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

439

42Fabián C. Piedimonte, MD

Fundación CENIT para la Investigación en Neurociencias, Caba, Argentina

Surgical Treatment for Neuropathic Pain

Educational Objectives

1. Review the background and rational use of inter-

ventional pain techniques.

2. Assess adequate patient selection, indications, and

the evidence to support the use of surgical inter-

ventional therapies for neuropathic pain.

3. Identify pros and cons of diff erent surgical abla-

tive and functional neurosurgical interventional

therapies to help determine the proper choice of

technique for the treatment of chronic neuropathic

pain.

Introduction

“Any professional who handles pain patients should

be familiar with all therapeutic modalities currently

available”

– John Bonica

According to the defi nition by the International Asso-

ciation for the Study of Pain (IASP), neuropathic pain is

caused by a lesion or disease of the somatosensory ner-

vous system. Its treatment may be diffi cult. Medications

and psychotherapy are often insuffi cient to reduce the

pain to a tolerable level. In some well-defi ned circum-

stances, functional neurosurgery may provide an alter-

native treatment strategy. Before deciding on the most

appropriate surgical procedure for a particular patient

with neuropathic pain, the anatomical and physiologi-

cal mechanisms involved in the pain must be analyzed

carefully. Analgesic surgery, a branch of functional neu-

rosurgery, provides some eff ective strategies for those

patients in whom less invasive conservative treatment

has failed or in cases in which medication causes signif-

icant adverse eff ects. Th e fundamental principle to keep

in mind is that any indication for an invasive procedure

must arise from an interdisciplinary consensus, taking

into account a comprehensive evaluation of pain char-

acteristics and the psychological condition of the pa-

tient. Neurosurgical procedures available for the treat-

ment of chronic neuropathic pain can be divided into

three broad groups, as follows:

• Anatomical procedures treating the pain etiology.

• Lesional or ablative procedures making selective

therapeutic lesions in well-defi ned and identifi ed

targets demonstrated to sustain pain.

• Neuromodulation techniques using electrical

stimulation or implanted drug delivery systems.

We will describe each of these groups below.

Anatomical Procedures

In those cases in which neuropathic pain is due to an

identifi able anatomical cause, a treatment option is to

perform a procedure to correct the disturbance and

thus control the symptoms. Th is procedure should

440 Fabián C. Piedimonte

achieve its goal (pain relief ) without any impact on

other neurological functions. Unfortunately, there are

few neuropathic pain conditions secondary to a specifi c

anatomical disorder that is easily amenable to surgi-

cal intervention. A typical example may be trigeminal

neuralgia (TN) caused by nerve compression owing to

an expansive lesion or secondary to a neurovascular

anomaly in the posterior fossa, a situation that is re-

solved by microsurgical resection of the lesion or re-

ducing the arterial loop responsible for trigeminal irri-

tation, respectively (Fig. 1). Another typical example is

compressive radiculopathy secondary to disc herniation

that is refractory to conservative treatment. In this case,

relief of pain is achieved by radicular decompression by

microdiscectomy.

Ablative or Lesional Procedures

“Pain may seem to run in front of the knife”

– Otfrid Foerster

Th e mechanism of action of ablative procedures is

based on the interruption of a nociceptive pathway at

any of its levels, or of those structures related to the ori-

gin and/or maintenance of the pain. Th e interruption

of nociceptive information is performed via various

ablative techniques such as the use of surgical sections,

neurolytic agents (phenol, alcohol, etc.), radiofrequen-

cy (RF), cryosurgery, and radiosurgery, among oth-

ers. Whereas ablative techniques were commonly used

during the past century, particularly for cancer pain

management, their use has been limited today owing

to their irreversibility, morbidity, the high incidence of

deaff erentation pain, and the emergence of modern, less

risky, and more eff ective options.

From a topographic point of view, ablative pro-

cedures can be grouped into peripheral procedures

(neurectomy, gangliectomy, rhizotomy, and sympa-

thectomy), spinal cord procedures (dorsal root entry

zone [DREZ] lesion, cordotomy, commissurotomy, ex-

tralemniscal myelotomy, commissural myelotomy, and

cordectomy), and encephalic/cranial procedures (tri-

geminal nucleotomy, bulbar and pontine spinothalamic

tractotomy, mesencephalic tractotomy, thalamotomy,

hypothalamotomy, cingulotomy, and hypophysectomy).

Presently, there are few ablative procedures that can be

considered useful in the treatment of specifi c neuro-

pathic pain conditions. Th e following is a discussion of

some important conditions for which surgical therapies

may be indicated:

Trigeminal Rhizotomy

Idiopathic TN refractory to medical therapy is, un-

doubtedly, one of the best examples of neuropathic pain

for which ablative procedures remain extremely useful,

eff ective, and carry very low risk. Percutaneous RF tri-

geminal rhizotomy is a remarkably eff ective treatment

option, after which most patients are free of pain and

can discard the medications they take for this condi-

tion. Th e procedure relies on the application of RF elec-

tric current to a portion of the trigeminal root, either

Fig. 1. Coronal magnetic resonance image showing (a) trigeminal neurinoma (arrows), and (b) complete removal after microsurgical resection.

a b

Surgical Treatment for Neuropathic Pain 441

in or just behind the gasserian ganglion, to generate

heat locally in order to destroy some of the nerve fi bers

within it, predominantly nociceptive fi bers, because of

their greater susceptibility to heat. Th e aim is to achieve

a total or almost total analgesia in the cutaneous area

that corresponds to the heated portion of the trigeminal

root, accompanied by only partial hypoesthesia in the

same area.

