection criteria for IDD [55].
Table I
Patient selection for intrathecal therapy
Malignant Pain
Life expectancy greater than 3 months
Inadequate pain relief and/or intolerable
side effects from systemic agents
Favorable response to screening trial
Nonmalignant Pain
Objective evidence of pathology
Inadequate pain relief and/or intolerable
side effects from systemic agents
Lack of drug-seeking behavior
Favorable response to screening trial

Patients with a psychological prole deemed


appropriate for IDD therapy have better outcomes than
those deemed inappropriate; therefore, psychological
clearance is important to success. Psychological exclusion criteria include: (1) active psychosis, (2) active suicidality, (3) active homicidality, (4) major uncontrolled
depression or other mood disorders, (5) somatization
or other somatoform disorders, (6) alcohol or drug dependency, (7) compensation or litigation resolution, (8)
lack of appropriate social support, and (9) neurobehavioral or cognitive decits [4]. The choice of screening
technique for IDD remains controversial. Both continuous infusion and bolus dosing have been used. A recent polyanalgesic consensus panel published the rst
recommendations for IDD (Table II) [9].
Table II
Recommended doses for
intrathecal drug bolus trialing
Recommended
Drug
i.t. Bolus Dose
Morphine
0.21.0 mg
Hydromorphone 0.040.2 mg
Ziconotide
15 g
Fentanyl
2575 g
Bupivacaine
0.52.5 mg
Clonidine
520 g
Sufentanil
520 g

Even more controversial is whether to withdraw systemic opioids prior to trying IDD. Advantages
include: (1) reversal of tolerance, (2) identication of
patients with strong physical dependence, (3) possible
identication of patients with psychological dependence and addiction, and (4) possible reduction of total

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IDD dose over time. Disadvantages include increasing
pain and suering while the patient is o the opioids
and delays in initiation of IDD. Guidelines have been
published for the management of both cancer and noncancer pain (Tables IIIVI) [10,11].
Table III
Recommended starting dosage range and titration
for intrathecal drugs
Drug

Recommended
Starting Dose

Incremental
Increase

Morphine

0.10.5 mg/day

0.5 mg

Hydromorphone

0.020.5 mg/day

0.1 mg

Ziconotide

0.52.4 g/day

10 g

Fentanyl

2575 g/day

2.5 g

Bupivacaine

14 mg/day

0.1 g

Clonidine

40100 g/day

1 mg

Sufentanil

1020 g/day

10 g

Source: Modified from Deer et al. [13].

Drugs Used for IDD


Opioids
Agonism of pre- and postsynaptic -opioid receptors in
the dorsal horn reduces presynaptic neurotransmitter
release and hyperpolarizes the postsynaptic membrane.
Morphine is the gold standard and the only opioid with
U.S. Food and Drug Administration (FDA) approval for
IDD. Other commonly used opioids include hydromorphone, fentanyl, and sufentanil. Side eects include respiratory depression with overdose, nausea, urinary retention, pruritus, and peripheral edema [24,39,40].

Ziconotide
Ziconotide is the rst nonopioid approved for IDD to
treat chronic pain. Its mechanism is through presynaptic N-type calcium channel blockade in the dorsal
horn to reduce presynaptic neurotransmitter release.
Ziconotide is indicated for the management of severe
chronic pain in patients for whom IDD is warranted,
and who are intolerant of or refractory to other treatments such as systemic analgesics, adjunctive therapies, or IDD morphine. Two fast-titration trials (one
for malignant and one for nonmalignant pain) and one
slow-titration trial led to FDA approval. The malignant and nonmalignant pain study showed a 53.1% vs.
18.1% and 31.2% vs. 6% reduction in pain (ziconotide
vs. placebo), respectively; however, there was a high
dropout rate due to side eects [48,53]. A follow-up
3-week slow-titration trial in chronic pain patients
with preexisting implanted IDD pumps showed a

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Mark S. Wallace
Table IV
2011 polyanalgesic consensus for intrathecal drugs for neuropathic pain
Line 1

Morphine

Ziconotide

Morphine + bupivacaine

Line 2

Hydromorphone

Hydromorphone + bupivacaine or
hydromorphone + clonidine

Morphine + clonidine

Line 3

Clonidine

Ziconotide + opioid

Fentanyl + bupivacaine or
fentanyl + clonidine

Line 4

Opioid + clonidine + bupivacaine

Line 5

Baclofen

Fentanyl

Bupivacaine + clonidine

Table V
2011 polyanalgesic consensus for intrathecal drugs for nociceptive pain
Line 1

Morphine

Hydromorphone

Ziconotide

Fentanyl

Line 2

Morphine + bupivacaine

Ziconotide + opioid

Hydromorphone
+ bupivacaine

Fentanyl +
bupivacaine

Line 3

Opioid (morphine, hydromorphone, or fentanyl + clonidine)

Sufentanil

Line 4

Opioid + clonidine + bupivacaine

Sufentanil + bupivacaine or clonidine

Line 5

Sufentanil + bupivacaine + clonidine

Table VI
Recommended maximum daily dose and
concentration for intrathecal drug delivery
Drug

Maximum Dose/
24 Hours

Maximum
Concentration

Morphine

10 mg

20 mg/mL

Hydromorphone

10 mg

20 mg/mL

Fentanyl

500 g

2000 g/mL

Sufentanil

250 g

1000 g/mL

Ziconotide

2.5 g

20

Bupivacaine

10 mg

20

Clonidine

250 g

2000

Source: Modified from Deer et al. [13].

used. It has few side eects with minimal sensory and


motor disturbances at doses <20 mg/day [55].

