British Journal of Anaesthesia, 117 (S2): ii95ii106 (2016)

doi: 10.1093/bja/aew212
Special Issue

Pain management in patients with vascular disease

M. Seretny and L. A. Colvin*
Department of Anaesthesia, Critical Care and Pain Medicine, University of Edinburgh, Western General Hospital,
Crewe Road, Edinburgh EH4 2XU, UK
*Corresponding author: E-mail: lesley.colvin@ed.ac.uk

Downloaded from http://bja.oxfordjournals.org/ by guest on September 9, 2016

Abstract
Vascular disease covers a wide range of conditions, including arterial, venous, and lymphatic disorders, with many of these
being more common in the elderly. As the population ages, the incidence of vascular disease will increase, with a consequent
increase in the requirement to manage both acute and chronic pain in this patient population. Pain management can be
complex, as there are often multiple co-morbidities to be considered. An understanding of the underlying pain mechanisms is
helpful in the logical direction of treatment, particularly in chronic pain states, such as phantom limb pain or complex regional
pain syndrome. Acute pain management for vascular surgery presents a number of challenges, including coexisting
anticoagulant medication, that may preclude the use of regional techniques. Within the limited evidence base, there is a
suggestion that epidural analgesia provides better pain relief and reduced respiratory complications after major vascular
surgery. For carotid endarterectomy, there is again some evidence supporting the use of local anaesthetic analgesia, either by
inltration or by supercial cervical plexus block. Chronic pain in vascular disease includes post-amputation pain, for which
well-known risk factors include high pain levels before amputation and in the immediate postoperative period, emphasizing
the importance of good pain control in the perioperative period. Complex regional pain syndrome is another challenging
chronic pain syndrome with a wide variety of treatment options available, with the strongest evidence being for physical
therapies. Further research is required to gain a better understanding of the underlying pathophysiological mechanisms in pain
associated with vascular disease and the best analgesic approaches to manage it.

Key words: acute pain; chronic pain; vascular; peripheral arterial disease; vascular diseases; vascular surgical procedures

Editors key points Vascular disease refers to a complex and diverse range of disease
entities that include arterial disease [ peripheral arterial disease
Pain associated with severe vascular disease can be the re-
(PAD), renal arterial disease, and aneurysms], venous disease (in-
sult of a combination of nociceptive, inammatory, and
cluding varicose veins and thromboembolic disease), lymphatic
neuropathic mechanisms.
disease, Buergers disease, and Raynauds phenomenon (Table 1).
Cross-talk between sensory neurones and the sympathetic
Although cardiac disease is a major contributor to morbidity and
nervous system (sympatheticafferent coupling) may con-
mortality, for the purposes of this review, pain will be considered
tribute to the pain of vascular disease.
in the context of patients with vascular disease managed for
There is no clear evidence that the choice of intraoperative
non-cardiac vascular problems.
or postoperative analgesic technique in patients undergo-
Pain is a key feature of vascular disease, with a major impact
ing amputation impacts on long-term outcome.
on quality of life and function.2628 Pre-existing chronic pain and
Pre-emptive analgesic strategies may reduce the emer-
multiple associated co-morbidities, such as impaired renal func-
gence of chronic pain states in patients with severe periph-
tion, obesity, diabetes mellitus, cognitive impairment, and is-
eral vascular disease.
chaemic heart disease, often complicate pain management in

Accepted: May 4, 2016

The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: journals.permissions@oup.com

ii95
ii96 | Seretny and Colvin

Table 1 Diseases included in the umbrella term vascular disease. Please note that renal artery disease, thromboembolic disease, lymphatic
disease, Buergers disease, Raynauds phenomenon, and in some instances, sickle cell crisis are also associated with the vasculature but are
most frequently managed by physicians and are beyond the scope of this review

Disease Prevalence Summary of pathological Postulated pain Related

process mechanisms involved references

Peripheral artery disease 12% of general population Atherosclerotic occlusion of Nociceptive (early) 16
peripheral arteries, leading Ischaemic (late)
to tissue ischaemia Neuropathic (late)

Aortic aneurysms Dependent on location, age, Dilatation affecting all three Nociceptive 79
and sex. Abdominal aortic layers of the vascular wall.
aneurysms: 25/100 000 Caused by degeneration of
men and 12/100 000 elastic laminae and
women leucocyte inltration,
leading to smooth muscle
cell loss. Likely to be
secondary to atherosclerosis
(except in familial

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instances)

