Pain 2014: Refresher Courses, 15th World Congress on PainSrinivasa N. Raja and Claudia L. Sommer, editorsIASP Press, Washington, D.C. © 2014

247

23Mark S. Wallace, MD

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

Interventional and Nonpharmacological Th erapies

for Neuropathic Pain

Educational Objectives

1. To review the challenges of applying evidence to in-

terventional therapies.

2. To describe current and emerging implantable ther-

apies to treat chronic neuropathic pain.

3. To outline some nonpharmacological therapies to

treat chronic neuropathic pain.

Interventional Th erapies

Applying Evidence to Interventional Th erapies

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 circum-

stances” [18]. In 2011, this definition was revised as

“statements that include recommendations intended

to optimize patient care that are informed by a sys-

tematic review of evidence and an assessment of the

benefits and harms of alternative care options ” [20].

The new definition acknowledged that, for many

clinical domains, high-quality evidence is lacking or

even nonexistent. Despite such constraints, guideline

developers should still be able to produce trustwor-

thy clinical practice guidelines.

Unlike the case for pharmaceuticals, there are

obvious challenges in applying high levels of evidence

to surgical or minimally invasive procedures. Th ese

challenges include ethical limitations of blinded sur-

gical and sham procedures, prohibitive costs, and the

need to recruit adequate numbers to complete a trial.

In addition, there are wider variations in the defi ni-

tion of successful outcomes. For example, an Ameri-

can Academy of Neurology task force reported on

the effi cacy of epidural steroid injections (ESIs). Th ey

reviewed all of the literature on ESIs for lumbar ra-

diculopathy 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 lum-

bar radiculopathy [2]. Th is conclusion is contrary to

the general opinion that 3 months of pain relief from

a single ESI is both clinically meaningful and cost-ef-

fective. A recent recommendations paper on interven-

tional management of neuropathic pain from the IASP

Special Interest Group on Neuropathic Pain (Ne-

uPSIG) concluded that owing to the paucity of high-

quality clinical trials, no strong recommendations can

be made. However, on the basis of the available data,

they recommended against using sympathetic blocks

248 Mark S. Wallace

for postherpetic neuralgia or using radiofrequency le-

sions for radiculopathy [16].

Interventional treatment guidelines should

serve two purposes: (1) to apply evidence-based medi-

cine to improve patient selection and outcome and (2)

to implement best clinical practices for techniques to

improve outcome and safety. Th e latter point is impor-

tant, and often overlooked, because as clinical experi-

ence evolves, risks emerge from interventions that have

long been felt to be safe. An example is the transforami-

nal injection of particulate steroid, in which many re-

ports of serious injury and death are emerging [43].

General Principles of Interventional Th erapies for Neuropathic Pain

Th e application of interventional therapies for the treat-

ment of neuropathic pain is quite diff erent from that for

nociceptive pain. In addition, the application will diff er

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 ner-

vous 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 ad-

ditional injury from the neurolytic to cause pain is lon-

ger than the life of the patient.

Th e location of interventional therapies in

the pain treatment continuum will depend on the in-

vasiveness of the therapy. Simple treatments such as

epidural steroids (although controversial in the treat-

ment of neuropathic pain) or sympathetic blockade

might be used early on, whereas spinal cord stimula-

tion (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 increas-

ing reports on the risks and limited value of opioids in

chronic pain, SCS is being favored as a more conser-

vative and safe therapy.

Although a number of interventional therapies

are used in the management of chronic pain, this chap-

ter will focus on implantable therapies used to treat

neuropathic pain. NeuPSIG’s evidence-based guidelines

for other interventional therapies were reviewed re-

cently by Dworkin et al. [16].

Neural Stimulation

Electrical Basics

An understanding of basic electrical physics is criti-

cal for the application of SCS clinically. Ohm’s law is

as follows: Voltage (V) = Current (I) × Resistance (R).

We can control V and I, but not R. Patient factors that

aff ect R include cerebrospinal fl uid (CSF) depth, fl uids

(CSF, blood, injectates), dural thickness, epidural fat,

and scar tissue. Th ere are currently three systems on

the market, with the main diff erences based on Ohm’s

law: (1) single-source voltage-controlled, (2) single-

source current-controlled, and (3) multisource current

controlled. Although there are signifi cant technologies

behind these three systems, there are no controlled

studies comparing effi cacy. Th e 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 fl ow and nerve depolarization to occur,

there must be at least one negative (cathode) and one

positive (anode) electrode. Depolarization occurs un-

der the cathode. An increased ratio of anodes to cath-

odes will increase the charge density under the cathode.

