neural blockade for persistent pain after breast cancer surgery

Neural Blockade for Persistent Pain After BreastCancer Surgery

Nelun Wijayasinghe, MBBS, BSc, FRCA, Kenneth G. Andersen, MD, and Henrik Kehlet, MD, PhD

Abstract: Persistent pain after breast cancer surgery is predominantly aneuropathic pain syndrome affecting 25% to 60% of patients and relatedto injury of the intercostobrachial nerve, intercostal nerves, and othernerves in the region. Neural blockade can be useful for the identificationof nerves involved in neuropathic pain syndromes or to be used as atreatment in its own right. The purpose of this review was to examinethe evidence for neural blockade as a potential diagnostic tool or treat-ment for persistent pain after breast cancer surgery. In this systematicreview, we found only 7 studies (n = 135) assessing blocks directed at3 neural structures—stellate ganglion, paravertebral plexus, and inter-costal nerves—but none focusing on the intercostobrachial nerve. Thequality of the studies was low and efficacy inconclusive, suggesting a needfor well-designed, high-quality studies for this common clinical problem.

(Reg Anesth Pain Med 2014;39: 272–278)

Persistent pain after breast cancer surgery (PPBCS) affects 25%to 60% of patients treated for breast cancer,1,2 even several

years after surgery.3 Patients develop a syndrome of pain inthe axilla, medial side of the upper arm, and breast or lateralchest wall that is predominantly neuropathic in nature.4 Persis-tent pain is defined as pain lasting more than 3 months aftersurgery.1 It can develop after all forms of breast cancer surgerysuch as mastectomy with or without axillary lymph node dissec-tion and sentinel lymph node biopsy.

Neuropathic pain has been defined as “pain arising as a directconsequence of a lesion or disease affecting the somatosensorysystem” and its grading system explains the heterogeneity of neu-ropathic pain syndromes which can be applied to PPBCS.5 Theauthors of this definition also stress the importance of discriminat-ing between a central and peripheral neuropathic pain. Identi-fication of this “lesion” may be key in determining strategiesfor diagnosis and treatment of PPBCS.

The innervation of the breast arises from the intercostalnerves T2 to T6, and during surgery, the intercostobrachialnerve (ICBN) (T2) and medial cutaneous nerve of the arm(C8-T1) are also vulnerable to damage (Fig. 1). Other nerves that

may be affected during surgery are the long thoracic, thoracodorsal,lateral, and medial pectoral, but these lead mainly to functionaldeficits. Patients treated with axillary lymph node dissectionoften report more persistent pain than patients treated with sen-tinel lymph node biopsy,1 raising suspicions of damage of theICBN as an important part of the pain pathophysiology inPPBCS and confirmed by the distribution of pain and sensoryabnormalities.6,7 However, surgical strategies to preserve theICBN and prevent the development of PPBCS have beenequivocal.8–10

The mainstay treatment for PPBCS is predominantly phar-macological. However, neural blockade is a widely used proce-dure for chronic pain conditions and can be useful for diagnosisand treatment for neuropathic pain conditions.11,12 Thus, the pur-pose of this review is to examine the available evidence for neuralblockade for PPBCS.

METHODSWe wrote our protocol per instructions in the Cochrane

handbook13 for systematic reviews of interventional studiesand using PRISMA14 guidelines. In October 2013 and March 2014,we conducted literature searches using the following databases:MEDLINE via PubMed (1809-current date), Scopus (1823-currentdate), and EMBASE (1980-current date).We used the followingMeSH terms: [breast neoplasms/surgery AND neural blockade][breast neoplasms/surgery AND intercostobrachial] [breastcancer (MAJR topic) AND surgery (MAJR topic) AND pain(MAJR topic)] [breast cancer pain AND intercostobrachialnerve] and the following keywords in all three databases:[intercostobrachial], [(intercostobrachial AND breast cancer)],[(intercostobrachial) AND (breast cancer pain)], [(intercostobrachial)AND (blockade) AND (breast)], [(medial cutaneous nerve) AND(breast pain)], [(pectoral nerves) AND (breast pain)], [(long thoracicnerve) AND (breast pain)], [(thoracodorsal nerve) AND (breastpain)], [(intercostal nerves) AND (breast pain)] [(medial cutaneousnerve block) AND (breast cancer )], [(pectoral nerve block) AND(breast cancer)], [(long thoracic nerve block) AND (breast cancer)],[(thoracodorsal nerve block) AND (breast cancer)], [(intercostalnerve block) AND (breast cancer)].The reference lists from relevantpapers were also searched.

