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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
248
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].
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,
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.
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].
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
250
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.
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].
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
251
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
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
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
Sufentanil
Line 4
Line 5
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
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
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
253
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].
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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.