Th e approach is essentially the same as that de-

scribed by Härtel in 1914 for injection treatments [26].

Under fl uoroscopy guidance, the needle is inserted 2–3

cm lateral to the corner of the mouth on the symptom-

atic side of the face and then advanced in a superior,

posterior, and medial direction to reach the foramen

ovale and the gasserian ganglion while always remain-

ing under the mucosa. Once the tip of the needle has

passed through the foramen ovale, it is advanced fur-

ther until it just overlies the clival line under lateral

fl uoroscopic view (Fig. 2). Th e guide needle is removed,

and a few drops of cerebrospinal fl uid (CSF) generally

emerge from the needle. By this time, a stimulation test

is performed to elicit paresthesia in the area of pain.

Taha and Tew [88] state that the electrode tip should be

5 mm beyond the clival line for V1 stimulation, just at

the clival line for V2 stimulation, and 5 mm in front of

the clival line for V3 stimulation. Once the needle po-

sition has been confi rmed, RF lesions are performed,

usually at 65°C for 1 minute each. Th e endpoint is the

achievement of hypoalgesia or analgesia in the initially

painful area, with no more than partial hypoesthesia.

Gybels and Sweet [24], and more recently Kan-

polat et al. [36] evaluated the results of large series that

had been published emphasizing that early complete re-

lief of pain was obtained in more than 95% of patients

in all series. Th e rate of late recurrence requiring reop-

eration was generally in the range of 20% to 30%. Dys-

esthesia in the treated area is a common postoperative

phenomenon (5% to 24% in various series) that some-

times requires treatment with medication. Anesthesia

dolorosa is defi ned as dysesthesia arising in a totally an-

esthetic area and is much more rare (1.2%).

In addition to RF techniques, other ablative

procedures are used to control pain secondary to tri-

geminal neuralgia with satisfactory results. In 1971,

Lars Leksell published the results of two patients

with trigeminal neuralgia treated with his pioneering

a b

Fig. 2. Intraoperative fl uoroscopic image during percutaneous trigeminal rhizotomy: (a) lateral view, (b) head-on view of the foramen ovale. ST, sella turcica; CL, clival line; FO, foramen ovale.


technique of stereotactic radiosurgery in 1953 [42]. Th is

technique is now accepted as the least invasive of all sur-

gical procedures for the treatment of TN. However, it is

more expensive than percutaneous techniques. Results

vary among publications; however, it is estimated that

approximately 75% of patients are pain free initially, but

less than 60% maintain this outcome after 2 years, and

just over half of treated patients remain pain free on or

off medications at a 3-year follow-up [47].

In 1981, Sten Hakanson reported the retrogas-

serian glycerol rhizolysis technique for treating TN via

glycerol injection into the trigeminal cistern, a minimally

invasive method with low surgical risk and little impact

on facial sensibility [25]. In 1983, Mullan and Lichtor

pioneered the concept of percutaneous balloon com-

pression for trigeminal neuralgia [51]. Th is procedure is

especially useful in patients with fi rst division pain be-

cause it does not injure the myelinated fi bers that medi-

ate the blink refl ex, providing relative protection of cor-

neal sensation. It is also greatly helpful in patients with

pain across multiple trigeminal branch divisions because

it does not require multiple lesions. Furthermore, it is

advantageous in elderly patients with whom it would be

diffi cult to communicate during selective thermal rhi-

zotomy. It is relatively inexpensive and is a technically

and technologically simple operation.

Stereotactic Trigeminal Nucleotomy

Dysesthetic neuropathic or deaff erentation facial pain

still poses a challenge for the neurosurgeon. Surgical

attempts to further interrupt the already damaged pri-

mary aff erent neuron at any site, including trigeminal

tractotomy, have consistently failed. In fact, they usu-

ally aggravate rather than ameliorate the pain [23,68].

In contrast, lesioning the second-order neurons at the

nucleus caudalis, that is, at the putative focus of dener-

vation neuronal hyperactivity, appears to be a rational

approach [72]. Stereotactic trigeminal nucleotomy pre-

sumably removes the segmental pool of hyperexcitable

neurons and denervation hypersensitivity, eliminating

convergence and severing the ascending intranuclear

pathways. Th e technique has been well described [31].

In brief, patients undergo surgery under neuroleptic an-

algesia, with the head fully fl exed within a stereotactic

frame. Electrical stimulation clearly identifi es the tri-

geminal region, with its rostral dermatome located ven-

trolaterally and its caudal dermatome dorsomedially. It

is usually possible to further defi ne the dorsal border of

the nucleus by ipsilateral responses induced from the

cuneatus tract and its ventral border by contralateral

responses elicited from the spinothalamic tract, or at

times by motor responses obtained from a posteriorly

located corticospinal tract [68].

