British Journal of Anaesthesia, 117 (S2): ii95–ii106 (2016)

doi: 10.1093/bja/aew212
Special Issue

Pain management in patients with vascular disease

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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: [Link]@[Link]

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
infiltration or by superficial 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

Editor’s 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, inflammatory, and
cluding varicose veins and thromboembolic disease), lymphatic
neuropathic mechanisms.
disease, Buerger′s disease, and Raynaud’s phenomenon (Table 1).
• Cross-talk between sensory neurones and the sympathetic
Although cardiac disease is a major contributor to morbidity and
nervous system (sympathetic–afferent 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.26–28 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: [Link]@[Link]

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, Buerger’s disease, Raynaud’s 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) 1–6
peripheral arteries, leading Ischaemic (late)
to tissue ischaemia Neuropathic (late)

Aortic aneurysms Dependent on location, age, Dilatation affecting all three Nociceptive 7–9
and sex. Abdominal aortic layers of the vascular wall.

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aneurysms: 25/100 000 Caused by degeneration of
men and 12/100 000 elastic laminae and
women leucocyte infiltration,
leading to smooth muscle
cell loss. Likely to be
secondary to atherosclerosis
(except in familial
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 insufficiency in Nociceptive 12 13

Overall ∼16% superficial veins, leading to Inflammatory
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 14–17
syndrome leading to peripheral autonomic involvement)
sensitization, Inflammatory
inflammation, 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 18–20

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

Phantom limb and 50–80% of amputees Transection of nerve(s) at Neuropathic (with or without 21–25
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- management, including a multimodal approach to analgesia.33–36
current hospital admissions and multiple surgeries. Uncon- We provide a summary of the pain mechanisms important in
trolled pain, acute or chronic, will result in pathophysiological vascular disease, followed by an outline of the management of
changes, including an increased stress response and activation pain in the various contexts of vascular disease.
of the autonomic system, which may be particularly detrimental
in patients with vascular disease.29–32
The mechanisms of pain applicable to vascular disease pa-
Pain mechanisms relevant to vascular disease
tients are multifaceted and incompletely understood. Knowledge A complex range of mechanisms underpins pain in patients with
of these processes is important to guide effective, targeted pain vascular disease. Nociceptive, inflammatory, and neuropathic
 Managing pain in vascular disease | ii97

mechanisms may all occur. Recognition of the predominant ischaemic pain, and the persistent pain that may occur after
pathophysiological process driving pain in individual vascular surgery.10 43 There are characteristic changes in neuropathic
disease patients is essential for successful pain management, be- pain, which include alterations in ion channels, G-protein-
cause the varied mechanisms warrant specific approaches to an- coupled receptors, neurotransmitters, and central activation
algesic choice.21 (Fig. 2).22 23 44 45

Involvement of the autonomic nervous system

Nociceptive pain
in neuropathic pain
Nociceptive pain occurs after thermal, chemical, or mechanical In normal conditions, there is no cross-talk between the sympa-
stimulation of peripheral nociceptors on unmyelinated C fibres thetic nervous system and primary sensory neurones. During
or small, myelinated Aδ fibres.37 It constitutes a physiological re- conversion to chronic pain, the two systems can become asso-
sponse to real or threatened non-neuronal tissue damage and re- ciated in a process known as sympathetic–afferent coupling.24