Carotid artery disease Dependent on age and Atherosclerotic plaques, Usually pain free 10 11
location; 20% prevalence leading to occlusion of Nociceptive (after surgery)
of non-stenosing plaques vessel lumen
in common carotid

Varicose veins Dependent on age and sex. Valvular insufciency in Nociceptive 12 13

Overall 16% supercial veins, leading to Inammatory
increased pressure and Ischaemic
dilatation. Possible genetic
component shown in twin
studies

Chronic regional pain 20/100 000 Minor peripheral damage, Neuropathic (with or without 1417
syndrome leading to peripheral autonomic involvement)
sensitization, Inammatory
inammation, changes in
muscle and bone, and
eventual central
sensitization and shift to
facilitation in descending
pain modulation

Thoracic outlet Unclear Compression of veins (2%), Ischaemic 1820

syndrome arteries (1%), and brachial Neuropathic
plexus (95%) passing
through thoracic outlet

Phantom limb and 5080% of amputees Transection of nerve(s) at Neuropathic (with or without 2125
stump pain amputation leads to axonal autonomic involvement)
sprouting and changed
peripheral responses to
stimuli, neuroma formation,
sympathetic afferent
coupling, and peripheral,
and eventually, central
sensitization

this patient group. Many vascular disease patients have had re-
current hospital admissions and multiple surgeries. Uncon-
trolled pain, acute or chronic, will result in pathophysiological
changes, including an increased stress response and activation
of the autonomic system, which may be particularly detrimental
in patients with vascular disease.2932
The mechanisms of pain applicable to vascular disease pa-
tients are multifaceted and incompletely understood. Knowledge
of these processes is important to guide effective, targeted pain
management, including a multimodal approach to analgesia.3336
We provide a summary of the pain mechanisms important in
vascular disease, followed by an outline of the management of
pain in the various contexts of vascular disease.
Pain mechanisms relevant to vascular disease
A complex range of mechanisms underpins pain in patients with
vascular disease. Nociceptive, inammatory, and neuropathic