A decreased ratio of anodes to cathodes will reduce

the charge density under the cathode. Th is ratio con-

trols the shape and density of the electrical fi eld, which

in turn will determine the nerve fi 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 superfi cially. Multiple elec-

trodes placed cephalad/caudad and medial/lateral over

the spinal cord can be used to steer the current.

Amplitude

Defi ned as the strength of the stimulus measured in

volts or milliamps, amplitude is the primary control

over the intensity of the stimulus sensation. Th e higher

the amplitude, the greater the size of the electrical fi eld,

resulting in the depolarization of nerves over a larger

area. Higher amplitudes can result in painful sensations.

Pulse Width

Defi ned 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 Th erapies 249

resulting in depolarization of fi bers with higher thresh-

olds (sequential recruitment). Adjustment in pulse

width can activate fi bers that normally would require

higher amplitudes, resulting in painful stimulation.

Pulse width can be used in conjunction with ampli-

tude adjustment to control the intensity of the stimu-

lation pulse.

Frequency

Frequency is defi ned as the number of stimulation puls-

es 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. Chang-

es in frequency result in changes in sensation. Low fre-

quency results in a pulsing sensation, and high frequen-

cy results in a fl utter sensation. Higher frequencies will

increase the rate of battery depletion.

Spinal Cord Stimulation

Conventional Paresthesia Stimulation

Spinal cord stimulation (SCS) is indicated for the treat-

ment of neuropathic pain. Neuropathic pain that is

continuous and unchanging responds the best. SCS

is not indicated for activity-related non-neuropathic

pain. Th e goal of SCS is to apply suffi cient electrical

current over the dorsal columns to result in pares-

thesias that overlap the painful area while minimizing

paresthesias in extraneous areas. Th e 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 lat-

ter syndromes, overlapping paresthesias can be chal-

lenging, and it is more common for patients to report

pain in spite of overlapping stimulation. Th e mecha-

nism of action is thought to be based on the gate con-

trol theory of pain by selectively depolarizing large-

fi ber aff erents in the dorsal column, thus closing the

gate to small-fi ber aff erents 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 aff ected by SCS. SCS does not appear

to alter the μ-opioid receptor system [32].

Th e cost-eff ectiveness of SCS versus reopera-

tion or versus conventional medical management for

failed back surgery syndrome has been shown in ran-

domized controlled trials [28,38]. However, these trials

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 terminat-

ed due to diffi culties in enrolling subjects. Th is failure

stresses the challenges of performing high-quality stud-

ies on interventional therapies to treat pain.

Burst Stimulation

Burst spinal cord stimulation is an emerging tech-

nique 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 tradition-

al stimulation parameters. For example, a traditional

waveform is 5 mA, 200 μs, and 40 Hz. A similar burst

stimulation waveform is fi ve 1-mA, 1000- μs bursts

within a 40-Hz frequency. A typical burst stimula-

tion parameter is fi ve 1-μs bursts separated by 1-μs

intervals in a 10-μs period, which results in a pares-

thesia-free stimulation. Th e lateral thalamic cells fi re

in a tonic pattern, and medial thalamic cells fi re in

a burst pattern. Th erefore, the theory behind burst

stimulation is that the medial thalamic cells are acti-

vated, resulting in a dissociation from the pain. Th ese

observations have been confi rmed with studies show-

ing that burst stimulation produces signifi cantly more

alpha activity in the dorsal anterior cingulate cortex

(the medial pain system), which controls the aff ec-

tive/attentional component of the pain experience

[15,22,25,34]. De Ridder et al. showed a statistically

signifi cant benefi t of burst stimulation versus tonic

for the general pain visual analogue scale. Th ere was

also a signifi cant benefi t of burst stimulation versus

tonic stimulation with respect to attention to pain and

attention to changes in pain. Further studies are cur-

rently 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.