In addition, threshold stimulation often mim-

ics the patient’s neuropathic pain. Th is procedure al-

lows for the placement of accurate stereotactic lesions

with concomitant electrophysiological control of cranial

nerves V, VII, IX, and X, as well as of the second and

third cervical roots, at the nucleus caudalis (Fig. 3). Sch-

varcz has used this technique since 1971, terming the

Fig. 3. Postsurgical magnetic resonance image after stereotactic trigeminal nucleotomy. Arrows show that the radiofrequency lesion is entirely within the nucleus caudalis area: (a) axial view, (b) coronal view.

a b


procedure trigeminal nucleotomy to emphasize the

signifi cance of lesioning primarily the second-order

neurons at the oral pole of the nucleus caudalis, which

are heavily involved in intrinsic mechanisms pertain-

ing to dysesthetic facial pain [65,71]. From a series of

204 consecutive nucleotomies performed on 196 pa-

tients, 143 underwent this procedure for deaff erenta-

tion pain [57]. In this study, Piedimonte and Schvarcz

reported abolition of allodynia and a marked reduc-

tion of deep background pain in 75.0% of patients with

postherpetic dysesthesia, 71.7% of those with dyses-

thesia, 66.7% of those with anesthesia dolorosa, and

77.8% of those with posttraumatic neuropathy [57].

Siqueira described a method for open surgical

trigeminal nucleotomy [84], and Kanpolat et al. devel-

oped an elegant computed tomography–guided per-

cutaneous technique for trigeminal nucleotomy [35];

both of these methods were for deaff erentation pain.

Grigorian and Slavin also reported good results with

ultrasound-guided trigeminal nucleotomy for deaff er-

entation pain [21]. Even though stereotactic trigeminal

nucleotomy is a reasonably straightforward technique,

especially suitable for elusive dysesthetic facial pain

phenomena, its use has been diminished with the de-

velopment of neuromodulation techniques.

Dorsal Root Entry Zone Lesions

In the 1960s, several neurophysiological investigations

showed that the dorsal horn is the fi rst, and an impor-

tant, level of modulation for pain sensation. Th is was

popularized in 1965 by the gate-control theory [49],

which drew neurosurgeons’ attention to this area as a

possible target for augmentative (spinal cord stimula-

tion) and ablative pain surgery.

Sindou and colleagues have attempted a micro-

surgical DREZotomy procedure in patients with neuro-

pathic pain syndromes, such as those associated with

paraplegia and brachial plexus avulsion, since 1972,

owing to encouraging early results with malignancies

(mainly Pancoast syndrome) [82,83]. Soon thereafter,

Nashold and colleagues began to perform DREZ lesions

via RF thermocoagulation in the substantia gelatinosa

of the dorsal horn [55] and later along the entire DREZ

[54], especially for pain caused by brachial plexus avul-

sion. More recently, DREZ procedures have been per-

formed via CO2 and argon laser by Levy et al. [45] and

Powers et al. [59], respectively.

Th e microsurgical DREZotomy procedure con-

sists of a longitudinal incision of the dorsolateral sulcus,

ventrolaterally at the entrance of the rootlets into the

sulcus, and microbipolar coagulations performed con-

tinuously down to the apex of the dorsal horn, along all

of the spinal cord segments selected for surgery. Th e av-

erage lesion is 2–3 mm deep and is made at a 35° angle

medially and ventrally. Th is method was conceived with

the aim of preventing complete abolition of tactile and

proprioceptive sensations and avoiding deaff erentation

phenomena [33].

DREZ procedures, whatever their modality, are

eff ective for pain developing after brachial plexus avul-

sion [61,80,95], pain caused by spinal cord and/or cauda

equina lesions [52,61,64,81], pain related to peripheral

nerve injuries, and pain after limb amputation result-

ing in phantom limb pain and/or pain in the stump. Few

groups have reported results for postherpetic pain. Only

superfi cial pain, especially of the allodynic type, in the

aff ected dermatome(s) is signifi cantly improved [18,61].

Neuromodulation Techniques

Th e growing knowledge of pain mechanisms makes it

clear that simple interruption of the peripheral or cen-

tral nervous system does not necessarily prevent an

impulse from reaching the brain [7]. In addition, the

limited effi cacy and signifi cant potential complications

associated with neuroablative procedures have led to

the development of neuroaugmentative techniques in-

cluding electrical stimulation of the brain, spinal cord,

and peripheral nerves, as well as chronic infusion of an-

algesic substances into the lumbar spinal and intraven-

tricular CSF. It has been shown that these procedures

are more eff ective than conventional destructive opera-

tions, with extremely low morbidity.

It is essential to be aware of the criteria for suc-

cess, among which are as follows:

• Failure of less expensive and invasive therapies.

• Th e existence of an objective pathology consistent

with the pain reported by the patient.

• Further surgical interventions are not indicated.

• Th ere is no serious untreated habit of drug abuse.

• Th ere are no psychological barriers to a successful

outcome.

• Th ere is no absolute contraindication for implan-

tation.

• A trial has been conducted to test effi cacy (chemi-

cal and electrical neuromodulation) and to rule

out toxicity (chemical neuromodulation).


Chemical Neuromodulation

Morphine, known since ancient times and considered

by the Sumerian culture more than 5000 years ago [10],

is an extremely eff ective analgesic agent. Unfortunately,

systemic administration tends to cause side eff ects, and

its use for prolonged periods can result in tolerance and

the potential for opioid addiction.