mechanisms may all occur. Recognition of the predominant
pathophysiological process driving pain in individual vascular
disease patients is essential for successful pain management, be-
cause the varied mechanisms warrant specic approaches to an-
algesic choice.21
Nociceptive pain
Nociceptive pain occurs after thermal, chemical, or mechanical
stimulation of peripheral nociceptors on unmyelinated C bres
or small, myelinated A bres.37 It constitutes a physiological re-
sponse to real or threatened non-neuronal tissue damage and re-
ects normal adaptive functioning of the somatosensory
nervous system. It is typically a reversible type of pain that sub-
sides when the insult is removed.10 In vascular patients, nocicep-
tive pain is a key component of intermittent claudication ( pain
and cramping after repeated muscle action or exercise).1 A
range of peripheral receptors (ion channels and G-protein-
coupled receptors) found on A and C bres is involved in the
generation of nociceptive pain. These include acid-sensing ion
channels, responsive to calcium, and the transient receptor po-
tential (TRP) channel family.38 The acid-sensing ion channels
are important in the initial pain response, but are also key in con-
version to chronic pain states, and may therefore serve as targets
for analgesic drug development.39
Inammatory pain
This type of pain constitutes the response of the somatosensory
nervous system to tissue damage and inammation. In the per-
iphery, increased inammatory mediators, such as cytokines
and chemokines, sensitize local nociceptors, lowering their
threshold for responsiveness ( peripheral sensitization).37 40
This increased responsiveness results in potential stimulation
of pain pathways after innocuous input and in exaggerated re-
sponses to noxious stimulation.
Pain modulated by the inammatory response involves acti-
vation of a number of receptors and ion channels, with interac-
tions between peripheral immune cells, alterations in local
blood ow, and changes in the chemical and electrical activity
of the peripheral afferent neurones (Fig. 1).
The plasticity that underpins these changes is rapid (occur-
ring in minutes) and is an almost inevitable consequence of sur-
gery and tissue trauma. This upregulation of nociception should
normally resolve as wound healing occurs. Maladaptive re-
sponses, including inadequate resolution of these changes after
inammation, are likely to be central to conversion from acute to
chronic pain states.42
Neuropathic pain
Pain resulting from a lesion or disease of the somatosensory ner-
vous system is termed neuropathic.37 The lesion may occur at the
molecular, cellular, or tissue level and impact on function and
structure of the somatosensory nervous system. The result is a
combination of sensory loss and increased responsiveness to
both noxious and innocuous stimuli.40 Positive phenomena,
such as allodynia ( pain after non-painful stimuli), hyperalgesia
(heightened pain after painful stimuli), and hyperpathia (an
eruptive pain extending beyond the duration of a stimulus), are
common clinical features of neuropathic pain.37 In vascular pa-
tients, neuropathic mechanisms may underpin much of the
chronicity in pain presentations. In particular, neuropathic pain
is a key component in critical limb ischaemia, the associated
Managing pain in vascular disease | ii97
ischaemic pain, and the persistent pain that may occur after
surgery.10 43 There are characteristic changes in neuropathic
pain, which include alterations in ion channels, G-protein-
coupled receptors, neurotransmitters, and central activation
(Fig. 2).22 23 44 45
Involvement of the autonomic nervous system
in neuropathic pain
In normal conditions, there is no cross-talk between the sympa-
thetic nervous system and primary sensory neurones. During
conversion to chronic pain, the two systems can become asso-
ciated in a process known as sympatheticafferent coupling.24
The mechanisms thought to play a role in sympatheticafferent
coupling include the expression of adrenergic receptors on affer-
ent nociceptive neurones, sprouting of sympathetic axons into
dorsal root ganglia, and increased local inammatory mediators
(e.g. interleukin-8) maintained by sympathetically induced local
vasoconstriction that causes nociceptor activation and sensitiza-
tion.4648 Sympatheticafferent coupling can induce central sen-
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sitization, which is the increased responsiveness of brain and
spinal cord nociceptive neurones to normal or subthreshold af-
ferent input.37 Alterations in the sympathetic nervous system
are central to complex regional pain syndrome (CRPS), with
clear changes in vascular reactivity, and may also be important
in phantom limb pain (PLP).14 24
Pain in the acute vascular (surgical) setting
Vascular surgery entails a broad range of procedures varying
from day-case varicose vein surgery to complex open abdominal
aortic aneurysm (AAA) repair. The associated morbidity ranges
from negligible to 2.4% for elective infrarenal AAA repair and
50% for emergency ruptured AAA surgery.49 Pain management
options in some surgeries may be limited by the use of anticoagu-
lant medication. Below, we present pain management considera-
tions and evidence-based treatment options for key vascular
procedures, focusing on areas where pain management may be
challenging.
Aortic aneurysm repair
Aortic aneurysm repair may be elective or emergency, involve
the abdominal or thoracic cavity or both, and be either open
or endovascular (EVAR). Acute aortic syndromes usually present
with pain, with an increasing incidence in the last decade. 50
Mortality and long-term survival rates have been robustly stud-
ied in terms of open repair vs EVAR.5153 Pain was not included
as an outcome of interest in any of these large well-designed
trials.
Three smaller studies from the same period investigated bod-
ily pain as part of quality-of-life assessments after aortic aneur-
ysm repair (Table 2).5456 These studies suggested that apart from
a more rapid postoperative return to baseline quality-of-life
scores, EVAR had no longer-term advantage over open repair in
terms of pain. A more recent study investigating long-term qual-
ity of life in 171 postoperative AAA patients (26 emergency rup-
ture repair, 98 elective open repair, and 47 EVAR) showed that
despite overall better quality of life compared with a matched
general population, patients after ruptured AAA repair suffered
signicant pain long term.7
Specic investigations of anaesthetic or analgesic choice for
aortic aneurysm repair are limited to one retrospective study
comparing a locoregional technique with general anaesthesia
(GA) in elective EVAR59 and case reports related to paravertebral
ii98 | Seretny and Colvin