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flects normal adaptive functioning of the somatosensory The mechanisms thought to play a role in sympathetic–afferent
nervous system. It is typically a reversible type of pain that sub- coupling include the expression of adrenergic receptors on affer-
sides when the insult is removed.10 In vascular patients, nocicep- ent nociceptive neurones, sprouting of sympathetic axons into
tive pain is a key component of intermittent claudication ( pain dorsal root ganglia, and increased local inflammatory mediators
and cramping after repeated muscle action or exercise).1 A (e.g. interleukin-8) maintained by sympathetically induced local
range of peripheral receptors (ion channels and G-protein- vasoconstriction that causes nociceptor activation and sensitiza-
coupled receptors) found on Aδ and C fibres is involved in the tion.46–48 Sympathetic–afferent coupling can induce central sen-
generation of nociceptive pain. These include acid-sensing ion sitization, which is the increased responsiveness of brain and
channels, responsive to calcium, and the transient receptor po- spinal cord nociceptive neurones to normal or subthreshold af-
tential (TRP) channel family.38 The acid-sensing ion channels ferent input.37 Alterations in the sympathetic nervous system
are important in the initial pain response, but are also key in con- are central to complex regional pain syndrome (CRPS), with
version to chronic pain states, and may therefore serve as targets clear changes in vascular reactivity, and may also be important
for analgesic drug development.39 in phantom limb pain (PLP).14 24

Inflammatory pain Pain in the acute vascular (surgical) setting

This type of pain constitutes the response of the somatosensory Vascular surgery entails a broad range of procedures varying
nervous system to tissue damage and inflammation. In the per- from day-case varicose vein surgery to complex open abdominal
iphery, increased inflammatory mediators, such as cytokines aortic aneurysm (AAA) repair. The associated morbidity ranges
and chemokines, sensitize local nociceptors, lowering their from negligible to 2.4% for elective infrarenal AAA repair and
threshold for responsiveness ( peripheral sensitization).37 40 ∼50% for emergency ruptured AAA surgery.49 Pain management
This increased responsiveness results in potential stimulation options in some surgeries may be limited by the use of anticoagu-
of pain pathways after innocuous input and in exaggerated re- lant medication. Below, we present pain management considera-
sponses to noxious stimulation. tions and evidence-based treatment options for key vascular
Pain modulated by the inflammatory response involves acti- procedures, focusing on areas where pain management may be
vation of a number of receptors and ion channels, with interac- challenging.
tions between peripheral immune cells, alterations in local
blood flow, and changes in the chemical and electrical activity
Aortic aneurysm repair
of the peripheral afferent neurones (Fig. 1).
The plasticity that underpins these changes is rapid (occur- Aortic aneurysm repair may be elective or emergency, involve
ring in minutes) and is an almost inevitable consequence of sur- the abdominal or thoracic cavity or both, and be either open
gery and tissue trauma. This upregulation of nociception should or endovascular (EVAR). Acute aortic syndromes usually present
normally resolve as wound healing occurs. Maladaptive re- with pain, with an increasing incidence in the last decade. 50
sponses, including inadequate resolution of these changes after Mortality and long-term survival rates have been robustly stud-
inflammation, are likely to be central to conversion from acute to ied in terms of open repair vs EVAR.51–53 Pain was not included
chronic pain states.42 as an outcome of interest in any of these large well-designed
trials.
Three smaller studies from the same period investigated bod-
Neuropathic pain
ily pain as part of quality-of-life assessments after aortic aneur-
Pain resulting from a lesion or disease of the somatosensory ner- ysm repair (Table 2).54–56 These studies suggested that apart from
vous system is termed neuropathic.37 The lesion may occur at the a more rapid postoperative return to baseline quality-of-life
molecular, cellular, or tissue level and impact on function and scores, EVAR had no longer-term advantage over open repair in
structure of the somatosensory nervous system. The result is a terms of pain. A more recent study investigating long-term qual-
combination of sensory loss and increased responsiveness to ity of life in 171 postoperative AAA patients (26 emergency rup-
both noxious and innocuous stimuli.40 Positive phenomena, ture repair, 98 elective open repair, and 47 EVAR) showed that
such as allodynia ( pain after non-painful stimuli), hyperalgesia despite overall better quality of life compared with a matched
(heightened pain after painful stimuli), and hyperpathia (an general population, patients after ruptured AAA repair suffered
eruptive pain extending beyond the duration of a stimulus), are significant pain long term.7
common clinical features of neuropathic pain.37 In vascular pa- Specific investigations of anaesthetic or analgesic choice for
tients, neuropathic mechanisms may underpin much of the aortic aneurysm repair are limited to one retrospective study
chronicity in pain presentations. In particular, neuropathic pain comparing a locoregional technique with general anaesthesia
is a key component in critical limb ischaemia, the associated (GA) in elective EVAR59 and case reports related to paravertebral
ii98 | Seretny and Colvin