Th e discovery of opioid receptors in the sub-

stantia gelatinosa of the spinal cord led to the recogni-

tion that opioids have both spinal and supraspinal an-

algesic action. Fields and Basbaum in the United States,

and subsequently Besson in France, elucidated and

described the descending inhibitory pain system. Th is

pathway begins with projections from the frontal cor-

tex and hypothalamus to the midbrain periaqueductal

gray, which then projects to the dorsal pons and dor-

soventral medulla and end in the substantia gelatinosa

of the spinal cord dorsal horn. Th ese eff erent pathways

inhibit ascending nociceptive second-order neurons,

thus blocking the transmission of pain. Understanding

the mechanism by which opioids exert their antinoci-

ceptive activity at the spinal level led to the fi rst trials

of spinal administration of these agents, with morphine

administered epidurally [9] and intrathecally [105] for

the treatment of cancer pain. Th e advantage of intra-

thecal drug therapy for treating pain is that the eff ects

of the drug are restricted to the specifi c area related

to the conduction of nociceptive input. Th us, a sig-

nifi cantly lower total dose is required to produce anal-

gesia, and the systemic eff ects of the drug are greatly

diminished. Morphine is particularly suitable for this

application because of its hydrophilicity and resulting

low absorption from the CSF. Th us, it is not uncom-

mon for the eff ects of intrathecal morphine analgesia

to last up to 24 hours [9].

Th e discovery of multiple receptor systems in-

volved in nociceptive transmission and modulation at

the spinal level has allowed for the evaluation and ap-

plication of specifi c drugs such as opioid receptor ago-

nists, α2-adrenoceptor agonists, gamma aminobutyric

acid B (GABA B) agonists, calcitonin, and somatosta-

tin and its analog octreotide, among others. Th ere are

more than 100 open studies (of which at least 16 have

evaluated scales to measure pain pre- and postinterven-

tion) supporting the use of intrathecal drug delivery for

long-term pain relief and improvement of quality of life.

Four of these obtained good results for quality of life

according to the guidelines of the University of York,

United Kingdom [5,28,99,108]. However, controlled

blinded trials are still lacking, and hence the role of in-

trathecal therapies for chronic, noncancer, neuropathic

pain requires further investigation.

For all indications, patient selection is extreme-

ly important and should include a multidisciplinary

and comprehensive assessment of symptoms, illness,

psychological and social factors, current and previous

treatments, and other treatment options. Intrathecal

administration of drugs may be concurrent and ad-

juvant with other forms of pain management. Not all

patients with neuropathic pain benefi t from intraspi-

nal drug delivery. For this reason, it is essential to per-

form a prior therapeutic trial with predictive purpose.

Various approaches have been proposed for intrathecal

drug testing, including single versus multiple injections,

administration via catheter versus lumbar puncture,

epidural versus intrathecal routes, and bolus drug ad-

ministration versus continuous infusion. Th e test with a

single intraspinal dose of an active agent poses a signifi -

cant possibility of placebo eff ect, which can occur in at

least 30% of cases.

Robert Levy has developed a quantitative,

crossover, double-blind protocol to identify preimplant

candidates for the chronic infusion of drugs for the

control of refractory pain [44]. Th e implementation of

this protocol has resulted in the elimination of approxi-

mately 30% of potential candidates. Of those patients

with successful detection, 70% have had long-term pain

relief ranging from good to excellent. Th is detection

paradigm appears to be both reliable and easily appli-

cable [44].

Several studies have demonstrated the cost ef-

fectiveness of intrathecal therapy with implantable de-

vices. Th ese studies have analyzed all of the costs relat-

ed to intrathecal drug infusion therapy [86]. Th e results

suggest that this therapy is more cost eff ective than sys-

temic medication beyond 11–22 months for noncancer

pain.

Routes of Administration

Th e opioid epidural equianalgesic dose is almost 10

times greater than the intrathecal dose. Since 80% to

90% of the epidural dose is absorbed systemically, the

larger dose requirement may lead to more systemic side

eff ects including constipation and urinary retention.

Th ese larger doses increase even more the likelihood of

developing opioid tolerance. In addition, because there

is a fi xed maximum solubility of morphine in saline of


approximately 55 mg/mL, and pump reservoirs are of

limited size, the larger dose requirement implies the

need to fi ll the reservoir more frequently. Furthermore,

epidural catheter placement has been associated with

epidural fi brosis, resulting in failure owing to catheter

occlusion, torsion, or displacement.

Although intrathecal drug administration

avoids these complications, it carries the disadvantage

of potential loss of postural spinal CSF and associated

spinal headache, respiratory depression owing to opiate

supraspinal distribution, and increased risk of menin-

geal infection or neural damage. However, the advan-

tages of the intrathecal route, including the requirement

of lower dose, leading to increased intervals between

pump refi lling; the low risk of catheter failure; and the

low potential complication rate, suggest that this is the

favored route for intraspinal drug delivery.

Drug Options

Drugs can be used individually or in combination to

maximize analgesic eff ects and minimize side eff ects.

Th e most commonly used intrathecal pharmacological

agents are listed below.