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Fig 1 Mediators of inammatory pain. Local inammatory cells and inltrating cells release mediators including pro-inammatory cytokines [tumour necrosis
factor (TNF; formerly known as TNF), bradykinin, prostaglandins, interleukin-1 (IL-1), and interleukin-6 (IL-6)], H+, ATP, nerve growth factors (NGFs), and pro-
inammatory chemokines [CC-chemokine ligand 2 (CCL2), CXC-chemokine ligand 1 (CXCL1) and ), CXC-chemokine ligand 5 (CXCL5)]. Receptors for these
inammatory mediators, including G-protein-coupled receptors (GPCRs), ionotropic receptors, and tyrosine kinase receptors, are expressed on nociceptive
neurones. Stimulation causes generation of second messengers, such as cyclic AMP and Ca2+, and downstream activation of kinases [ protein kinase A (PKA),
protein kinase C (PKC), extracellular signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K), calcium/calmodulin-dependent protein kinase (CaMK), and
the mitogen-activated protein kinases (MAPKs), p38 MAPK, and JUN N-terminal kinase (JNK)]. Activation of these kinases causes peripheral sensitization by
modulating transduction molecules (e.g. transient receptor potential cation channel subfamily A member 1 (TRPA1) and TRPV1) and conduction (voltage-gated
sodium channels Nav1.71.9). Activated nociceptors release substance P and calcitonin gene-related peptide (CGRP), involved in the generation of neurogenic
inammation and (CGRP) regulation of lymphadenopathy. Bacterial infection with Staphylococcus aureus induces neuronal hyperexcitability by releasing bacterial
N-formylated peptides (FPs) and the formation of the pore-forming toxin -haemolysin (-HL). The bacteria can also directly activate nociceptors. 4-HNE, 4-
hydroxynonenal; 5,6-EET, 5,6- epoxyeicosatrienoic acid; ASIC, acid-sensing ion channel; FPR1, formyl peptide receptor 1; HETE, 5-hydroxyeicosatetraenoic acid;
HMGB1, high mobility group protein B1; P2X3, P2X purinergic receptor 3; PGE2, prostaglandin E2; RTK, receptor tyrosine kinase. Figure reproduced with permission
from Macmillan Publishers Ltd.41

blocks in thoracic or thoraco-abdominal aortic aneurysm re-
pairs.58 60 Pain does not feature as an outcome measure in the
retrospective observational work of Asakura and colleagues59 in-
vestigating the locoregional technique in EVAR. It remains un-
clear whether locoregional use in EVAR impacts on short- or
long-term analgesic requirements or pain scores as compared
with GA. In relation to thoracic aortic aneurysm repair, published
case reports suggest that paravertebral block or paravertebral
catheter insertion and postoperative local anaesthetic (LA) infu-
sion are effective in terms of pain relief in the operative and
postoperative period. Long-term pain outcomes are not reported
in these publications.
The only clear evidence regarding anaesthetic and analgesic
technique for aortic aneurysm repair comes from a well-con-
ducted study investigating the impact of epidural anaesthesia
on morbidity and mortality outcomes in high-risk patients
undergoing major surgery.57 Of 915 patients, 142 patients in
this cohort had aortic aneurysm repair and were randomized to
receive GA with epidural or GA with opioid analgesia. Pain scores
at 3 days after surgery were signicantly lower in the epidural
 Managing pain in vascular disease | ii99

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B

C D

Fig 2 Mechanisms of neuropathic pain. () Primary afferent pathways connecting to the spinal cord dorsal horn. Nociceptive C bres (red) terminate in upper
laminae (yellow neurone), whereas non-nociceptive myelinated A bres project to deeper laminae. Second-order neurones (WDR type) receive direct
nociceptive input, synaptic input, and multisynaptic input from myelinated A bres (non-noxious information; blue neurone system). Microglia (grey cell)
facilitate synaptic transmission. GABAergic interneurones (green neurone) normally exert inhibitory synaptic input on the second-order neurone. Descending
modulatory systems synapse at the second-order neurone (only the inhibitory projection; green descending terminal). () Peripheral changes underpinning
peripheral sensitization at primary afferent neurones after damage. Note that some axons are damaged and degenerate (axons 1 and 3), whereas some remain
intact and connected to the peripheral end organ (skin; axons 2 and 4). Expression of sodium channels is increased on damaged neurones (axon 3). Products
such as nerve growth factor are released in the vicinity of spared bres (arrow). These trigger the expression of channels and receptors (e.g. sodium channels,
TRPV1 receptors, and adrenoreceptors) on uninjured bres. () Spontaneous activity in C nociceptors induces spinal cord hyperexcitability (central sensitization
of second-order nociceptive neurones; star in yellow neurone). These cause input from mechanoreceptive A bres (blue neurone system; light touching and
punctate stimuli) to be perceived as pain (dynamic and punctate mechanical allodynia; + indicates gating at synapse). Several presynaptic (opioid receptors and
calcium channels) and postsynaptic molecular structures (glutamate receptors, AMPA/kainate receptors, sodium/5-HT receptors, GABA receptors, and sodium
channels) are involved in central sensitization. Inhibitory interneurones and descending modulatory control systems (green neurons) are dysfunctional after
nerve lesions. () Peripheral nerve injury activates spinal cord glial cells (grey cell) via chemokines, such as CCL2, acting on chemokine receptors. Activated
microglia further enhance excitability in second-order neurones by releasing cytokines and growth factors (e.g. tumour necrosis factor and bone-derived nerve
factor) and increasing glutamate concentrations. CCL2, chemokine (C-C motif ) ligand 2; KA, kainate; NE, norepinephrine; TRPV1, transient receptor potential V1;
WDR, wide dynamic range. Figure reproduced with permission from Elsevier.23
 ii100
Table 2 Summary of evidence related to pain outcomes and management in aortic aneurysm repair patients. *Abstract only available. AA, aortic aneurysm; BPI, brief pain inventory; EVAR,
endovascular aneurysm repair; GA, general anaesthesia; OR, open repair; PV, paravertebral; QoL, quality of life; RCT, randomized controlled trial; SF-36, Medical Outcomes Study Short-form 36-