Th e exact mechanism of pain relief is unclear, but pre-

clinical studies have shown that a high-frequency alter-

nating-current sinusoidal waveform applied to a nerve

will result in a reversible block of activity [3]. Th is block

occurs in three phases: an onset response, a period of

asynchronous fi ring, and a steady state of complete or

250 Mark S. Wallace

partial block. Th is 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 bat-

tery. Th is method is used primarily to treat back pain,

with some eff ect on lower-extremity pain. Intraopera-

tive paresthesia mapping is not necessary, and leads are

placed anatomically over T9 in the midline, thus short-

ening procedure time. A U.S. pilot study in 24 patients

with back and leg pain demonstrated a signifi cant re-

duction 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 signifi cant reduction in both back

and leg pain. Th ere was also a signifi cant improvement

in the Average Oswestry Disability Index Score. Sleep

disturbance was improved, and patient satisfaction was

high [50]. Perruchoud et al. performed a blinded, sham-

controlled study interspersing high-frequency and

sham stimulation between conventional stimulation pe-

riods. Th ey demonstrated no diff erence between high-

frequency and sham stimulation. However, they placed

the leads for conventional stimulation with frequencies

of 5 kHz [41]. Th e current system approved in Europe

uses 10 kHz with all leads placed a specifi c location,

which may explain the results.

Dorsal Root Ganglion Stimulation

Th e dorsal root ganglion (DRG) has an important role

in the development and maintenance of chronic neuro-

pathic pain. In addition, CRPS, distal leg and foot pain,

inguinal pain, and truncal pain have been diffi cult ar-

eas to target with conventional paresthesia stimulation.

Th erefore, the DRG is a reasonable target for stimula-

tion to treat these challenging pain syndromes. Th e

predictable location of the DRG in the epidural space

and the lack of overlying CSF allows for increased en-

ergy effi ciency 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 re-

taining loops that reduce lead migration. A prospec-

tive study was performed in 32 patients with chronic

pain of the limbs and/or trunk. At 6 months after im-

plant, more than half of the participants reported 50%

or greater pain relief, with the proportions experienc-

ing 50% or more reduction in pain specifi c to back, leg,

and foot regions being 57%, 70% and 89% respectively.

Th ey 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 fi 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

eff ective in the treatment of peripheral nerve injuries.

Th ere are several ongoing clinical trials with DRG stim-

ulation for the treatment of traumatic nerve injury and

CRPS. Th e mechanism of PNS is unclear, but some sug-

gest that it changes the neurotransmitter milieu of the

peripheral nerve to relieve pain. Th e classic gate control

theory has also been suggested [6,51].

Indications for PNS include pain in the dis-

tribution of an accessible peripheral nerve. Th e most

common nerves to be treated are the supraorbital, in-

fraorbital, greater occipital, ulnar, median, suprascapu-

lar, intercostal, ilioinguinal, iliohypogastric, genito-

femoral, lateral femoral cutaneous, saphenous, sciatic,

posterior tibial, superfi cial peroneal, and sural nerves.

With the use of ultrasound, the percutaneous place-

ment of leads is becoming more common, at least in

trials. Th e same concepts of electrical physics described

for SCS also apply to PNS [44].

Th ere are few studies on the long-term out-

comes of PNS. Deer et al. published a recent study

showing relief from a device that does not require an

implantable pulse generator. Th ey are currently con-

ducting a multicenter trial. Hassenbusch and Stanton-

Hicks published a study evaluating PNS for CRPS.

Th e success rate was more than 60% with devices that

would now be considered antiquated. Th ere are also fa-

vorable 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 inva-

sive and labor-intensive therapy. Th erefore, appropri-

ate 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 Th erapies 251

failed to respond to spinal cord stimulation (if indicat-

ed), (3) multiple pain sites with truncal/axial pain, and

(4) static or changing pain. Table I summarizes selec-

tion criteria for IDD [55].

Patients with a psychological profi le deemed

appropriate for IDD therapy have better outcomes than

those deemed inappropriate; therefore, psychological

clearance is important to success. Psychological exclu-

sion criteria include: (1) active psychosis, (2) active sui-

cidality, (3) active homicidality, (4) major uncontrolled

depression or other mood disorders, (5) somatization

or other somatoform disorders, (6) alcohol or drug de-

pendency, (7) compensation or litigation resolution, (8)

lack of appropriate social support, and (9) neurobehav-

ioral or cognitive defi cits [4]. Th e choice of screening

technique for IDD remains controversial. Both contin-

uous infusion and bolus dosing have been used. A re-

cent polyanalgesic consensus panel published the fi rst

recommendations for IDD (Table II) [9].