Opioids

Morphine is considered the gold standard drug owing

to its stability, affi nity for receptors, and extensive ex-

perience with its use for this route of administration

[56]. Hydromorphone is approximately fi ve times more

potent than morphine and is used when there is intol-

erance to morphine. Th e adverse eff ect profi le of hy-

dromorphone is equivalent to, or more favorable than,

that of morphine [5]. Diacetylmorphine (diamorphine)

is highly soluble in saline and with bupivacaine and/or

clonidine, making it attractive for use in a combination

of drugs intrathecally.

Th e central side eff ects of intrathecal opioids

include delayed respiratory depression [20], itching,

nausea, vomiting, urinary retention, sedation, constipa-

tion, edema, weight gain, excessive sweating, changes

in memory and mood, and headache. Endocrine eff ects

include hypogonadism, loss of libido, and hypocorti-

solism [1]. Infl ammatory granuloma of the catheter tip

has been described in recent years. It occurs between

the spinal cord and the dura, mostly in the chest area,

with an estimated incidence of 0.5% per patient. Infl am-

matory granuloma can cause compression of the spinal

cord and roots, producing irradiating pain and progres-

sive neurological defi cit. It is usually associated with

failure of analgesia because the infusion is unable to

reach the neural tissue target. Th e etiology is unknown,

but it could be due to a reaction to the catheter tip,

low-grade infection, or be related to the infused medi-

cation. Animal models suggest that the cause could be

high opioid concentration. Granulomatous masses have

been reported with morphine, hydromorphone, and

baclofen, and low-fl ow pumps could be a risk factor. In

some cases, assessment or even withdrawal of the cath-

eter is necessary. In the situation of systematic spinal

cord compression, urgent simple decompression may

be indicated [27].

Th ere are several studies on the effi cacy of mor-

phine administered via the subarachnoid spinal route

for the treatment of pain. Auld et al. reported two stud-

ies of intraspinal narcotics for the treatment of nonma-

lignant pain. In the fi rst, 21 of 32 patients achieved ad-

equate pain relief [7]; in the second, 14 of 20 patients

achieved satisfactory pain relief with intraspinal mor-

phine [8].

Local Anesthetics

Intrathecal bupivacaine is usually used in combination

with morphine to provide better pain control in pa-

tients with neuropathic pain. Th ere is evidence that bu-

pivacaine acts synergistically with morphine, reducing

the need to increase the dose of intrathecal morphine

[3,100]. Local anesthetics can cause sensory defi cit, mo-

tor disturbances, signs of autonomic dysfunction, and

neurotoxicity. Th ere is less likely to be a problem if con-

tinuous infusions are used instead of a bolus. Clinically

relevant side eff ects do not appear with bupivacaine

doses less than 25 mg/day. Urinary retention, weakness,

drowsiness, and paresthesia have been reported with

larger doses.

Clonidine

Clonidine has been shown to be eff ective in the treat-

ment of neuropathic pain [17]. It is generally used in

combination with morphine and/or bupivacaine. Th e

synergistic combination of morphine and clonidine has

proved to be eff ective in patients with pain as a result of

spinal cord injury [78]. Th e most common side eff ects

of intrathecal clonidine are hypotension, bradycardia,

and sedation. Tamsen and Gordh originally studied two

patients with pain of nonmalignant origin [90]. Th e fi rst

patient received an epidural infusion of 150 mg cloni-

dine and 5 mg morphine. Analgesia lasted for more

than 9 hours compared to less than 3 hours for each


drug separately. Th e second patient received epidural

clonidine, which provided analgesia equivalent to that

obtained with epidural narcotic alone or in combina-

tion with clonidine. No side eff ects were reported.

In contrast to clonidine, the α2-adrenergic ago-

nist tizanidine does not appear to induce hypotension.

Th is agent has proved to be an eff ective analgesic when

administered intrathecally in experimental chronic neu-

ropathic pain [41]. Tizanidine appears to be particularly

useful in treating neuropathic pain syndromes refrac-

tory to narcotics.

Baclofen

Intrathecal baclofen has been established for the relief

of severe spasticity. Th ere may be some analgesic ef-

fects [89]. Although it is rarely used for chronic pain

not related to spasticity, there are a small number of

case series documenting its eff ectiveness in the treat-

ment of nonmalignant chronic pain such as phantom

pain, failed back surgery syndrome (FBSS), peripher-

al nerve injury, and complex regional pain syndrome

(CRPS) [101,109]. Side eff ects associated with con-

tinuous infusion of baclofen are rare but include se-

dation, dizziness, and constipation. Lesser degrees

of overdose may cause ataxia, dizziness, and mental

confusion. Th ese eff ects are more common after a bo-

lus dose compared to continuous infusion. Excessive

muscular hypotonia may result in unwanted or even

dangerous weakness, owing to a reduction in respi-

ratory muscle tone. Physostigmine has been used for

overdose, but a ventilation period may be required;

central eff ects should resolve within 24 hours. With-

drawal can occur if the pump is not properly refi lled

or if there are malfunctions of the pump or catheter,

and may result in rebound spasticity, motor hyperac-

tivity, headache, drowsiness, disorientation, hallucina-

tions, rhabdomyolysis, seizures, or even death.