| Seretny and Colvin

item survey; VAS, visual analogue scale; WHOQOL-BREF, World Health Organization Quality of Life-BREF

Study (citation) Design Population Intervention or comparison Pain-related outcomes Pain assessment Conclusion related to pain
measures management

Rigg and RCT 142 high-risk patients for OR Randomized to GA+epidural Pain scores for 3 days VAS GA+epidural group had decreased
colleagues57 or GA+standard care after surgery pain scores
Prinssen and RCT 153 patients Randomized to OR or EVAR QoL measures SF-36 and EuroQoL-5D; No specic pain management
colleagues54 administered ve questions conclusions. Overall QoL slightly
times for 1 yr after regarding bodily better initially after EVAR. After 6
surgery pain and months, QoL better in OR group
discomfort
Shine and Case report One patient for thoracic AA Paravertebral catheter Routine care. Pain VAS Continuous infusion of ropivacaine
colleagues58 repair insertion after surgery assessment for 3 0.2% for 3 days resulted in VAS<3
days after surgery and no additional opioid use
Soulez and RCT 40 low-risk patients Randomized to OR or EVAR Pain in early Numerical rating scale No specic pain management
colleagues55 postoperative (010) conclusions. Pain was equal
period and at 1 BPI between groups after surgery,
month Karnofsky score and but better in the OR group at 1
SF-36; questions month
regarding bodily
pain and
discomfort
Aljabri and Prospective 76 patients (43 EVAR+33 OR) Administration of QoL QoL measures SF-36; questions No specic pain management
colleagues56 cohort measure to patients administered 1 regarding bodily conclusions. EVAR patients had
undergoing either surgery week, 1 month, and pain and lower overall QoL scores than OR
type 6 months after discomfort at 6 months
surgery
Asakura and Retrospective 31 patients for EVAR Comparison of GA in 19 None specied None specied No specic pain management
colleagues59 case review patients with locoregional conclusions. Feasibility of EVAR
(epidural or nerve block) under locoregional technique
in 12 patients on outcome proposed
of EVAR
Hinterseher and Retrospective 249 patients with known Comparison of QoL in QoL measures WHOQOL-BREF and SF- No specic pain management
colleagues7 cohort abdominal aortic abdominal aortic administered at 36; questions conclusions. Patients after EVAR
aneurysm (78 under aneurysm cohort with one time point regarding bodily or OR had QoLthan general
surveillance, 171 after general population pain and population. Patients after
repair) discomfort emergency OR had signicant
long-term pain
Sato and Case report Seven patients for thoraco- Paravertebral block for Unclear Unclear Pain relief after PV block was
colleagues60* abdominal AA repair thoraco-abdominal AA comparable to epidural.
repair Postoperative neurological
monitoring was easier with PV
block

