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Anaesthesia. Author manuscript; available in PMC 2021 August 17.
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Published in final edited form as:

Anaesthesia. 2021 January ; 76(Suppl 1): 8–17. doi:10.1111/anae.15256.

The role of regional anaesthesia and multimodal analgesia in the

prevention of chronic postoperative pain: a narrative review
Y.-Y.K. Chen1, K.A. Boden2, K.L. Schreiber3 [Assistant Professor]
1Regional Anaesthesia and Acute Pain Medicine Fellow, Brigham and Women’s Hospital, Boston,
MA, USA
2Anaesthesia Resident, Brigham and Women’s Hospital, Boston, MA, USA
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3Department of Anesthesiology, Peri-operative and Pain Medicine, Brigham and Women’s

Hospital, Boston, MA, USA

Summary
Effective prevention of chronic postoperative pain is an important clinical goal, informed by a
growing body of studies. Peri-operative regional anaesthesia remains one of the most important
tools in the multimodal analgesic toolbox, blocking injury-induced activation and sensitisation
of both the peripheral and central nervous system. We review the definition and taxonomy of
chronic postoperative pain, its mechanistic basis and the most recent evidence for the preventative
potential of multimodal analgesia, with a special focus on regional anaesthesia. While regional
anaesthesia targets several important aspects of the mechanistic pathway leading to chronic
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postoperative pain, evidence for its efficacy is still mixed, possibly owing to the heterogeneity
of risk profiles within the surgical patient, but also to variation in techniques and medications
reported in the literature.

Keywords
chronic postoperative pain; multimodal analgesia; regional anaesthesia

Importance of chronic postoperative pain

Chronic postoperative pain has important personal and social ramifications, reducing quality
of life and contributing to the economic burden of chronic pain. Accordingly, the prevention
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of chronic postoperative pain is an important goal, with the International Association for the
Study of Pain (IASP) naming 2017 the Global Year Against Pain After Surgery. Chronic
postoperative pain is defined as pain persisting for at least 3 months after surgery, which
was either not present before or differs from pre-operative pain, and which is localised to
the surgical site, and without other obvious cause [1, 2]. Increasingly, investigators have
recognised that surgery could serve as a substantial source of chronic pain generation,

Correspondence to: Y.-Y. K. Chen, ykchen@partners.org.

Supporting Information
Additional supporting information may be found online via the journal website.
Appendix S1. References for studies in Table 3.
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with an early study reporting up to 40% of patients in multiple pain clinics in the UK
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exhibiting chronic pain resulting from surgical or traumatic injury [3]. Subsequent studies
have confirmed substantial rates of chronic postoperative pain after a variety of surgical
procedures, and revealed important demographic, genetic and psychosocial risk factors
for chronic postoperative pain, which may further inform study design, prevention and
treatment [4]. While traumatic injury is clearly not predictable, elective surgery allows us to
investigate factors that may influence pain chronicity.

Multimodal analgesia is a term that refers to the use of several different analgesic
medications or techniques simultaneously, to target multiple receptors within nociceptive
and neuropathic pathways, thus reducing acute postoperative pain and the surgical stress
response, as well as potentially impacting the mechanistic chain of events that can lead
to chronic postoperative pain [4]. The effort to provide opioid-reduced, or opioid-free,
anaesthesia by the application of multimodal techniques has regional anaesthesia (RA) at its
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core. Accordingly, studies investigating the ability of RA to prevent chronic postoperative

pain have been a focus in recent years. By 2012, 23 randomised controlled trials had
investigated the impact of RA on rates of chronic postoperative pain, and by 2018,
approximately 40 new randomised controlled trials had been performed [5]. The conclusions
of these studies have varied depending on the surgical procedure performed, the patient
sample, the definition of chronic postoperative pain used and the measurement tools used for
pain outcomes.