Inclusion CriteriaWe only included studies written in English concerning

patients who had undergone breast cancer surgery, had developedpersistent pain, and received a local anesthetic block in the courseof their treatment for their pain.

Exclusion CriteriaWe excluded studies on phantom breast pain, the use of neu-

ral blockade in the perioperative period, and treatments for PPBCSthat did not target nerves (Fig. 2). The studies were graded usingthe Grades of Recommendation, Assessment, Development andEvaluation15 approach to determine the quality of the evidence.The Grades of Recommendation, Assessment, Developmentand Evaluation approach classifies studies into the following

From the Section for Surgical Pathophysiology, Rigshospitalet, University ofCopenhagen, Copenhagen, Denmark.Accepted for publication April 14, 2014.Address correspondence to: Nelun Wijayasinghe, MBBS, BSc, FRCA,

Section for Surgical Pathophysiology 4074, Rigshospitalet, Universityof Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark(e‐mail: [email protected]).

The authors declare no conflict of interest.This study was funded by a grant from the Danish Cancer Society and the study

is part of the European Collaboration, which has received support from theInnovative Medicines Initiative Joint Undertaking, under grant agreementno. 115007, resources which are composed of financial contributions fromthe European Union’s Seventh Framework Programme (FP7/2007-2013)and EFPIA companies in kind contribution.

Copyright © 2014 by American Society of Regional Anesthesia and PainMedicine

ISSN: 1098-7339DOI: 10.1097/AAP.0000000000000101

REVIEWARTICLE

272 Regional Anesthesia and Pain Medicine • Volume 39, Number 4, July-August 2014

Copyright © 2014 American Society of Regional Anesthesia and Pain Medicine. Unauthorized reproduction of this article is prohibited.

categories: high, moderate, low, or very low, depending on thetype of evidence.

RESULTS

Study Selection and CharacteristicsThe literature search yielded a total of 752 articles, of which

only 8 were eligible (Fig. 1). The large number of duplicates wasdue to the large overlap between PubMed and Scopus databases.There were no studies involving the medial cutaneous, lateral pec-toral, medial pectoral, thoracodorsal, or long thoracic nerves. Onestudy using paravertebral plexus stimulation16 was excluded as itdid not include any form of local anesthetic blockade (Fig. 1).

Thus, our searches identified 7 studies for analysis, namely,4 studies17–20 that used diagnostic nerve blocks and 3 therapeuticnerve block studies.21,22 Two of the analyzed studies also includedthoracotomy patients18,23 or abdominal surgical patients,18 butonly the breast surgery patients from these studies were analyzed.All of the diagnostic nerve blocks involved the intercostal nervesand the therapeutic nerve blocks involved 2 stellate ganglion block(SGB) studies and 1 paravertebral block (PVB) study (Table 1).

Intercostal Nerve Block StudiesAll of the 4 intercostal nerve block studies were performed in

case series (n = 15) and 8 (53%) of 15 patients had complete pain

relief from the local anesthetic blockade.17–20 All 4 studies usedthe block to aid the course of further treatment that consisted of3 surgical treatments17,18,20 and 1 neurolytic treatment.19 The in-sufficient design, heterogeneity of pain evaluation, and lack ofcontrol groups in these studies made statistical analysis and con-clusions impossible (Table 1).

SGB StudiesThe 2 SGB studies21,22 showed statistically significant re-

ductions in pain scores for up to 3 months after the blocks, but8 (11%) of 75 patients were nonresponders to the block (Table 1).However, gabapentin provided better pain relief (reduction innumerical rating scale) than SGB in 1 study.21 The low qualityof the studies, with lack of appropriate control group and blindingof investigators impedes sufficient interpretation.