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Fig 1 Mediators of inflammatory pain. Local inflammatory cells and infiltrating cells release mediators including pro-inflammatory cytokines [tumour necrosis
factor (TNF; formerly known as TNFα), bradykinin, prostaglandins, interleukin-1β (IL-1β), and interleukin-6 (IL-6)], H+, ATP, nerve growth factors (NGFs), and pro-
inflammatory chemokines [CC-chemokine ligand 2 (CCL2), CXC-chemokine ligand 1 (CXCL1) and ), CXC-chemokine ligand 5 (CXCL5)]. Receptors for these
inflammatory 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 Nav1.7–1.9). Activated nociceptors release substance P and calcitonin gene-related peptide (CGRP), involved in the generation of neurogenic
inflammation 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 α-haemolysin (α-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- postoperative period. Long-term pain outcomes are not reported
pairs.58 60 Pain does not feature as an outcome measure in the in these publications.
retrospective observational work of Asakura and colleagues59 in- The only clear evidence regarding anaesthetic and analgesic
vestigating the locoregional technique in EVAR. It remains un- technique for aortic aneurysm repair comes from a well-con-
clear whether locoregional use in EVAR impacts on short- or ducted study investigating the impact of epidural anaesthesia
long-term analgesic requirements or pain scores as compared on morbidity and mortality outcomes in high-risk patients
with GA. In relation to thoracic aortic aneurysm repair, published undergoing major surgery.57 Of 915 patients, 142 patients in
case reports suggest that paravertebral block or paravertebral this cohort had aortic aneurysm repair and were randomized to
catheter insertion and postoperative local anaesthetic (LA) infu- receive GA with epidural or GA with opioid analgesia. Pain scores
sion are effective in terms of pain relief in the operative and at 3 days after surgery were significantly 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 fibres (red) terminate in upper
laminae (yellow neurone), whereas non-nociceptive myelinated A fibres project to deeper laminae. Second-order neurones (WDR type) receive direct
nociceptive input, synaptic input, and multisynaptic input from myelinated A fibres (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 fibres (arrow). These trigger the expression of channels and receptors (e.g. sodium channels,
TRPV1 receptors, and adrenoreceptors) on uninjured fibres. () 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 fibres (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

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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 specific pain management
colleagues54 administered five 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 specific pain management
colleagues55 postoperative (0–10) 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 specific 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 specified None specified No specific 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 specific 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 QoL≥than general
surveillance, 171 after general population pain and population. Patients after
repair) discomfort emergency OR had significant
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
 Managing pain in vascular disease | ii101

group across the whole cohort. Apart from respiratory failure, bypass graft surgery and contributed to the overall results of
which was also significantly lower in the epidural group, all the trial showing decreased pain scores at 3 days after surgery.
other outcomes were equal between groups. Otherwise, no clear data regarding optimal analgesic technique
In summary, there is currently limited evidence to guide opti- for this procedure are available.
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 Limb amputation
the documented importance of pain outcomes to patients after In contrast to the few studies on pain management for revascu-
aortic aneurysm repair.8 larization procedures, there are a number of studies assessing
analgesic approaches for amputation surgery. This may relate
Carotid endarterectomy to the challenges in effective pain control in this group of pa-
tients, who are known to be at high risk of persistent postsurgical