Ziconotide

Ziconotide produces its analgesic eff ect via specifi c

blockade of N-type calcium channels located in pr-

esynaptic terminals of the dorsal horn [12]. Side eff ects

include dizziness, nausea, nystagmus, abnormal gait,

confusion, and urinary retention. Serious but rare side

eff ects include psychosis, suicide, and rhabdomyoly-

sis. Ziconotide may be initiated at 2.4 μg/day and sub-

sequently titrated according to the analgesic response

and adverse eff ects. Increases must be ≤2.4 μg/day to a

maximum dose of 21.6 μg/day. Th e minimum interval

between dose increments is 24 hours. For safety reasons,

the recommended interval is 48 hours or longer [62].

Two randomized, double-blind, placebo-con-

trolled studies support the use of ziconotide in the

treatment of chronic nonmalignant pain; although the

clinical signifi cance was modest, side eff ects were prob-

lematic, and experience with use of this drug is limit-

ed [62,104]. Th e combination of intrathecal ziconotide

with other intrathecal drugs, including morphine, hy-

dromorphone, clonidine, or baclofen, is associated with

a reduction in the concentration of ziconotide of ap-

proximately 20% within a few weeks [75–77].

Infusion System Options

Despite the popularity of implantable pumps, there are

a signifi cant number of methods by which intraspinal

drug administration can be achieved. Th ese systems in-

clude percutaneous epidural catheters coupled to exter-

nal pumps, internalized passive reservoirs and catheters

requiring percutaneous administration of drugs, me-

chanical systems activated by the patient, constant-fl ow

infusion pumps, and programmable infusion pumps.

Taking into account the signifi cant cost of the implant-

able device and the surgical procedure, the choice of

delivery system should be made with careful consider-

ation of the benefi ts of continuous infusion versus bo-

lus infusion, the patient’s general medical condition, the

outpatient condition, and estimated life expectancy.

It has been suggested that continuous infusion

may result in a reduced rate of opioid receptor tachy-

phylaxis [14] and a lower risk of tardive respiratory

depression [13]. Clinical studies have not clearly con-

fi rmed the superiority of continuous versus bolus intra-

spinal infusion. Gourlay et al. reported that epidural ad-

ministration morphine of both continuous infusion and

intermittent bolus provided equivalent pain relief, and

there was no consistent diff erence in depression or neu-

ropsychological function [19]. Other researchers have

similarly reported that either infusion method provides

analgesia without signifi cant eff ect on the level of con-

sciousness, with a low complication rate and probably

not resulting in addiction [13].

Fixed-rate delivery systems are less expensive

than programmable-rate delivery systems but lack fl ex-

ibility in terms of delivery. Dose changes are made by

modifying the concentration of the solution to be in-

fused. Th us, there is increased patient discomfort and

cost when dose modifi cations are indicated. In addition,

these devices are subject to slight variations in the rates


of drug release with changes in temperature and atmo-

spheric pressure. Because the system does not depend

on a power source, it should last the life of the patient.

Programmable pumps allow for telemetric,

transcutaneous, and noninvasive modifi cation of the

drug dose, as well as sophisticated drug-dosing regi-

mens. Because these pumps are battery run, they re-

quire surgical replacement; under normal conditions,

this occurs approximately every 4 to 6 years. Both

types of systems, fi xed-fl ow pumps and programmable

pumps, need to be refi lled every 1 to 3 months depend-

ing on the rate of release and stability of the drug used.

Electrical Neuromodulation

Electricity has been used to treat a variety of human

pain conditions for many centuries. Th erapeutic eff ects

of electric discharges from the electric ray Torpedo were

well known in ancient times and described by Scribo-

nius Largus for the treatment of patients with gout or

headaches. In 1860, Julius Althaus wrote on pain con-

trol with electricity applied directly to a peripheral sen-

sory nerve [4]. Th ere are presently diverse and clinically

useful structures for electrical neurostimulation, the

most important of which are described below.

Peripheral Nerve Stimulation

In 1967, Wall and Sweet reported that nonpainful elec-

trical stimulation of peripheral nerve does indeed sup-

press pain perception in the area that it innervates.

Th ey confi rmed their experimental fi ndings by inserting

electrodes into their own infraorbital foramina [103].

Th e exact mechanism by which peripheral nerve stim-

ulation (PNS) reduces chronic pain remains unknown.

Experimental evidence suggests that it may have both

a central eff ect and a peripheral eff ect on acute pain

perception by acting at multiple sites and via various

mechanisms. In an early report by Nashold et al., dis-

tinguished by its lengthy follow-up (4–9 years), patients

reported more than 90% subjective pain relief [53]. A

total of 35 patients were implanted over a period of 8

years. Th e patients were off all analgesic medications

and continued to use the stimulator regularly. Th e long-

term success rate for patients with upper-extremity

pain secondary to peripheral nerve injury was 53% (9 of

17 patients).

In 1997, Shetter et al. described one of the larg-

est experiences with PNS [74]. A total of 125 nerve

implants were performed for stimulation in 117 pa-

tients. Two-thirds of the patients had pain in an upper

extremity, owing to injury of a peripheral nerve. Th ere

were 101 patients available to follow-up at postoperative

intervals of 1 to 53 months. A total of 78 patients (77%)

were described as having good to excellent pain relief.

Hassenbusch et al. prospectively evaluated 34

patients with refl ex sympathetic dystrophy or CRPS

type II [29]. During the trial, 32 patients experienced

more than 50% pain reduction. At a mean follow-up of

2.2 years, 63% were considered to have a good or fair

outcome characterized by pain reduction of at least 25%

associated with improvement in vasomotor tone, tro-

phic changes, or motor function.