PVB StudyIn the PVB study,23 2 (20%) of 10 patients were pain-free

after 5 months. Interpretation of this study is hindered by incon-sistent number of blocks in each patient, lack of control, and in-sufficient blinding of investigators (Table 1).

DISCUSSIONThis review demonstrates a lack of high-quality research into

neural blockade in PPBCS which is predominantly a “neuropathic

FIGURE 1. Innervation of the breast and location of the nerves at risk during breast cancer surgery. ICBN indicates intercostobrachialnerve (sensory only); II-VI, intercostal nerves 2 to 6, lateral cutaneous branches (sensory only); LPN, lateral pectoral nerve (mixed sensory andmotor); LTN, long thoracic nerve (motor only); MCN, medial cutaneous nerve of the arm (sensory only); MPN, medial pectoral nerve(mixed sensory and motor); TDN, thoracodorsal nerve (motor only).

Regional Anesthesia and Pain Medicine • Volume 39, Number 4, July-August 2014 Nerve Blocks for PPBCS

© 2014 American Society of Regional Anesthesia and Pain Medicine 273


pain syndrome.”1,4 Thus, most (4 of 7) studies were small caseseries of 5 patients or less,17–20 1 retrospective study (10 patients)23

and only 2 randomized but not placebo-controlled trials(110 patients).21,22 None of the studies was investigator-blinded.Three studies had unclear pain assessments.17,18,23 The use ofgrading scales places this evidence as low to very low quality.15

No study specifically addressed the potential for blockade ofthe ICBN, despite the high probability of this nerve’s involvementin the development of PPBCS.1,8,9 Finally, there was a surprisinglack of studies of diagnostic and/or therapeutic local anestheticperipheral nerve blocks, in contrast to the common use in otherpain conditions24 and in relation to the general acceptance ofthe clinical importance of PPBCS.

Local anesthetic injection could potentially be used as a diag-nostic tool, as seen in 4 of the studies in our review, for assessingthe suitability of different treatments.17–20 Thus, positive responseto local anesthetic injection of the intercostal nerves was a neces-sary criterion for the diagnosis of neuroma17,20 and nerve entrap-ment18 as well as identification of the paravertebral nerves forradiofrequency ablation,19 and interestingly, each study had a dif-ferent level of response to the local anesthetic. These 4 caseseries17–20 represent the only data that we could find in the litera-ture of diagnostic blocks in PPBCS, thereby challenging the valueof a diagnostic neural blockade in the characterization of PPBCSas well as suitability for neurectomy or neurolysis.

The use of the SGB for the treatment of neuropathic painconditions of the arm is not a new concept25 but for PPBCS wefound only 2 studies with this block.21,22 However, the rationalefor the use of SGB is unclear with respect to the anatomy ofPPBCS as these studies state that 80% to 100% of patients withPPBCS had damage to the ICBN,21,22 which originates from thesecond intercostal nerve. But, the stellate ganglion encompasseslower cervical roots and the first thoracic root, hence questioningthe rationale for SGB. Interestingly, gabapentin gave a better anal-gesic response when compared to SGB.21

Surprisingly, there was only 1 therapeutic study of PVBs forPPBCS,23 whereas the rationale for these blocks is sound and therisk profile is similar to SGBs. A high proportion of blocks (88%)provided good initial pain relief, but unfortunately this was a ret-rospective study with insufficient study design.23 Nevertheless,the positive data from trials with “preventive” PVBs on develop-ment of PPBCS after breast surgery26 emphasize the need for fur-ther studies with a randomized, placebo-controlled design.