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Carotid endarterectomy (CEA) can be performed under regional pain (stump and phantom pain).10 Evidence regarding analgesic
(RA) or general anaesthesia. Regional anaesthesia may be in the management for limb amputation can be divided broadly into in-
form of a deep or superficial cervical plexus block; with some sug- vestigations of pre-emptive analgesia, started in some instances
gestion that superficial plexus block is safer and provides better up to 2 days before surgery,72–74 and studies assessing intra- and
analgesia.61 The General Anaesthesia vs Local Anaesthesia for postoperative analgesic regimens.75–77
Carotid Surgery (GALA) trial demonstrated no clear benefit of Assessment of pre-emptive analgesic techniques is linked to
RA over GA in terms of mortality, stroke, myocardial infarction, known pain mechanisms involved in the generation of post-am-
or cost-effectiveness.62 63 In this trial, pain was considered only putation pain. Original work investigating pre-emptive analgesia
in terms of reasons for conversion from RA to GA during surgery. found that preoperative epidurals, continued after surgery, re-
No long-term pain assessment was carried out. Subgroup ana- duced the risk of development of PLP.78 There were, however, a
lysis relating to early postoperative cognitive outcomes sup- number of methodological issues with that study. Subsequent
ported use of RA over GA in terms of cognitive function, but did randomized controlled trials found no reduction in PLP from epi-
not explicitly assess postoperative pain.64 A survey of mostly dural analgesia (either pre-emptive or placed immediately before
USA-based anaesthetists suggests that 89% continue to use GA surgery), although they demonstrated good postoperative pain
for CEA procedures.65 control.72 79 A summary of evidence regarding pre-emptive anal-
A recent Cochrane review, comparing stroke outcomes after gesia for chronic post-amputation pain is covered in the review
GA or RA in CEA, planned to assess pain indirectly as part of re- by Ypsilantis and Tang.74 The authors conclude that pre-emptive
ported patient satisfaction outcomes.66 Of the 14 included stud- analgesia is effective in the immediate postoperative period but
ies (4596 patients), four assessed satisfaction, and none found that there is no evidence for any long-term decrease in pain
that patients preferred either technique to the other. No study in- after amputation. This in contrast to a more recent single-centre
cluded in that review directly assessed pain. study showing decreased pain before surgery, after surgery, and
Direct investigation of analgesic outcomes after CEA was at 6 months in amputees receiving pre-emptive fentanyl patient-
undertaken in only two studies. The first, published before the controlled analgesia or epidural analgesia vs routine non-pre-
GALA trial, investigated GA with superficial plexus block or pla- emptive preoperative analgesia.73 The results of the study need
cebo,67 whereas a more recent study compared GA plus surgical to be confirmed in a wider patient population.
wound infiltration with ropivacaine 0.75%, 20 ml with GA plus Studies investigating intraoperative perineural catheter
surgical saline infiltration.68 Both showed decreased opioid con- placement and postoperative local anaesthetic infiltration regi-
sumption in the recovery room, with lower pain score in the mens suggest decreased pain in the immediate postoperative
groups receiving LA. period. There are, however, no long-term data on pain outcomes.
In summary, there is a small amount of evidence to suggest These studies are limited by their retrospective design75 77 or
that additional infiltration of LA, either by surgeons or in the their lack of blinding and control groups.76
form of a superficial plexus block, improves analgesia in the im- One of the key challenges in assessing long-term analgesic
mediate post-CEA period. There is no evidence regarding long- outcomes in PAD amputees is their high mortality rate. Conse-
term pain outcomes after CEA. quently, studies investigating this question remain underpow-
ered because of problems with either recruitment or patient
Revascularization procedures dropout. Despite this, overall trends in the pre-emptive analgesic
studies discussed above suggest that epidural or i.v. analgesia
In the context of vascular surgery, limb amputation is performed started ∼2 days before amputation may be effective for decreas-
for PAD when revascularization procedures are unsuccessful or ing pain in both the short and the long term. However, no specific
deemed inappropriate. Little evidence is available regarding intra- or postoperative analgesic technique has a clear evidence
pain management for revascularization procedures. This is high- base for impacting on long-term outcomes.
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
Conversion of pain from acute to chronic
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
in vascular patients
rest is one of the reasons for unscheduled hospital readmission The mechanisms involved in the conversion of pain from acute
after revascularization surgery, although it is unclear whether to chronic in vascular patients include maladaptive inflamma-
this is postsurgical or disease-related pain.70 71 tory and neuropathic pain syndromes. These processes may be
Limited support for epidural use in revascularization proce- amenable to the influence of analgesic choice both in the peri-
dures comes from the trial by Rigg and colleagues57 discussed operative period and, potentially, earlier, when the patient ini-
above. Three per cent of this cohort underwent aorto-femoral tially presents with vascular-related pain.
ii102 | Seretny and Colvin