Even more controversial is whether to with-

draw systemic opioids prior to trying IDD. Advantages

include: (1) reversal of tolerance, (2) identifi cation of

patients with strong physical dependence, (3) possible

identifi cation of patients with psychological depen-

dence and addiction, and (4) possible reduction of total

IDD dose over time. Disadvantages include increasing

pain and suff ering while the patient is off the opioids

and delays in initiation of IDD. Guidelines have been

published for the management of both cancer and non-

cancer pain (Tables III–VI) [10,11].

Drugs Used for IDD

Opioids

Agonism of pre- and postsynaptic μ-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 hydromor-

phone, fentanyl, and sufentanil. Side eff ects include re-

spiratory depression with overdose, nausea, urinary re-

tention, pruritus, and peripheral edema [24,39,40].

Ziconotide

Ziconotide is the fi rst nonopioid approved for IDD to

treat chronic pain. Its mechanism is through presyn-

aptic 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 treat-

ments such as systemic analgesics, adjunctive thera-

pies, or IDD morphine. Two fast-titration trials (one

for malignant and one for nonmalignant pain) and one

slow-titration trial led to FDA approval. Th e malig-

nant 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 eff ects [48,53]. A follow-up

3-week slow-titration trial in chronic pain patients

with preexisting implanted IDD pumps showed a

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

Table II Recommended doses for

intrathecal drug bolus trialing

Drug

Recommended i.t. Bolus Dose

Morphine 0.2–1.0 mg

Hydromorphone 0.04–0.2 mg

Ziconotide 1–5 μg

Fentanyl 25–75 μg

Bupivacaine 0.5–2.5 mg

Clonidine 5–20 μg

Sufentanil 5–20 μg

Table III Recommended starting dosage range and titration

for intrathecal drugs

Drug

Recommended Starting Dose

Incremental Increase

Morphine 0.1–0.5 mg/day 0.5 mg

Hydromorphone 0.02–0.5 mg/day 0.1 mg

Ziconotide 0.5–2.4 μg/day 10 μg

Fentanyl 25–75 μg/day 2.5 μg

Bupivacaine 1–4 mg/day 0.1 μg

Clonidine 40–100 μg/day 1 mg

Sufentanil 10–20 μg/day 10 μg

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

252 Mark S. Wallace

14.7% vs. 7.2% reduction in pain (ziconotide vs. place-

bo) at 3 weeks (P = 0.36). Side eff ects were much less

severe, and the dropout rate did not diff er between

the ziconotide and placebo group [42]. Although zi-

conotide has a high incidence of cognitive side eff ects,

there is a wide margin of safety in overdose. Cognitive

side eff ects are reduced with slow titration. Th ere 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. Th ey work

through blockade of pre- and postsynaptic sodium

channels. Th ey are most commonly used in combination

with other IDD agents. Bupivacaine is most commonly

used. It has few side eff ects with minimal sensory and

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

Clonidine

Clonidine works through agonism of pre- and postsyn-

aptic adrenergic α2 receptors, resulting in a reduction

in presynaptic neurotransmitter release and hyperpo-

larization of the postsynaptic membrane. It is FDA ap-

proved for epidural use in cancer pain only; however, it

is widely used in IDD therapy. Side eff ects include hy-

potension, bradycardia, and sedation. It is often used in

combination with other IDD agents [55].

Baclofen

Baclofen is a GABAB agonist with antispasmodic ef-

fects through decrease release of excitatory neu-

rotransmitters from IA, IB, and A-α aff erents in the

spinal cord. Analgesic eff ects may be due to eff ects on

voltage-sensitive calcium channels. It is FDA approved

as an antispasmodic [55].

IDD Systems

Th ere are currently two FDA-approved systems on

the market used to treat chronic pain. Th e Medtronic

Synchromed II comes in 20- and 40-mL reservoir vol-

umes. 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. Th e Flowonix

Prometra pump uses a pressurized gas chamber as

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 Fentanyl + bupivacaine or fentanyl + clonidine

Line 4 Opioid + clonidine + bupivacaine Bupivacaine + clonidine

Line 5 Baclofen

Table V2011 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 μg 2000 μg/mL

Sufentanil 250 μg 1000 μg/mL

Ziconotide 2.5 μg 20

Bupivacaine 10 mg 20

Clonidine 250 μg 2000

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

Interventional and Nondrug Neuropathic Pain Th erapies 253

the driving force with a programmable fl ow-metering

valve for variable rate delivery, resulting in much low-

er energy requirements and thus longer battery life

(10 years) [19].