In 1999, Weiner and Reed [107] described a

percutaneous technique of electrode insertion in the vi-

cinity of the greater and lesser occipital nerves to treat

occipital neuralgia, with successful results. Since then,

the use of this technique has increased and its indica-

tions have expanded to include cervicogenic headache,

transformed migraine, cluster headache, and tension

headache, among others. Weiner [106] reported 75%

good to excellent long-term pain control in more than

150 patients treated during the period 1993 to 2005.

Th e good results achieved with occipital nerve stimu-

lation have encouraged other physicians to attempt

percutaneous electrode placement adjacent to the su-

praorbital and infraorbital nerves for the treatment of

postherpetic and posttraumatic trigeminal neuropathy.

Good outcomes have been described in several small

series [34,85]. More recently, synergistic stimulation,

approaching more than one target involved in pain gen-

esis or maintenance, was described for diff erent com-

plex neuropathic pain conditions (Fig. 4).

Spinal Cord Stimulation

Spinal cord stimulation (SCS) is an exceptionally good

example of translational pain research. In fact, in the

gate-control theory published in 1965, Melzack and

Wall explicitly stated that the theory could have thera-

peutic implications by means of selectively activating

large-diameter fi ber systems for the control of pain

[49]. Based on this theory, Shealy et al. reported the

fi rst trials with SCS as a clinical pain therapy [73]. Pres-

ently, SCS is presumably the most commonly practiced

neuromodulation technique for neuropathic pain. Th e

mechanism of action of SCS in neuropathic pain is in-

completely understood. Th e original conceptual basis

presupposes antidromic activation of ascending dorsal

column fi bers. Th e presence of paresthesia-coverage of

the painful area, indicating the activation of the dorsal


column, is a prerequisite for pain relief. Pain associ-

ated with extensive deaff erentation or direct injury of

dorsal column fi bers (where it is not possible to ob-

tain paresthesia at the painful site) fails to respond to

SCS. Th ere is some evidence that SCS increases the

substance P content in human CSF and the spinal re-

lease of substance P and serotonin in cats [46] and re-

duces the release of excitatory amino acids (glutamate,

aspartate) while at the same time augmenting GABA

release [16].

At present, various forms of neuropathic pain

conditions are the main indications for SCS therapy.

Th e favorable experience of SCS as a unique treatment

option has materialized in two consensus documents

[15,22]. Th e benefi cial eff ect of SCS may persist for a

long time. Several literature reports have documented

that patients continue to experience good relief from

pain for many years, even decades [39]. Th e most com-

mon indication for SCS is lumbar radicular pain after

FBSS, presented as irradiating pain in one or both legs.

Low back pain, also present in FBSS, is much more dif-

fi cult to alleviate, owing to the fact that it is diffi cult to

produce paresthesia in the lumbar area and because of

its predominantly nociceptive nature.

Th e Prospective Randomised Controlled

Multicentre Trial of the Eff ectiveness of Spinal Cord

Stimulation (PROCESS, ISRCTN 77527324) recruited

100 patients in a total of 12 centers in Europe, Can-

ada, Australia, and Israel. A total of 52 patients were

assigned to the SCS group and 48 to the conventional

medical management group. Results of this interna-

tional, multicenter, prospective, randomized controlled

trial show that SCS provides pain relief and improves

health-related quality of life and functional capacity

in patients with neuropathic pain secondary to FBSS.

In contrast, conventional medical management alone

provided little or no pain relief or no other outcome

benefi t [38].

Th e other principal indication for SCS is CRPS

type I. Th is is the only diagnosis for which the effi cacy

of SCS has attained the highest degree of evidence lev-

el. Taylor et al. analyzed data from 25 case studies on

SCS treatment of CRPS, with a mean follow-up of 33

months [92,93]. Th ey found that 67% of the patients

were reported to have a >50% relief from pain. A similar

result was reported by a European task force for evalu-

ation of neurostimulation, but the evidence quality has

been ranked as low (grade C) [15].

Th e usefulness of SCS for other neuropathic

pain indications is substantiated only in retrospective

case series and observational studies, among which in-

clude CRPS type II, peripheral nerve injury, diabetic

neuropathy, brachial plexus injury (partial), cauda equi-

na injury, phantom limb and stump pain, intercostal

neuralgia, postherpetic neuralgia [79], and painful legs

and moving toes [60].

Th e majority of electrode leads selected for

implant are percutaneous. Surgical leads (plate elec-

trodes) are considered to be less likely to dislocate and

are greatly preferred when a percutaneous cable lead

has been dislocated several times or when scar tissue

prevents the passing of such an electrode to the tar-

get area (Fig. 5). A stimulation trial using temporary

percutaneous extension cables is an indispensable step

Fig. 4. Postsurgical frontal (a) and lateral (b) X-ray control images showing tetrapolar electrodes for the synergic stimulation of the spheno-palatine ganglion (SPG) and great occipital nerve (GON).

a b


in deciding whether or not a complete stimulation sys-

tem should be permanently implanted [22]. In many

countries, a period of trial stimulation is required for

reimbursement.