A recent meta-analysis assessed the use of regional anaesthe- Complex regional pain syndrome
sia for the prevention of chronic postoperative pain. As a result of
Complex regional pain syndrome is a debilitating pain syndrome
methodological heterogeneity, it was not possible to pool data
occurring in ∼20 per 100 000 patients. The incidence is minimal in
statistically from the four amputation studies identified. In the
childhood, with a mean age of occurrence between 37 and 52 yr,
non-vascular surgeries included in the meta-analysis, there
and an increased female-to-male distribution ratio.15 Complex
was no definite evidence favouring epidural and paravertebral
regional pain syndrome is classified into types I and II, based
analgesia for prevention of postoperative chronic pain.80 Risk fac-
on clinical and scientific consensus but not pathophysiological
tors associated with the conversion to chronic pain are well de-
mechanisms.14 Diagnosis of CRPS is based on physical examin-
scribed.10 They include a high degree of acute, baseline, or
ation and patients meeting the ‘Budapest’ criteria.16 92
preoperative pain, psychosocial variables, such as catastrophiz-
The pathophysiological mechanisms underpinning CRPS are
ing, female sex, and poorly defined genetic susceptibility. In vas-
complex, with autonomic dysfunction resulting in marked changes
cular patients, the high degree of baseline pain is a key factor in
in vascular reactivity. Effective treatments centre around known

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the conversion rate to chronic pain states.81 82
pathophysiological pathways.17 93 There is recent interest in the
Taken together, this evidence suggests that, where possible,
use of immunoglobulins or bisphosphonates in CRPS.65 94 Despite
use of pre-emptive analgesic strategies in subgroups of vascular
the clear neuropathic nature of CRPS, there is no strong evidence
patients at high risk of conversion to chronic pain states, such as
base for the use of any analgesics typically used in neuropathic
PAD patients, may be of benefit in minimizing conversion to
pain (opioids, antidepressants, and gabapentinoids). There is
chronic pain states.
some evidence for the use of repetitive transcranial magnetic
stimulation in CRPS.95 There is evidence for the use of spinal cord
Chronic pain in vascular patients stimulation in ischaemic pain (PAD) and for intractable CRPS, as re-
commended by the National Institute for Health and Care Excel-
Many anaesthetists will encounter patients with vascular disease
lence (NICE), UK.96 97 The mechanisms of analgesia from spinal
who have pre-existing chronic pain and who require surgery. The
cord stimulation are complex, including changes in endothelial ni-
epidemiology, aetiology (where known), and management options
tric oxide concentrations and altered spinal processing.98 99 Physic-
for common chronic pain conditions in vascular disease patients
al therapies have the strongest evidence base for management of
are presented below.
CRPS.95 Within this category, graded motor imagery (a physical
therapy that uses imagined movement and mirror therapy) also
Phantom limb pain and stump pain has some evidence base.100 101