Morbidity Related to IDD

Th e most common cause of morbidity relates to cath-

eter problems. Th e 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, fi lling errors, and programming er-

rors have been reported and can be life threatening.

Increasing reports of catheter tip granuloma forma-

tion were thought to be the result of high drug con-

centrations. Th e exact drug concentration that will

predispose to granuloma formation is unknown

[7,12,13,23,57].

Effi cacy of IDD for Chronic Pain

Th ere is only one prospective randomized controlled

trial on IDD, in which 202 cancer patients with uncon-

trolled pain were randomized to either IDD or compre-

hensive medical management (CMM). Clinical success

was defi ned as at least 20% reduction in visual analogue

scale (VAS) scores or equal scores with at least 20% re-

duction 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.

Th ere was a nonsignifi cant change in mean VAS be-

tween groups (IDD 52%, CMM 39%). IDD patients had

a signifi cantly greater change in toxicity scores (52% vs.

17%; P = 0.004). Th ere was no diff erence in survival be-

tween 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

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. Th e mechanism is

not clear, but acupuncture appears to work peripherally

by stimulating Aδ aff erents and centrally through the

endorphin system [17,30]. Th ere is also evidence of a

neurohumoral eff ect [26]. One animal study suggested

a long-term eff ect on neuroplasticity in rats with neu-

ropathic pain [56]. Th ere are two clinical trials showing

benefi ts 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. Th ere are two main stimulation pat-

terns: (1) a low-frequency, 1–4-Hz, long-pulse-width,

high-intensity stimulation that causes muscle contrac-

tion; (2) a high-frequency 50–120-Hz, low-intensity

stimulation. Th e low-frequency pattern mimics acu-

puncture, whereas the high frequency uses the gate

control theory. Th e evidence is poor in supporting the

effi cacy of TENS.

References

[1] Abuaisha BB, Costanzi JB, Boulton AJM. Acupuncture for the treat-ment of chronic painful peripheral diabetic neuropathy: a long term study. Diabetic Res Clin Pract 1998;39:115–21.

[2] Armon C, Argoff CE, Samuels J, Backonja MM. Assessment: use of epidural steroid injections to treat radicular lumbosacral pain: report of the Th erapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2007;68:723–9.

[3] Bhadra N, Kilgore KL. High-frequency electrical conduction block of mammalian peripheral motor nerve. Muscle Nerve 2005;32:782–90.

[4] Brandwin MA, Kewman DG. MMPI indicators of treatment response to spinal epidural stimulation in patients with chronic pain and patients with movement disorders. Psychol Rep 1982;51:1059–64.

[5] Butler LD, Symons BK, Henderson SL, Shortliff e LD, Spiegel D. Hypno-sis reduces distress and duration of an invasive medical procedure for children. Pediatrics 2005;115:e77–85.

[6] Chung JM, Lee KH, Hori Y, Endo K, Willis WD. Factors infl uencing peripheral nerve stimulation produced inhibition of primate spinotha-lamic tract cells. Pain 1984;19:277–93.

[7] Coff ey RJ, Burchiel K. Infl ammatory mass lesions associated with intra-thecal drug infusion catheters: report and observations on 41 patients. Neurosurgery 2002;50:78–87.

[8] Deer TR, Levy RM, Rosenfeld EL. Prospective clinical study of a new implantable peripheral nerve stimulation device to treat chronic pain. Clin J Pain 2010;26:359–72.

[9] Deer TR, Prager J, Levy R, Burton A, Buschser E, Caraway D, Cousins M, De Andres J, Diwan S, Erdek M, Grigsby E, Huntoon M, Jacobs M, Kim P, Kumar K, Leong M, Liem L, McDowell G, Panchal SJ, Rauck R, Saulino M, Staats P, Stanton-Hicks M, Stearns L, Sitzman BT, Wal-lace M, Willis K, Witt W, Yaksh T, Mekhail N. Polyanalgesic Consensus Conference 2012: recommendations on trialing for intrathecal (intra-spinal) drug delivery: report of an interdisciplinary expert panel. Neu-romodulation 2012;15:420–35.