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group across the whole cohort. Apart from respiratory failure,
which was also signicantly lower in the epidural group, all
other outcomes were equal between groups.
In summary, there is currently limited evidence to guide opti-
mal pain management options for aortic aneurysm repair. Fur-
ther research is needed in terms of both the known risks of
conversion to chronic pain states after complex surgery10 and
the documented importance of pain outcomes to patients after
aortic aneurysm repair.8
Carotid endarterectomy
Carotid endarterectomy (CEA) can be performed under regional
(RA) or general anaesthesia. Regional anaesthesia may be in the
form of a deep or supercial cervical plexus block; with some sug-
gestion that supercial plexus block is safer and provides better
analgesia.61 The General Anaesthesia vs Local Anaesthesia for
Carotid Surgery (GALA) trial demonstrated no clear benet of
RA over GA in terms of mortality, stroke, myocardial infarction,
or cost-effectiveness.62 63 In this trial, pain was considered only
in terms of reasons for conversion from RA to GA during surgery.
No long-term pain assessment was carried out. Subgroup ana-
lysis relating to early postoperative cognitive outcomes sup-
ported use of RA over GA in terms of cognitive function, but did
not explicitly assess postoperative pain.64 A survey of mostly
USA-based anaesthetists suggests that 89% continue to use GA
for CEA procedures.65
A recent Cochrane review, comparing stroke outcomes after
GA or RA in CEA, planned to assess pain indirectly as part of re-
ported patient satisfaction outcomes.66 Of the 14 included stud-
ies (4596 patients), four assessed satisfaction, and none found
that patients preferred either technique to the other. No study in-
cluded in that review directly assessed pain.
Direct investigation of analgesic outcomes after CEA was
undertaken in only two studies. The rst, published before the
GALA trial, investigated GA with supercial plexus block or pla-
cebo,67 whereas a more recent study compared GA plus surgical
wound inltration with ropivacaine 0.75%, 20 ml with GA plus
surgical saline inltration.68 Both showed decreased opioid con-
sumption in the recovery room, with lower pain score in the
groups receiving LA.
In summary, there is a small amount of evidence to suggest
that additional inltration of LA, either by surgeons or in the
form of a supercial plexus block, improves analgesia in the im-
mediate post-CEA period. There is no evidence regarding long-
term pain outcomes after CEA.
Revascularization procedures
In the context of vascular surgery, limb amputation is performed
for PAD when revascularization procedures are unsuccessful or
deemed inappropriate. Little evidence is available regarding
pain management for revascularization procedures. This is high-
lighted by a recent Cochrane review investigating neuraxial block
for revascularization procedures, which found no data regarding
postoperative pain or patient satisfaction in this cohort.69 One of
the reasons for this may be the confounding effect of pain being a
key feature of PAD both before and after surgery. Indeed, pain at
rest is one of the reasons for unscheduled hospital readmission
after revascularization surgery, although it is unclear whether
this is postsurgical or disease-related pain.70 71
Limited support for epidural use in revascularization proce-
dures comes from the trial by Rigg and colleagues57 discussed
above. Three per cent of this cohort underwent aorto-femoral
Managing pain in vascular disease | ii101
bypass graft surgery and contributed to the overall results of
the trial showing decreased pain scores at 3 days after surgery.
Otherwise, no clear data regarding optimal analgesic technique
for this procedure are available.
Limb amputation
In contrast to the few studies on pain management for revascu-
larization procedures, there are a number of studies assessing
analgesic approaches for amputation surgery. This may relate
to the challenges in effective pain control in this group of pa-
tients, who are known to be at high risk of persistent postsurgical
pain (stump and phantom pain).10 Evidence regarding analgesic
management for limb amputation can be divided broadly into in-
vestigations of pre-emptive analgesia, started in some instances
up to 2 days before surgery,7274 and studies assessing intra- and
postoperative analgesic regimens.7577
Assessment of pre-emptive analgesic techniques is linked to
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known pain mechanisms involved in the generation of post-am-
putation pain. Original work investigating pre-emptive analgesia
found that preoperative epidurals, continued after surgery, re-
duced the risk of development of PLP.78 There were, however, a
number of methodological issues with that study. Subsequent
randomized controlled trials found no reduction in PLP from epi-
dural analgesia (either pre-emptive or placed immediately before
surgery), although they demonstrated good postoperative pain
control.72 79 A summary of evidence regarding pre-emptive anal-
gesia for chronic post-amputation pain is covered in the review
by Ypsilantis and Tang.74 The authors conclude that pre-emptive
analgesia is effective in the immediate postoperative period but
that there is no evidence for any long-term decrease in pain
after amputation. This in contrast to a more recent single-centre
study showing decreased pain before surgery, after surgery, and
at 6 months in amputees receiving pre-emptive fentanyl patient-
controlled analgesia or epidural analgesia vs routine non-pre-
emptive preoperative analgesia.73 The results of the study need
to be conrmed in a wider patient population.
Studies investigating intraoperative perineural catheter
placement and postoperative local anaesthetic inltration regi-
mens suggest decreased pain in the immediate postoperative
period. There are, however, no long-term data on pain outcomes.
These studies are limited by their retrospective design75 77 or
their lack of blinding and control groups.76
One of the key challenges in assessing long-term analgesic
outcomes in PAD amputees is their high mortality rate. Conse-
quently, studies investigating this question remain underpow-
ered because of problems with either recruitment or patient
dropout. Despite this, overall trends in the pre-emptive analgesic
studies discussed above suggest that epidural or i.v. analgesia
started 2 days before amputation may be effective for decreas-
ing pain in both the short and the long term. However, no specic
intra- or postoperative analgesic technique has a clear evidence
base for impacting on long-term outcomes.
Conversion of pain from acute to chronic
in vascular patients
The mechanisms involved in the conversion of pain from acute
to chronic in vascular patients include maladaptive inamma-
tory and neuropathic pain syndromes. These processes may be
amenable to the inuence of analgesic choice both in the peri-
operative period and, potentially, earlier, when the patient ini-
tially presents with vascular-related pain.
ii102 | Seretny and Colvin
A recent meta-analysis assessed the use of regional anaesthe-