Phantom limb pain occurs in 50–80% of amputees.83 The me-

chanisms underpinning PLP development can be subdivided into Ischaemic pain in peripheral arterial disease
those occurring peripherally, affecting afferent transmission, and The prevalence of PAD is ∼12% in the general adult population.2–4
those occurring centrally, impacting on efferent signalling.24 Per- Asymptomatic disease can occur, and ∼17.8% of the population at
ipherally, transection of the nerve during the amputation causes low risk for cardiovascular disease are thought to have asymptom-
regenerative sprouting of axons. These predispose to maladaptive atic PAD.5 Pain is a key diagnostic feature of PAD, and worsening
responses to chemical and mechanical stimuli and neuroma for- pain is associated with disease progression. Intermittent claudica-
mation. The resulting ectopic nerve impulses give rise to typical tion presents with pain on exercise, relieved by rest, whereas de-
neuropathic pain symptoms. Additionally, sympathetic afferent velopment of critical limb ischaemia is heralded by pain at rest.
coupling may occur, and this leads to sympathetically maintained The pathophysiological mechanisms underpinning these
pain. Centrally, reorganization of dorsal horn neurones and changes relate to atherosclerotic obstruction to blood flow. This
somatosensory cortices after limb loss leads to changes that results in inadequate oxygen supply to peripheral tissue and
alter efferent signalling and maintain PLP. Neuroimaging work leads to muscle ischaemia, increase in inflammatory mediators,
has demonstrated cortical remapping as a key component of PLP and subsequent dying off and remodelling of local nerve end-
maintenance.25 84 Recent evidence suggests that pain catastophiz- ings.102 This cascade of inflammatory pain results in peripheral
ing, independent of anxiety and depression, is a key feature in the and, subsequently, central sensitization.
central changes sustaining PLP.85 86 For earlier stages of PAD, exercise is recommended in the
Treatment options for PLP reflect the complex mechanisms management of intermittent claudication, although the best
that underpin the condition, requiring multimodal management. form of delivery for exercise therapy is unclear.103 Despite the in-
Peripheral mechanisms can be targeted with topical therapies, creasing incidence of advanced PAD and critical limb ischaemia,
such as lidocaine patches or capsaicin patches, botulin toxin in- limited evidence exists regarding effective management op-
jection at neuroma sites, and transcutaneous electrical nerve tions.104 Somewhat promisingly, recent reviews of spinal cord
stimulation of the stump, although the level of evidence support- stimulation in ischaemic pain suggest that this is a viable option
ing these treatments is low.87 88 A wide variety of agents, with in PAD patients who do not respond to conventional analgesic re-
variable-quality evidence, have been used to target central gimens.105 106 In particular, patients who have severe ischaemic
changes. These include gabapentinoids, ketamine, opioids, and pain seem to derive significant benefit from the implantation of
topiramate (a new-generation antiepileptic), and memantine in a spinal cord stimulator.107 However, if analgesic measures and
the early acute phase of PLP presentation.88 revascularization procedures fail, amputation remain the only
Psychological treatments, including biofeedback, mirror ther- solutions. As discussed above, amputation is associated with a
apy, mental imagery, hypnosis, and meditation, have all been high risk of PLP.
studied in the context of PLP.89 90 These treatments may be
used in conjunction with pharmacological measures as part of
Thoracic outlet syndrome
the multimodal approach to PLP management. For further read-
ing regarding PLP management options, we direct readers to two Thoracic outlet syndrome (TOS) is a complex chronic pain syn-
recent reviews.88 91 drome that is related to vascular disease because of involvement
 Managing pain in vascular disease | ii103

of major veins and arteries. Thoracic outlet syndrome comprises 5. Cimminiello C, Kownator S, Wautrecht J-C, et al. The PAN-
three related syndromes: compression of major blood vessels in DORA study: peripheral arterial disease in patients with
the upper chest (vascular TOS), compression of the brachial non-high cardiovascular risk. Intern Emerg Med 2011; 6:
plexus (neurogenic TOS), or painful non-specific or disputed 509–19
TOS.18 Diagnostic criteria for TOS are non-standardized, and evi- 6. Jensen SA, Vatten LJ, Myhre HO. The prevalence of chronic
dence on incidence and prevalence is lacking.19 Thoracic outlet critical lower limb ischaemia in a population of 20,000 sub-
syndrome is associated with severe pain, attributable to both is- jects 40–69 years of age. Eur J Vasc Endovasc Surg 2006; 32:
chaemic and neuropathic mechanisms. The only treatment op- 60–5
tion associated with clear evidence of improved pain is first rib 7. Hinterseher I, Kuffner H, Berth H, et al. Long-term quality of
resection.108 Other treatments (including local anaesthetic sca- life of abdominal aortic aneurysm patients under surveil-
lene muscle injections, exercise and physiotherapy, and stand- lance or after operative treatment. Ann Vasc Surg 2013; 27:
ard neuropathic pain treatments) have a mixed evidence base 553–61

