Neural blockade for persistent pain after breast cancer surgery

1. Neural Blockade for Persistent Pain After Breast
Cancer Surgery
Nelun Wijayasinghe, MBBS, BSc, FRCA, Kenneth G. Andersen, MD, and Henrik Kehlet, MD, PhD
Abstract: Persistent pain after breast cancer surgery is predominantly a
neuropathic pain syndrome affecting 25% to 60% of patients and related
to injury of the intercostobrachial nerve, intercostal nerves, and other
nerves in the region. Neural blockade can be useful for the identification
of nerves involved in neuropathic pain syndromes or to be used as a
treatment in its own right. The purpose of this review was to examine
the evidence for neural blockade as a potential diagnostic tool or treat-
ment for persistent pain after breast cancer surgery. In this systematic
review, we found only 7 studies (n = 135) assessing blocks directed at
3 neural structures—stellate ganglion, paravertebral plexus, and inter-
costal nerves—but none focusing on the intercostobrachial nerve. The
quality of the studies was low and efficacy inconclusive, suggesting a need
for 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 in
the axilla, medial side of the upper arm, and breast or lateral
chest wall that is predominantly neuropathic in nature.4
Persis-
tent pain is defined as pain lasting more than 3 months after
surgery.1
It can develop after all forms of breast cancer surgery
such 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 direct
consequence of a lesion or disease affecting the somatosensory
system” and its grading system explains the heterogeneity of neu-
ropathic pain syndromes which can be applied to PPBCS.5
The
authors 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 strategies
for diagnosis and treatment of PPBCS.
The innervation of the breast arises from the intercostal
nerves T2 to T6, and during surgery, the intercostobrachial
nerve (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 functional
deficits. Patients treated with axillary lymph node dissection
often report more persistent pain than patients treated with sen-
tinel lymph node biopsy,1
raising suspicions of damage of the
ICBN as an important part of the pain pathophysiology in
PPBCS and confirmed by the distribution of pain and sensory
abnormalities.6,7
However, surgical strategies to preserve the
ICBN and prevent the development of PPBCS have been
equivocal.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 diagnosis
and treatment for neuropathic pain conditions.11,12
Thus, the pur-
pose of this review is to examine the available evidence for neural
blockade for PPBCS.
METHODS
We wrote our protocol per instructions in the Cochrane
handbook13
for systematic reviews of interventional studies
and 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-current
date), and EMBASE (1980-current date). We used the following
MeSH terms: [breast neoplasms/surgery AND neural blockade]
[breast neoplasms/surgery AND intercostobrachial] [breast
cancer (MAJR topic) AND surgery (MAJR topic) AND pain
(MAJR topic)] [breast cancer pain AND intercostobrachial
nerve] 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 thoracic
nerve) AND (breast pain)], [(thoracodorsal nerve) AND (breast
pain)], [(intercostal nerves) AND (breast pain)] [(medial cutaneous
nerve block) AND (breast cancer )], [(pectoral nerve block) AND
(breast cancer)], [(long thoracic nerve block) AND (breast cancer)],
[(thoracodorsal nerve block) AND (breast cancer)], [(intercostal
nerve block) AND (breast cancer)].The reference lists from relevant
papers were also searched.
Inclusion Criteria
We only included studies written in English concerning
patients who had undergone breast cancer surgery, had developed
persistent pain, and received a local anesthetic block in the course
of their treatment for their pain.
Exclusion Criteria
We excluded studies on phantom breast pain, the use of neu-
ral blockade in the perioperative period, and treatments for PPBCS
that did not target nerves (Fig. 2). The studies were graded using
the Grades of Recommendation, Assessment, Development and
Evaluation15
approach to determine the quality of the evidence.
The Grades of Recommendation, Assessment, Development
and Evaluation approach classifies studies into the following
From the Section for Surgical Pathophysiology, Rigshospitalet, University of
Copenhagen, Copenhagen, Denmark.
Accepted for publication April 14, 2014.
Address correspondence to: Nelun Wijayasinghe, MBBS, BSc, FRCA,
Section for Surgical Pathophysiology 4074, Rigshospitalet, University
of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
(e‐mail: nelun.wijayasinghe@regionh.dk).
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 the
Innovative Medicines Initiative Joint Undertaking, under grant agreement
no. 115007, resources which are composed of financial contributions from
the European Union’s Seventh Framework Programme (FP7/2007-2013)
and EFPIA companies in kind contribution.
Copyright © 2014 by American Society of Regional Anesthesia and Pain
Medicine
ISSN: 1098-7339
DOI: 10.1097/AAP.0000000000000101
REVIEW ARTICLE
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.

2. categories: high, moderate, low, or very low, depending on the
type of evidence.
RESULTS
Study Selection and Characteristics
The literature search yielded a total of 752 articles, of which
only 8 were eligible (Fig. 1). The large number of duplicates was
due 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. One
study using paravertebral plexus stimulation16
was excluded as it
did 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 therapeutic
nerve block studies.21,22
Two of the analyzed studies also included
thoracotomy patients18,23
or abdominal surgical patients,18
but
only the breast surgery patients from these studies were analyzed.