254 Mark S. Wallace

[10] Deer TR, Prager J, Levy R, Burton A, Buschser E, Caraway D, Cousins M, De Andres J, Diwan S, Erdek M, Grigsby E, Huntoon M, Jacobs M, Kim P, Kumar K, Leong M, Liem L, McDowell G, Panchal SJ, Rauck R, Saulino M, Staats P, Stanton-Hicks M, Stearns L, Sitzman BT, Wal-lace M, Willis K, Witt W, Yaksh T, Mekhail N. Polyanalgesic Consensus Conference 2012: recommendations for the management of pain by in-trathecal (intraspinal) drug delivery: report of an interdisciplinary ex-pert panel. Neuromodulation 2012;15:436–66.

[11] Deer TR, Smith HS, Burton AW, Pope JE, Doleys DM, Levy RM, Staats PS, Wallace M, Webster LR, Rauck R, Cousins M. Comprehensive con-sensus based guidelines on intrathecal drug delivery systems in the treat-ment of pain caused by cancer pain. Pain Physician 2011;14:E283–312.

[12] Deer TR, Prager J, Levy R, Burton A, Buschser E, Caraway D, Cousins M, De Andres J, Diwan S, Erdek M, Grigsby E, Huntoon M, Jacobs M, Kim P, Kumar K, Leong M, Liem L, McDowell G, Panchal SJ, Rauck R, Saulino M, Staats P, Stanton-Hicks M, Stearns L, Sitzman BT, Wal-lace M, Willis K, Witt W, Yaksh T, Mekhail N. Polyanalgesic Consensus Conference 2012: recommendations to reduce morbidity and mortal-ity in intrathecal (intraspinal) drug delivery in the treatment of chronic pain. Neuromodulation 2012;15:467–82.

[13] Deer TR, Prager J, Levy R, Burton A, Buschser E, Caraway D, Cousins M, De Andres J, Diwan S, Erdek M, Grigsby E, Huntoon M, Jacobs M, Kim P, Kumar K, Leong M, Liem L, McDowell G, Panchal SJ, Rauck R, Saulino M, Staats P, Stanton-Hicks M, Stearns L, Sitzman BT, Wal-lace M, Willis K, Witt W, Yaksh T, Mekhail N. Polyanalgesic Consen-sus Conference 2012: consensus on diagnosis, detection and treatment of catheter tip granulomas (infl ammatory masses). Neuromodulation 2012;15:483–96.

[14] De Ridder D, Vanneste S, Plazier M, van der Loo E, Menovsky T. Burst spinal cord stimulation: Toward paresthesia-free pain suppression. Neurosurgery 2010;66:986–90.

[15] De Ridder D, Vanneste S, van der Loo E, Plazier M, Menovsky T, van de Heyning P. Burst stimulation of the auditory cortex: a new form of neurostimulation for noise-like tinnitus suppression. J Neurosurg 2010;112:1289–94.

[16] Dworkin RH, O’Connor AB, Kent J, Mackey SC, Raja SN, Stacey BR, Levy RM, Backonja M, Baron R, Harke H, Loeser JD, Treede RD, Turk DC, Wells CD. Interventional management of neuropathic pain: NeuP-SIG recommendations. Pain 2013;154:2249–61.

[17] Fei H, Xie GX, Han JS. Diff erential release of met-enkephalin and dyn-orphin in spinal cord by electroacupuncture of diff erent frequencies. Kexue Tongbo 1986;31:1512–5.

[18] Field MJ, Lohr KN, editors. Committee to advise the public health ser-vice on clinical practice guidelines, Institute of Medicine. Washington, DC: National Academy Press; 1990.

[19] Furnish T, Wallace M. Intrathecal drug delivery: patient selection, trial-ing, and implantation. In: Benzon H et al., editors. Practical manage-ment of pain. Philadelphia: Elsevier; 2013. p. 953–65.

[20] Graham R, Mancher M, Wolman DM, editors. Committee on Stan-dards for developing trustworthy clinical practice guidelines; Institute of Medicine. Washington, DC: National Academy Press; 1990.

[21] Hamza MA, Proctor TJ, White PF, Craig WF, Ghoname ES, Ahmed HE, Proctor TJ, Noe CE, Vakharia AS, Gajraj N. Percutaneous electri-cal nerve stimulation: a novel analgesic therapy for diabetic neuropath-ic pain. Diabetes Care 2000;23:365–70.