Although chronic pain practitioners may use peripheralnerve blockade in their practice as part of their treatment re-gimens, we could not find any studies supporting this practice inPPBCS or high-quality studies in other types of persistent postop-erative pain.24,27 Vlassakov et al24 found 12 studies of differentperipheral nerve blockades in chronic pain conditions and allshowed convincing results in terms of greater than 50% pain reliefand pain relief that outlasted the conduction block of the local an-esthetic. Again, these were small case series and none of thesestudies were placebo-controlled, thereby limiting any firm con-clusions as to the usefulness of these treatments. The importanceof using placebo can be seen in a well-designed randomized,placebo-controlled, double-blinded crossover trial examining theeffects of peripheral nerve blockade in postherniotomy painpatients.28 The results showed the same pain response after pla-cebo comparedwith after local anesthetic blockade and also founda high proportion (5 of 12) of patients were placebo responders,casting doubt on much of the previous research on peripheralnerve blockade.

It is generally assumed that ICBN injury may contribute toPPBCS, especially in axillary dissection.1,8,9 It is therefore sur-prising that no specific ICBN blockade study is available in the lit-erature. No studies assessing the role of the medial cutaneousnerve in PPBCS were found despite its vulnerable location inthe axilla. The same is true for the other nerves that are poten-tially at risk; we did not find any studies looking at the thora-codorsal, medial pectoral, lateral pectoral, or long thoracic nerves

FIGURE 2. Flow of information for nerve blockade for PPBCS.

Wijayasinghe et al Regional Anesthesia and Pain Medicine • Volume 39, Number 4, July-August 2014

274 © 2014 American Society of Regional Anesthesia and Pain Medicine


TABL

E1.

Nerve

Bloc

kStud

iesin

PPBC

S

Block

Stud

yAutho

ran

dYe

arStud

yDescriptio

nLAUsed

Outcomean

dPurpo

seof

Blockad

eCom

ments

Diagnostic

blocks

Intercostal

nerveblock

Wong1

72001

Caseseries:5postmastectom

ypatientsundergoing

neurom

aresection

Lidocaine

1%at

siteof

Tinelsign

Allptshadcompletepain

relief.

Thisprovided

confirm

ation

asacandidateforsurgery

Weaknesses

1patient

developedpain

inthe

region

oftheICBNafter

surgerybutp

tswith

ICBN

involvem

entw

eresupposed

tobe

excluded

Pain

evaluatio

nnotd

escribed

Nopain

scores

presented

Smalln

umberof

patients

Nocontrolg

roup

Noblinding

ofinvestigators

Qualityof

evidence:v

erylow

DucicandLarson1

82006

Caseseries:4patientsafter

breastsurgeryundergoing

surgicalreleaseof

nerves

undertension;

3patientshad

previous

surgeryforbreast

cancer

and1mastopexy

Lidocaine

1%“around”

branch

ofintercostal

nerve

Allpatientshadatleast

50%

reliefof

symptom

s.Thisresponse

was

used

toidentifythenerves

forsurgery

Weaknesses

The

specificsymptom

salleviated

byLAnotdescribed

Pain

scores

notp

resented

Heterogeneous

groupof

patients

Smalln

o.patients

Noblinding

ofinvestigators

Nocontrolg

roup

Qualityof

evidence:v

erylow

Uchida1

92009

Caseseries:3postmastectom

ypatientsundergoing

radiofrequency

ablation

tothoracicparavertebral

nerves

multiplelevels

LAnotstated.Intercostal

nerveblock

Allpatientshadatemporary

response:>

80%

pain

relief

with

LA.T

hisresponse

was

used

toidentifythelevelsfor

radiofrequency

ablatio

n

Strengths

Pain

assessmentd

escribed

Neuropathiccomponentsof

pain

assessed

Weaknesses

Glucocorticoids

addedto

LAinjection

Temporary

response

notd

efined

Smalln

o.patients

Noblinding

ofinvestigators

Nocontrolg

roup

Qualityof

evidence:v

erylow

(Contin

uednextpage)




TABL

E1.

(Con

tinued) Block

Stud

yAutho

ran

dYe

arStud

yDescriptio

nLAUsed

Outcomean

dPurpo

seof

Blockad

eCom

ments

Nguyenetal20

2012

Caseseries:3postbreast

surgerypatients

undergoing

neurom

aresectionsurgery.