Clonidine
Clonidine works through agonism of pre- and postsynaptic adrenergic 2 receptors, resulting in a reduction
in presynaptic neurotransmitter release and hyperpolarization of the postsynaptic membrane. It is FDA approved for epidural use in cancer pain only; however, it
is widely used in IDD therapy. Side eects include hypotension, bradycardia, and sedation. It is often used in
combination with other IDD agents [55].

Baclofen
14.7% vs. 7.2% reduction in pain (ziconotide vs. placebo) at 3 weeks (P = 0.36). Side eects were much less
severe, and the dropout rate did not dier between
the ziconotide and placebo group [42]. Although ziconotide has a high incidence of cognitive side eects,
there is a wide margin of safety in overdose. Cognitive
side eects are reduced with slow titration. There is
no acute drug withdrawal syndrome upon cessation of
the ziconotide. Ziconotide can be used in combination
with other drugs, but there is some loss of potency
when it is mixed with morphine [54].

Local Anesthetics
Local anesthetics are widely used in IDD. They work
through blockade of pre- and postsynaptic sodium
channels. They are most commonly used in combination
with other IDD agents. Bupivacaine is most commonly

Baclofen is a GABAB agonist with antispasmodic effects through decrease release of excitatory neurotransmitters from IA, IB, and A- aerents in the
spinal cord. Analgesic eects may be due to eects on
voltage-sensitive calcium channels. It is FDA approved
as an antispasmodic [55].

IDD Systems
There are currently two FDA-approved systems on
the market used to treat chronic pain. The Medtronic
Synchromed II comes in 20- and 40-mL reservoir volumes. It uses a programmable peristaltic rotor system
for variable rate delivery. A patient-controlled bolus
dosing allows for treatment of breakthrough pain.
It has a 5-year battery life and is FDA approved for
morphine, baclofen, and ziconotide. The Flowonix
Prometra pump uses a pressurized gas chamber as

Interventional and Nondrug Neuropathic Pain Therapies


the driving force with a programmable ow-metering
valve for variable rate delivery, resulting in much lower energy requirements and thus longer battery life
(10 years) [19].

Morbidity Related to IDD


The most common cause of morbidity relates to catheter problems. The track record for drug delivery by
the system is quite good, with rare reports of system
over- or under-infusion. Occasionally, the system can
shut down if the rotor stalls, resulting in acute drug
withdrawal. Filling of the pump pocket with high drug
concentrations, lling errors, and programming errors have been reported and can be life threatening.
Increasing reports of catheter tip granuloma formation were thought to be the result of high drug concentrations. The exact drug concentration that will
predispose to granuloma formation is unknown
[7,12,13,23,57].

Ecacy of IDD for Chronic Pain


There is only one prospective randomized controlled
trial on IDD, in which 202 cancer patients with uncontrolled pain were randomized to either IDD or comprehensive medical management (CMM). Clinical success
was dened as at least 20% reduction in visual analogue
scale (VAS) scores or equal scores with at least 20% reduction in toxicity. More IDD patients achieved success
(84.5% vs. 70.8%; P = 0.05). More IDD patients achieved
at least 20% reduction in both pain VAS and toxicity.
There was a nonsignicant change in mean VAS between groups (IDD 52%, CMM 39%). IDD patients had
a signicantly greater change in toxicity scores (52% vs.
17%; P = 0.004). There was no dierence in survival between the groups [45].

Nonpharmacological Treatments
Hypnosis
Hypnosis has been used for centuries to treat pain
by generating a state of highly focused attention that
results in a dissociation from the pain [46,47]. It can
reduce pain and anxiety related to pain in both adults
and children [5,29].

Acupuncture
Acupuncture originated in China over 4000 years ago. Its
traditional basis hinges on the existence of acupuncture

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points; however, studies have found a greater than 70%
correlation between myofascial trigger points, motor
points, and acupuncture points [33,36]. In addition, the
traditional meridians in the extremities highly resemble
the distribution of peripheral nerves. The mechanism is
not clear, but acupuncture appears to work peripherally
by stimulating A aerents and centrally through the
endorphin system [17,30]. There is also evidence of a
neurohumoral eect [26]. One animal study suggested
a long-term eect on neuroplasticity in rats with neuropathic pain [56]. There are two clinical trials showing
benets of acupuncture in painful diabetic peripheral
neuropathy [1,21].

Transcutaneous Electrical Nerve Stimulation


TENS is a widely used treatment for chronic pain. An
estimated 250,000 units are prescribed annually in the
United States. There are two main stimulation patterns: (1) a low-frequency, 14-Hz, long-pulse-width,
high-intensity stimulation that causes muscle contraction; (2) a high-frequency 50120-Hz, low-intensity
stimulation. The low-frequency pattern mimics acupuncture, whereas the high frequency uses the gate
control theory. The evidence is poor in supporting the
ecacy of TENS.

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Correspondence to: Professor Mark S. Wallace, MD, Department of Clinical Anesthesiology, University of California, San
Diego, 9300 Campus Point Drive, #7651, La Jolla, CA 92037,
USA. Email: mswallace@ucsd.edu.

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