[22] Harvey A, Swadlow I, Alexander G. Th e impact of “bursting” thalamic impulses at the neocortical synapse. Nat Neurosci 2001;4:402–8.

[23] Hassenbusch S, Burchiel K, Coff ey RJ, Cousins MJ, Deer T, Hahn MB, Du Pen S, Follett KA, Krames E, Rogers JN, Sagher O, Staats PS, Wal-lace MS, Willis KD. Management of intrathecal catheter-tip infl amma-tory masses: a consensus statement. Pain Med 2002;3:31323.

[24] Hassenbusch SJ, Portenoy RK. Current practices in intraspinal therapy: a survey of clinical trends and decision making. J Pain Symptom Man-age 2000;20:S4–11.

[25] Jahnsen H, Llinas R. Voltage-dependent burst-to-tonic switching of thalamic cell activity: an in vitro study. Arch Ital Biol 1984;122:73–82.

[26] Kaada B, Eielsen O. In search of mediators of skin vasodilation induced by transcutaneous nerve stimulation: II. Serotonin implicated. Gen Pharmacol 1983;14:635–41.

[27] Kemler MA, Barendse GAM, van Kleef M, de Vet HC, Rijks CP, Furnee CA, van den Wildenberg FA. Spinal cord stimulation in patients with chronic refl ex sympathetic dystrophy. N Engl J Med 2000;343:618.

[28] Kumar K, Taylor RS, Jacques L, Eldabe S, Meglio M, Molet J, Th om-son S, O’Callaghan J, Eisenberg E, Milbouw G, Buchser E, Fortini G, Richardson J, North RB. Spinal cord stimulation versus conventional medical management for neuropathic pain: a multicentre randomised controlled trial in patients with failed back surgery syndrome. Pain 2007;132:179.

[29] Lang E, Benotsch E, Fink L, Lutgendorf S, Berbaum ML, Berbaum KS, Logan H, Spiegel D. Adjunctive non-pharmacological analgesia for inva-sive medical procedures: a randomized trial. Lancet 2000;355:1486–90.

[30] Leung AY, Kim SJ, Schulteis G, Yaksh T. Th e eff ect of acupuncture du-ration on analgesia and peripheral sensory thresholds. BMC Comple-ment Altern Med 2008;8:18.

[31] Liem L, Russo M, Huygen FJ, van Buyten JP, Smet I, Verrillis P, Cousins M, Brooker C, Levy R, Deer T, Kramer J. A multicenter, prospective tri-al to assess the safety and performance of the spinal modulation dorsal root ganglion neurostimulator system in the treatment of chronic pain. Neuromodulation 2013;16:471–82.

[32] Linderoth B, Meyerson BA. Spinal cord stimulation, I. Mechanisms of action. In: Burchiel K, editor. Pain surgery. New York: Th ieme; 1999.

[33] Liu Y, Varela M, Oswald R. Th e correspondence between some motor points and acupuncture loci. Am J Chin Med 1975;3:347–58.

[34] Lopez-Garcia JA, King AE. Membrane properties of physiologically classifi ed rat dorsal horn neurons in vitro: correlation with cutaneous sensory aff erent input. Eur J Neurosci 1994;6:998–1007.

[35] Manchikanti L, Falco FJE, Singh V, Benyamin RM, Racz, GB, Helm S, Caraway DL, Calodney AK, Snook LT, Smith HS, Gupta S, Ward SP, Grider JS, Hirsh JA. An update of comprehensive evidence-based guidelines for interventional techniques in chronic spinal pain. Part I: Introduction and general considerations. Pain Physician 2013;16:S1–48.

[36] Melzack R, Stillwell DM, Fox EJ. Trigger points and acupuncture points for pain: correlations and implications. Pain 1977;3:3–23.

[37] Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150:971.

[38] North RB, Kidd D, Shipley J, Taylor R. Spinal cord stimulation versus reoperation for failed back surgery syndrome: A cost eff ectiveness and cost utility analysis based on a randomized, controlled trial. Neurosur-gery 2007;61:361.

[39] Oakley J, Staats P. Th e use of implanted drug delivery systems. In: Raj PP, editor. Th e practical management of pain. St Louis; Mosby: 2000. p. 768–78.

[40] Paice JA, Penn RD, Shott S. Intraspinal morphine for chronic pain: a ret-rospective, multicenter study. J Pain Symptom Manage 1996;11:71–80.