sia for the prevention of chronic postoperative pain. As a result of
methodological heterogeneity, it was not possible to pool data
statistically from the four amputation studies identied. In the
non-vascular surgeries included in the meta-analysis, there
was no denite evidence favouring epidural and paravertebral
analgesia for prevention of postoperative chronic pain.80 Risk fac-
tors associated with the conversion to chronic pain are well de-
scribed.10 They include a high degree of acute, baseline, or
preoperative pain, psychosocial variables, such as catastrophiz-
ing, female sex, and poorly dened genetic susceptibility. In vas-
cular patients, the high degree of baseline pain is a key factor in
the conversion rate to chronic pain states.81 82
Taken together, this evidence suggests that, where possible,
use of pre-emptive analgesic strategies in subgroups of vascular
patients at high risk of conversion to chronic pain states, such as
PAD patients, may be of benet in minimizing conversion to
chronic pain states.
Chronic pain in vascular patients
Many anaesthetists will encounter patients with vascular disease
who have pre-existing chronic pain and who require surgery. The
epidemiology, aetiology (where known), and management options
for common chronic pain conditions in vascular disease patients
are presented below.
Phantom limb pain and stump pain
Phantom limb pain occurs in 5080% of amputees.83 The me-
chanisms underpinning PLP development can be subdivided into
those occurring peripherally, affecting afferent transmission, and
those occurring centrally, impacting on efferent signalling.24 Per-
ipherally, transection of the nerve during the amputation causes
regenerative sprouting of axons. These predispose to maladaptive
responses to chemical and mechanical stimuli and neuroma for-
mation. The resulting ectopic nerve impulses give rise to typical
neuropathic pain symptoms. Additionally, sympathetic afferent
coupling may occur, and this leads to sympathetically maintained
pain. Centrally, reorganization of dorsal horn neurones and
somatosensory cortices after limb loss leads to changes that
alter efferent signalling and maintain PLP. Neuroimaging work
has demonstrated cortical remapping as a key component of PLP
maintenance.25 84 Recent evidence suggests that pain catastophiz-
ing, independent of anxiety and depression, is a key feature in the
central changes sustaining PLP.85 86
Treatment options for PLP reect the complex mechanisms
that underpin the condition, requiring multimodal management.
Peripheral mechanisms can be targeted with topical therapies,
such as lidocaine patches or capsaicin patches, botulin toxin in-
jection at neuroma sites, and transcutaneous electrical nerve
stimulation of the stump, although the level of evidence support-
ing these treatments is low.87 88 A wide variety of agents, with
variable-quality evidence, have been used to target central
changes. These include gabapentinoids, ketamine, opioids, and
topiramate (a new-generation antiepileptic), and memantine in
the early acute phase of PLP presentation.88
Psychological treatments, including biofeedback, mirror ther-
apy, mental imagery, hypnosis, and meditation, have all been
studied in the context of PLP.89 90 These treatments may be
used in conjunction with pharmacological measures as part of
the multimodal approach to PLP management. For further read-
ing regarding PLP management options, we direct readers to two
recent reviews.88 91
Complex regional pain syndrome
Complex regional pain syndrome is a debilitating pain syndrome
occurring in 20 per 100 000 patients. The incidence is minimal in
childhood, with a mean age of occurrence between 37 and 52 yr,
and an increased female-to-male distribution ratio.15 Complex
regional pain syndrome is classied into types I and II, based
on clinical and scientic consensus but not pathophysiological
mechanisms.14 Diagnosis of CRPS is based on physical examin-
ation and patients meeting the Budapest criteria.16 92
The pathophysiological mechanisms underpinning CRPS are
complex, with autonomic dysfunction resulting in marked changes
in vascular reactivity. Effective treatments centre around known
pathophysiological pathways.17 93 There is recent interest in the
use of immunoglobulins or bisphosphonates in CRPS.65 94 Despite
the clear neuropathic nature of CRPS, there is no strong evidence
base for the use of any analgesics typically used in neuropathic
pain (opioids, antidepressants, and gabapentinoids). There is
some evidence for the use of repetitive transcranial magnetic
Downloaded from http://bja.oxfordjournals.org/ by guest on September 9, 2016
stimulation in CRPS.95 There is evidence for the use of spinal cord
stimulation in ischaemic pain (PAD) and for intractable CRPS, as re-
commended by the National Institute for Health and Care Excel-
lence (NICE), UK.96 97 The mechanisms of analgesia from spinal
cord stimulation are complex, including changes in endothelial ni-
tric oxide concentrations and altered spinal processing.98 99 Physic-
al therapies have the strongest evidence base for management of
CRPS.95 Within this category, graded motor imagery (a physical
therapy that uses imagined movement and mirror therapy) also
has some evidence base.100 101
Ischaemic pain in peripheral arterial disease
The prevalence of PAD is 12% in the general adult population.24
Asymptomatic disease can occur, and 17.8% of the population at
low risk for cardiovascular disease are thought to have asymptom-
atic PAD.5 Pain is a key diagnostic feature of PAD, and worsening
pain is associated with disease progression. Intermittent claudica-
tion presents with pain on exercise, relieved by rest, whereas de-
velopment of critical limb ischaemia is heralded by pain at rest.
The pathophysiological mechanisms underpinning these
changes relate to atherosclerotic obstruction to blood ow. This
results in inadequate oxygen supply to peripheral tissue and
leads to muscle ischaemia, increase in inammatory mediators,
and subsequent dying off and remodelling of local nerve end-
ings.102 This cascade of inammatory pain results in peripheral
and, subsequently, central sensitization.
For earlier stages of PAD, exercise is recommended in the
management of intermittent claudication, although the best
form of delivery for exercise therapy is unclear.103 Despite the in-
creasing incidence of advanced PAD and critical limb ischaemia,
limited evidence exists regarding effective management op-
tions.104 Somewhat promisingly, recent reviews of spinal cord
stimulation in ischaemic pain suggest that this is a viable option
in PAD patients who do not respond to conventional analgesic re-
gimens.105 106 In particular, patients who have severe ischaemic
pain seem to derive signicant benet from the implantation of
a spinal cord stimulator.107 However, if analgesic measures and
revascularization procedures fail, amputation remain the only
solutions. As discussed above, amputation is associated with a
high risk of PLP.
Thoracic outlet syndrome
Thoracic outlet syndrome (TOS) is a complex chronic pain syn-
drome that is related to vascular disease because of involvement