All of the diagnostic nerve blocks involved the intercostal nerves
and the therapeutic nerve blocks involved 2 stellate ganglion block
(SGB) studies and 1 paravertebral block (PVB) study (Table 1).
Intercostal Nerve Block Studies
All 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 used
the block to aid the course of further treatment that consisted of
3 surgical treatments17,18,20
and 1 neurolytic treatment.19
The in-
sufficient design, heterogeneity of pain evaluation, and lack of
control groups in these studies made statistical analysis and con-
clusions impossible (Table 1).
SGB Studies
The 2 SGB studies21,22
showed statistically significant re-
ductions in pain scores for up to 3 months after the blocks, but
8 (11%) of 75 patients were nonresponders to the block (Table 1).
However, gabapentin provided better pain relief (reduction in
numerical rating scale) than SGB in 1 study.21
The low quality
of the studies, with lack of appropriate control group and blinding
of investigators impedes sufficient interpretation.
PVB Study
In 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).
DISCUSSION
This 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 intercostobrachial
nerve (sensory only); II-VI, intercostal nerves 2 to 6, lateral cutaneous branches (sensory only); LPN, lateral pectoral nerve (mixed sensory and
motor); 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
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3. pain syndrome.”1,4
Thus, most (4 of 7) studies were small case
series 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 of
grading scales places this evidence as low to very low quality.15
No study specifically addressed the potential for blockade of
the ICBN, despite the high probability of this nerve’s involvement
in the development of PPBCS.1,8,9
Finally, there was a surprising
lack of studies of diagnostic and/or therapeutic local anesthetic
peripheral nerve blocks, in contrast to the common use in other
pain conditions24
and in relation to the general acceptance of
the 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 assessing
the suitability of different treatments.17–20
Thus, positive response
to 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 for
radiofrequency ablation,19
and interestingly, each study had a dif-
ferent level of response to the local anesthetic. These 4 case
series17–20
represent the only data that we could find in the litera-
ture of diagnostic blocks in PPBCS, thereby challenging the value
of a diagnostic neural blockade in the characterization of PPBCS
as well as suitability for neurectomy or neurolysis.
The use of the SGB for the treatment of neuropathic pain
conditions of the arm is not a new concept25
but for PPBCS we
found only 2 studies with this block.21,22
However, the rationale
for the use of SGB is unclear with respect to the anatomy of
PPBCS as these studies state that 80% to 100% of patients with
PPBCS had damage to the ICBN,21,22
which originates from the
second intercostal nerve. But, the stellate ganglion encompasses
lower cervical roots and the first thoracic root, hence questioning
the 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 for
PPBCS,23 whereas the rationale for these blocks is sound and the
risk 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 peripheral
nerve blockade in their practice as part of their treatment re-
gimens, we could not find any studies supporting this practice in
PPBCS or high-quality studies in other types of persistent postop-
erative pain.24,27
Vlassakov et al24
found 12 studies of different
peripheral nerve blockades in chronic pain conditions and all
showed convincing results in terms of greater than 50% pain relief
and pain relief that outlasted the conduction block of the local an-
esthetic. Again, these were small case series and none of these
studies were placebo-controlled, thereby limiting any firm con-
clusions as to the usefulness of these treatments. The importance
of using placebo can be seen in a well-designed randomized,
placebo-controlled, double-blinded crossover trial examining the
effects of peripheral nerve blockade in postherniotomy pain
patients.28
The results showed the same pain response after pla-
cebo compared with after local anesthetic blockade and also found
a high proportion (5 of 12) of patients were placebo responders,
casting doubt on much of the previous research on peripheral
nerve blockade.
It is generally assumed that ICBN injury may contribute to
PPBCS, 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 cutaneous
nerve in PPBCS were found despite its vulnerable location in
the 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
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4. TABLE1.NerveBlockStudiesinPPBCS
BlockStudyAuthorandYearStudyDescriptionLAUsedOutcomeandPurposeofBlockadeComments
DiagnosticblocksIntercostal
nerveblock
Wong17
2001Caseseries:5postmastectomy
patientsundergoing
neuromaresection
Lidocaine1%at
siteofTinelsign
Allptshadcompletepainrelief.
Thisprovidedconfirmation
asacandidateforsurgery
Weaknesses
1patientdevelopedpaininthe
regionoftheICBNafter
surgerybutptswithICBN
involvementweresupposed
tobeexcluded
Painevaluationnotdescribed
Nopainscorespresented
Smallnumberofpatients
Nocontrolgroup
Noblindingofinvestigators
Qualityofevidence:verylow
DucicandLarson18
2006Caseseries:4patientsafter
breastsurgeryundergoing
surgicalreleaseofnerves
undertension;3patientshad
previoussurgeryforbreast
cancerand1mastopexy
Lidocaine1%“around”
branchofintercostal
nerve
Allpatientshadatleast
50%reliefofsymptoms.