[41] Perruchoud C, Eldabe S, Batterham AM, Madzinga G, Brookes M, Durrer A, Rosato M, Bovet N, West S, Bovy M, Rutschman B, Gulve A, Garner F, Buchser E. Analgesic effi cacy of high-frequency spinal cord stimulation: a randomized, double-blind placebo-controlled study. Neuromodulation 2013;16:363–9.

[42] Rauck RL, Wallace MS, Leong MS, MineHart M, Webster LR, Charapata SG, Abraham JE, Buffi ngton DE, Ellis D, Kartzinel R, Zi-conotide 301 Study Group. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage 2006;31:393–406.

[43] Scanlon GC, Moeller-Bertram T, Romanowsky SM, Wallace MS. Cer-vical transforaminal epidural steroid injections: more dangerous than we think? Spine 2007;32:1249–56.

[44] Silberstein SD, Dodick DW, Saper J, Huh B, Slavin KV, Sharan A, Reed K, Narouze S, Mogilner A, Goldstein J, Trentman T, Vaisma J, Ordia J, Weber P, Deer T, Levy R, Diaz RL, Washburn SN, Mekhail N. Safety and effi cacy of peripheral nerve stimulation of the occipital nerves for the management of chronic migraine: results from a randomized, mul-ticenter, double-blinded, controlled study. Cephalalgia 2012;32:1165–79.

[45] Smith TJ, Staats PS, Deer T, Stearns LJ, Rauck RL, Boortz-Marx RL, Buchser E, Català E, Bryce DA, Coyne PJ, Pool GE; Implantable Drug Delivery Systems Study Group. Randomized clinical trial of an implant-able drug delivery system compared with comprehensive medical man-agement for refractory cancer pain: impact on pain, drug-related toxic-ity, and survival. J Clin Oncol 2002;20:4040–9.

[46] Spiegel D. Th e mind prepared: hypnosis for surgery. J Natl Cancer Inst 2007;99:1280–1.

[47] Spiegel H, Spiegel D. Trance and treatment: clinical uses of hypnosis. Washington, DC: American Psychiatric Press; 2004.

[48] Staats PS, Yearwood T, Charapata SG, Presley RW, Wallace MS, Byas-Smith M, Fisher R, Bryce DA, Mangieri EA, Luther RR, Mayo M, Mc-Guire D. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer and AIDS: a randomized controlled trial. JAMA 2004;291:63–70.

[49] Tiede J, Brown L, Gekht G, Vallejo R, Yearwood T, Morgan D. Novel spinal cord stimulation parameters in patients with predominant back pain. Neuromodulation 2013;16:370–5.

[50] Van Buyten J-P, Al-Kaisy A, Smet I, Palmisani S, Smith T. High-fre-quency spinal cord stimulation for the treatment of chronic back pain patients: results of a prospective multicenter European clinical study. Neuromodulation 2013;16:59–66.

Interventional and Nondrug Neuropathic Pain Th erapies 255

[51] Wall PD, Gutnick M. Properties of aff erent nerve impulses originating from a neuroma. Nature 1974;248:740–3.

[52] Wall PD, Sweet WH. Temporary abolition of pain in man. Science 1967;155:108–9.

[53] Wallace MS, Charpata SG, Fisher R, Byas-Smith M, Staats PS, Mayo M, McGuire D, Ellis D; Ziconotide Nonmalignant Pain Study 96-002 Group. Intrathecal ziconotide in the treatment of chronic nonmalig-nant pain: a randomized, double-blind, placebo-controlled clinical trial. Neuromodulation 2006;9:75–86.

[54] Wallace MS, Rauck RL, Deer T. Ziconotide combination intrathecal therapy: rationale and evidence. Clin J Pain 2010;26:635–44.

[55] Wallace MS, Yaksh TL. Long-term intraspinal drug therapy: a review. Reg Anesth Pain Med 2000;25:117–57.

[56] Xing GG, Liu FY, Qu XX, Han JS, Wan Y. Long term synaptic plasticity in the dorsal horn neuron and its modulation by electroacupuncture in rats with neuropathic pain. Exp Neurol 2007; 208:323–32.

[57] Yaksh TL, Hassenbusch SJ, Burchiel K. Infl ammatory masses associ-ated with intrathecal drug infusion: a review of preclinical evidence and human data. Pain Med 2002;3:300–12.

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