of major veins and arteries. Thoracic outlet syndrome comprises
three related syndromes: compression of major blood vessels in
the upper chest (vascular TOS), compression of the brachial
plexus (neurogenic TOS), or painful non-specic or disputed
TOS.18 Diagnostic criteria for TOS are non-standardized, and evi-
dence on incidence and prevalence is lacking.19 Thoracic outlet
syndrome is associated with severe pain, attributable to both is-
chaemic and neuropathic mechanisms. The only treatment op-
tion associated with clear evidence of improved pain is rst rib
resection.108 Other treatments (including local anaesthetic sca-
lene muscle injections, exercise and physiotherapy, and stand-
ard neuropathic pain treatments) have a mixed evidence base
in TOS but continue to be implemented before or instead of sur-
gical intervention.20 109
Conclusion
Patients with vascular disease frequently experience pain and
have a high risk for suffering from chronic pain. In the acute set-
ting, pre-emptive analgesic strategies are recommended where
possible. Chronic pain in vascular patients is always complex,
with patients often having multiple co-morbidities. Multidiscip-
linary pain management is important in maximizing pain relief,
function, and quality of life for this patient group. Consideration
of interventional (e.g. spinal cord stimulation) and psychological
(e.g. cognitive behavioural therapy) treatments should be given
early. Further pain research is needed to improve quality of life
for patients with vascular disease in a number of areas, as fol-
lows: studies of outcomes from major vascular surgery should in-
clude both acute and chronic pain measures; a better
understanding is needed of the progression from acute to chronic
pain, and how to prevent this; and how best to manage estab-
lished chronic pain syndromes in vascular disease. There are
many challenges in such research, with cooperation between ex-
pert centres being necessary to deliver the high-quality evidence
that is urgently needed.
Authors contributions
Reviewing literature, writing the article, revising drafts, and ap-
proval of the nal version: M.S., L.A.C.
Declaration of interest
None declared.
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