Thisresponsewasused
toidentifythenerves
forsurgery
Weaknesses
Thespecificsymptoms
alleviatedbyLAnotdescribed
Painscoresnotpresented
Heterogeneousgroupofpatients
Smallno.patients
Noblindingofinvestigators
Nocontrolgroup
Qualityofevidence:verylow
Uchida19
2009Caseseries:3postmastectomy
patientsundergoing
radiofrequencyablation
tothoracicparavertebral
nervesmultiplelevels
LAnotstated.Intercostal
nerveblock
Allpatientshadatemporary
response:>80%painrelief
withLA.Thisresponsewas
usedtoidentifythelevelsfor
radiofrequencyablation
Strengths
Painassessmentdescribed
Neuropathiccomponentsof
painassessed
Weaknesses
Glucocorticoidsaddedto
LAinjection
Temporaryresponsenotdefined
Smallno.patients
Noblindingofinvestigators
Nocontrolgroup
Qualityofevidence:verylow
(Continuednextpage)
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5. TABLE1.(Continued)
BlockStudyAuthorandYearStudyDescriptionLAUsedOutcomeandPurposeofBlockadeComments
Nguyenetal20
2012
Caseseries:3postbreast
surgerypatients
undergoingneuroma
resectionsurgery.
Pt1haddouble
mastectomy+implants
but1-sidedbreast
pain.Pt2hadbreast
augmentationand
bilateralneuromas.
Pt3hadbreast
augmentationand
single-sidedneuroma
Pt1:Lidocaine
1%injected
intotender
point.Pt2and3:
LAinjectedinto
tenderpoints.
LAnotstated
Allpatientshadcomplete
painrelief.Thisresponse
confirmedthediagnosis
ofaneuroma
Pt3developedbilateralsubareolar
painandtheimplantswere
removed
Strengths
Painscores
Paindescription
Weaknesses
LAnotstatedin2of3patients
Heterogeneousgroupofpatients
Smallno.patients
Noblindingofinvestigators
Nocontrolgroup
Qualityofevidence:verylow
TherapeuticblocksSGBHoseinzadeetal21
2008
Randomizedtrialof
60patients.All
patientshadbreast
cancersurgery.
ComparisonofSGB
withgabapentinSGB
every5d(max
5blocksperpt)
8mL0.25%bupivacaineNRSreducedfrom
7.46(1.07)to1.73(1.59)
butgreaterreductionin
NRSwithgabapentin:
7.40(0.85)to0.53(0.50)
after3mo;5ptswere
nonresponders(ie,had
nopainrelieffromthe
block);5ptshad
“incompletepainrelief”
(seeweaknesses)
Strengths
Randomizedstudy
Painscores
Neuropathiccomponents
ofpainassessed
Strictinclusioncriteria
Weaknesses
Inconsistentno.blocksperpt
Noplacebocontrolgroup
Noblindingofinvestigators
Definitionofincomplete
painreliefwasnot
described
Qualityofevidence:low
NabilAbbasetal22
2011
Randomizedtrialof
50postmastectomy
patients.Comparison
of2differentapproaches
ofthesameblock.Total
of191SGBs:4oneach
patientat1-wkintervals;
25ptsclassicapproach;
25ptsobliqueapproach
5mL0.25%bupivacaine3ptswerenonresponders
(ie,hadnopainrelief
afterthefirstblock)
andwerewithdrawn
fromthestudy.47pts
had>50%reductionin
painonVASafter3mo
Thisstudyexaminedthe
differencebetweenthe
2techniquesofSGBand
nottheblock’sefficacy
Strengths
Randomizedstudy
Painscores
Allodyniaassessed
Ptsatisfactionscores
Weaknesses
Noplacebocontrolgroup
Noblindingofinvestigators
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6. in PPBCS. The intercostal nerves contribute to pain in the breast29
as opposed to pain in the axilla and arm that is more commonly
seen 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 analyzed
were of low quality due to unsystematic study design despite the
common problem of PPBCS. Although the studies included in
this review demonstrated a high proportion of positive results,
this could be due to publication bias where positive findings are
published more often than negative ones.30
Further research on
the usefulness of diagnostic or therapeutic neural blockade of
PPBCS 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 controlled
for, the variation in patient characteristics will render studies
with small numbers difficult to interpret. Finally, pain charac-
terization should be done using recommendations according to
the IMMPACT criteria32
and including procedure-specific mea-
surements of pain-related functional impairment.
In conclusion, this systematic review highlights the sparse
clinical data of nerve blockade in PPBCS despite being predomi-
nantly a “neuropathic pain” condition. Although injury to the
ICBN is an important pathogenic factor in PPBCS, no studies
are available aiming at blocking this nerve. Because PPBCS is
clinically important, well-designed, placebo-controlled nerve block
studies are warranted.
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278 © 2014 American Society of Regional Anesthesia and Pain Medicine
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