Motor Cortex Stimulation

Th e use of motor cortex stimulation (MCS) to con-

trol central pain was introduced by Tsubokawa et al.

especially for poststroke pain in 1991 [96], by Mey-

erson et al. for trigeminal neuropathic pain in 1993

[50], and by Katayama et al. for Wallenberg syndrome

in 1994 [37]. Despite encouraging results, the mecha-

nisms of MCS have yet to be elucidated. Th e surgical

technique consists of a small craniotomy performed

around the area identifi ed as the precentral gyrus

during preoperative planning. Somatosensory evoked

potentials are obtained with the use of electrode grids

to identify the central sulcus and its orientation via

the detection of N20-P20 phase reversal. Stimulation

is attempted with individual contacts of the grid. Th e

goal is to locate the contact that produces motor re-

sponses in the painful area. Th e positions of the iden-

tifi ed electrodes can be marked on the corresponding

dura mater, indicating the position and orientation

for electrodes to be implanted.

According to Tsubokawa et al., the best loca-

tion and orientation of the electrode array corresponds

to the site where bipolar stimulation produces muscle

twitches in the painful area with the lowest threshold

[97]. After identifi cation of the appropriate location,

the electrode array is sutured tightly on the dural sur-

face, and the stimulation system is internalized. On the

following days, the parameters for chronic stimulation

are selected to achieve optimal pain control. Outcomes

from series in the literature indicate that positive results

can be accomplished with this method and may be long

lasting.

Sindou et al. reported the results of 127 opera-

tions from diverse published series [80]. A total of 86

patients had pain after stroke, 29 presented with tri-

geminal neuropathic pain, and 12 experienced pain of

miscellaneous origin. Pain relief of >50% was obtained

after a 1-year follow-up in two-thirds of the patients

with poststroke pain and in patients with neuropathic

trigeminal pain. In most patients, relief persisted on

long-term follow-up (1–6 years; average 2 years).

ab

Fig. 5. Radiograph showing spinal cord stimulation surgical lead electrodes in a patient with failed back surgery sydrome after spinal lumbar fusion: (a) frontal view, (b) lateral view.


A double-blind assessment of a group of pa-

tients with implanted motor cortex stimulators has

corroborated the efficacy of this method [102]. In

this study, stimulation was randomized to the off

mode for a period of 30 days at 60 or 90 days post-

implantation with active stimulation, and pain levels

were reassessed. The results indicated that pain lev-

els were significantly reduced by stimulation and sig-

nificantly increased when the stimulation was turned

off. In all series, complications were limited to occa-

sional seizures by the time intensity parameters were

adjusted. In conclusion, MCS is recommended for

treating poststroke pain and trigeminal pain of neu-

ropathic origin.

Deep Brain Stimulation

Deep brain stimulation (DBS) has been used to treat in-

tractable pain for more than 50 years. Heath and Mick-

le [30] and Pool et al. [58] reported analgesic eff ects

in patients receiving stimulation in the septal region.

By the 1970s and 1980s, thalamic and periaqueductal

gray/periventricular gray stimulation were common-

ly used for the treatment of chronic refractory pain

[32,48,63,91,98]. Th ough no proper studies comparing

the outcomes of DBS in diff erent targets have been con-

ducted, the general consensus is that neuropathic pain

is more likely to respond to stimulation of the sensory

thalamus, whereas nociceptive pain responds better to

periaqueductal gray/periventricular gray stimulation

[43]. Patients with mixed pain may be implanted with

electrodes in both structures.

In addition to these more common targets,

DBS of the internal capsule has been routinely off ered

to poststroke patients with signifi cant thalamic atro-

phy [2,40]. Other targets leading to good outcomes in

small clinical series or case reports are the septal re-

gion [67,69], medial thalamus (including the centro-

median-parafascicular nuclei) [6,66,94], and cingulate

gyrus [87]. Within the past decades, there has been

a progressive decrease in the number of published

studies and the number of patients with chronic pain

treated with DBS. Th is has been partially attributed

to the development and use of less-invasive alterna-

tives for the management of neuropathic pain includ-

ing catheters and pumps for drug administration, new

pharmacological agents, and spinal cord and motor

cortex stimulation. Despite these facts, DBS continues

to be off ered routinely to patients with chronic refrac-

tory neuropathic pain.

Boccard et al. recently reported 85 patients

who underwent DBS for chronic neuropathic pain of

diff erent etiologies, targeting the periventricular gray

area in 33 patients, the ventral posterior nuclei of the

thalamus in 15, or both in 37. Almost 70% of the pa-

tients retained implants 6 months after surgery. A to-

tal of 39 of 59 (66%) of those who retained implants

gained benefi t and effi cacy, depending on etiology,

improving outcomes by 89% for amputation pain and

70% for stroke pain [11].

Final Remarks

As John Bonica presciently expressed, we should try to

know all the therapeutic options available for pain con-

trol, even if we are not the ones who will carry out these

techniques. Functional neurosurgery provides the nec-

essary tools for those complex cases that have not found

the solution with pharmacological treatment or less-

invasive techniques. Success depends on accurate diag-

nosis, adequate patient selection, proper choice of the

technique to be used, and its correct implementation.

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Correspondence to: Prof. Fabián C. Piedimonte, MD, Presi-dent, Fundación CENIT para la Investigación en Neuro-ciencias, Juncal 2222, 5º Piso, CABA, C1125ABD Argentina. Email: [email protected].

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