Pt1haddouble

mastectom

y+im

plants

but1

-sided

breast

pain.P

t2hadbreast

augm

entatio

nand

bilateraln

euromas.

Pt3hadbreast

augm

entatio

nand

single-sided

neurom

a

Pt1:

Lidocaine

1%injected

into

tender

point.

Pt2and3:

LAinjected

into

tender

points.

LAnotstated

Allpatientshadcomplete

pain

relief.Thisresponse

confirmed

thediagnosis

ofaneurom

a

Pt3developedbilateralsubareolar

pain

andtheim

plantswere

removed

Strengths

Pain

scores

Pain

descrip

tion

Weaknesses

LAnotstatedin

2of

3patients

Heterogeneous

groupof

patients

Smalln

o.patients

Noblinding

ofinvestigators

Nocontrolg

roup

Qualityof

evidence:v

erylow

Therapeuticblocks

SGB

Hoseinzadeetal21

2008

Randomized

trialof

60patients.All

patientshadbreast

cancer

surgery.

Com

parison

ofSG

Bwith

gabapentin

SGB

every5d(m

ax5blocks

perpt)

8mL0.25%

bupivacaine

NRSreducedfrom

7.46

(1.07)to1.73

(1.59)

butgreaterreductionin

NRSwith

gabapentin:

7.40

(0.85)to0.53

(0.50)

after3

mo;5ptsw

ere

nonresponders(ie,had

nopainrelieffromthe

block);5

ptsh

ad“incom

pletepainrelief”

(seeweaknesses)

Strengths

Randomized

study

Pain

scores

Neuropathiccomponents

ofpain

assessed

Strictinclusion

criteria

Weaknesses

Inconsistentno.blocksp

erpt

Noplacebocontrolg

roup

Noblinding

ofinvestigators

Definition

ofincomplete

pain

reliefwas

not

describ

edQualityof

evidence:low

NabilAbbas

etal22

2011

Randomized

trialof

50postmastectom

ypatients.Com

parison

of2differentapproaches

ofthesameblock.To

tal

of191SG

Bs:4on

each

patient

at1-wkintervals;

25ptsclassicapproach;

25ptsobliq

ueapproach

5mL0.25%

bupivacaine

3ptswerenonresponders

(ie,had

nopain

relief

afterthefirstb

lock)

andwerewith

draw

nfrom

thestudy.47

pts

had>5

0%reductionin

pain

onVASafter3mo

Thisstudyexam

ined

the

difference

betweenthe

2techniques

ofSG

Band

notthe

block’sefficacy

Strengths

Randomized

study

Pain

scores

Allo

dyniaassessed

Ptsatisfactionscores

Weaknesses

Noplacebocontrolg

roup

Noblinding

ofinvestigators




in PPBCS. The intercostal nerves contribute to pain in the breast29

as opposed to pain in the axilla and arm that is more commonlyseen in PPBCS. Therefore, thorough assessment of patients is cru-cial to identify the potential nerves involved to administer the ap-propriate block.

The main limitation of this review is that the studies analyzedwere of low quality due to unsystematic study design despite thecommon problem of PPBCS. Although the studies included inthis review demonstrated a high proportion of positive results,this could be due to publication bias where positive findings arepublished more often than negative ones.30 Further research onthe usefulness of diagnostic or therapeutic neural blockade ofPPBCS should be conducted in double-blind, randomized, con-trolled studies. Because several risk factors for the develop-ment of PPBCS have been identified1,9,31 and should be controlledfor, the variation in patient characteristics will render studieswith small numbers difficult to interpret. Finally, pain charac-terization should be done using recommendations according tothe IMMPACT criteria32 and including procedure-specific mea-surements of pain-related functional impairment.

In conclusion, this systematic review highlights the sparseclinical data of nerve blockade in PPBCS despite being predomi-nantly a “neuropathic pain” condition. Although injury to theICBN is an important pathogenic factor in PPBCS, no studiesare available aiming at blocking this nerve. Because PPBCS isclinically important, well-designed, placebo-controlled nerve blockstudies are warranted.

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