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in TOS but continue to be implemented before or instead of sur- 8. Dubois L, Novick TV, Power AH, DeRose G, Forbes TL. Identi-
gical intervention.20 109 fication of patient-derived outcomes after aortic aneurysm
repair. J Vasc Surg 2014; 59: 1528–34
9. Lilienfeld DE, Baxter J, Sprafka JM. Prevalence of aortic an-
Conclusion eurysms in the twin cities metropolitan areas, 1979–84.
Patients with vascular disease frequently experience pain and Public Health Rep 1993; 108: 506–10
have a high risk for suffering from chronic pain. In the acute set- 10. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain:
ting, pre-emptive analgesic strategies are recommended where risk factors and prevention. Lancet 2006; 367: 1618–25
possible. Chronic pain in vascular patients is always complex, 11. Pujia A, Rubba P, Spencer MP. Prevalence of extracranial ca-
with patients often having multiple co-morbidities. Multidiscip- rotid artery disease detectable by echo-Doppler in an elderly
linary pain management is important in maximizing pain relief, population. Stroke 1992; 23: 818–22
function, and quality of life for this patient group. Consideration 12. Ahumada M, Vioque J. Prevalence and risk factors of vari-
of interventional (e.g. spinal cord stimulation) and psychological cose veins in adults. Med Clin (Barc) 2004; 123: 647–51
(e.g. cognitive behavioural therapy) treatments should be given 13. van Eekeren RRJP, Boersma D, Konijn V, de Vries JPPM,
early. Further pain research is needed to improve quality of life Reijnen MMJP. Postoperative pain and early quality of life
for patients with vascular disease in a number of areas, as fol- after radiofrequency ablation and mechanochemical endo-
lows: studies of outcomes from major vascular surgery should in- venous ablation of incompetent great saphenous veins. J
clude both acute and chronic pain measures; a better Vasc Surg 2013; 57: 445–50
understanding is needed of the progression from acute to chronic 14. Jänig W, Baron R. Complex regional pain syndrome: mystery
pain, and how to prevent this; and how best to manage estab- explained? Lancet Neurol 2003; 2: 687–97
lished chronic pain syndromes in vascular disease. There are 15. Borchers AT, Gershwin ME. Complex regional pain syn-
many challenges in such research, with cooperation between ex- drome: a comprehensive and critical reviewd. Autoimmun
pert centres being necessary to deliver the high-quality evidence Rev 2014; 13: 242–65
that is urgently needed. 16. Harden RN, Bruehl S, Stanton-Hicks M, Wilson PR. Proposed
new diagnostic criteria for complex regional pain syndrome.
Pain Med 2007; 8: 326–31
Authors’ contributions 17. Gierthmuehlen J, Binder A, Baron R. Mechanism-based
treatment in complex regional pain syndromes. Nat Rev
Reviewing literature, writing the article, revising drafts, and ap-
Neurol 2014; 10: 518–28
proval of the final version: M.S., L.A.C.
18. Sanders RJ, Hammond SL, Rao NM. Diagnosis of thoracic
outlet syndrome. J Vasc Surg 2007; 46: 601–4
Declaration of interest 19. Laulan J, Fouquet B, Rodaix C, Jauffret P, Roquelaure Y,
Descatha A. Thoracic outlet syndrome: definition, aetio-
None declared. logical factors, diagnosis, management and occupational
impact. J Occup Rehabil 2011; 21: 366–73
20. Huang JH, Zager EL. Thoracic outlet syndrome. Neurosurgery
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Handling editor: Simon Howell