The incidence of chronic postoperative pain has been estimated between 10 and 50% when
a more lenient definition is used (any pain/pain ≥ 1/10, or pain ≥ 3/10), and approximately
5–10% when a more stringent definition of severe pain (pain > 5/10) [4, 6]. A lower
incidence (10%) is observed after surgery such as inguinal hernia repair and caesarean
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section, whereas a higher incidence (30–50%) is observed following amputation and

coronary artery bypass surgery [4]. The time-point of chronic postoperative pain assessment,
ranging from months to several years after surgery, may impact incidence estimates, with
longer follow-up times corresponding to lower incidence rates [6]. Methodological and
measurement variations aside, there also appears to be a true variation in the extent of
chronic postoperative pain between individuals, ranging from mild and inconsequential
to severe and debilitating, even among patients undergoing the same surgical procedure.
Thus, including assessment of individual patient characteristics that may contribute to this
variation in pain, as well as using a common taxonomy and set of measures among clinicians
and researchers, may be important for the effective interpretation of published studies.
Identifying patients at highest risk will aid in distinguishing the most important mechanisms
underlying chronic postoperative pain in humans, and inform how best to direct preventative
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and treatment options [6].

Consistency in the definition used for chronic pain can foster effective reproducibility and
generalisability of preventative trials across different countries and healthcare settings. Using
collaboratively created pain classification systems may align efforts across the research and
clinical arenas, to provide a common framework for multiple types of acute and chronic
pain, and with subsections for specific postoperative pain types [7, 8]. Pain disorders are
classified based on traditional diagnostic categories but, importantly, for each pain type,

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five dimensions are defined: core criteria; common features; modifying factors; functional
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impact; and putative mechanisms [7–9], providing a framework for comparison of pain
from different causes, including postoperative pain, and finding common elements to aid in
treating it.

Currently, the International Classification of Diseases version 10 (ICD-10) coding does not
have a diagnostic category for chronic postoperative pain [2].In preparation for the new
ICD-11, expected to be in effect in January 2022 by the World Health Organization (WHO),
the International Association for the Study of Pain published a series of narrative reviews
detailing the proposed need for different diagnostic classifications for the various types of
chronic pain. This notably includes chronic postoperative pain, given its pathophysiological
importance and difference from other types of chronic pain [2,10].

Mechanisms of pain and surgical influence on chronic postoperative pain

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Pain is an adaptive evolutionary response to noxious stimuli in order to prevent further

injury or damage [11]. However, the injury induced by surgery may lead to several
mechanistic events which ultimately result in pain that outlasts its usefulness. Several
distinct mechanistic pain types have been identified as contributing to both acute and
chronic pain after surgery (Table 1) [4, 9, 12, 13]. A surgical incision may involve all three
(nociceptive, inflammatory and neuropathic) to varying degrees. Upon activation by surgical
injury, peripheral nociceptors fire impulses, activating nociceptive pathways in the spinal
and supraspinal areas of the central nervous system [14]. Ongoing stimulation, acidosis
and inflammation at the site of injury fuels increased excitability and spontaneous firing
of peripheral nociceptors, including ectopic firing [4, 13]. The response to surgical injury
also includes changes in gene expression in the cell bodies of peripheral nociceptors (within
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the dorsal root ganglion) which underlies more long-lasting excitability and transmission of
the nociceptive signal [4]. With continued transmission of these nociceptive inputs, central
sensitisation at the level of the spinal cord may also occur [4]. The degree of activation
produced by a surgical insult, but also the response from surrounding immune, stromal and
glial cells, both in the periphery and in the spinal cord, influences the extent and duration of
pain, as well as its transition to a more chronic state [14].

Several studies have attempted to identify specific surgical factors that increase the risk of
developing chronic postoperative pain. The surgical location, duration and extent, as well
as the experience of the surgical team, have been implicated [14, 15]. Both longer duration
and an open (vs. laparoscopic) approach have been linked to chronic postoperative pain
[16]. Modifying surgical technique to minimise nerve damage and using minimally invasive
approaches decrease chronic postoperative pain risk [14].
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Biopsychosocial model of pain and risk-factors associated with chronic

postoperative pain
The degree of tissue damage or nerve injury alone cannot explain the degree of inter­
individual variation in the development of chronic postoperative pain. The biopsychosocial
model of pain includes biophysical differences between procedures or individuals

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(surgical extent, genetic variation, baseline nociceptive sensitivity, opioid dependence), and
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psychosocial factors involved in the processing of injury and pain (anxiety, depression,
coping strategies, social support) (Fig. 1) [8]. Biophysical factors include the extent of the
surgical procedure and also the response of the patient’s physiology to it. The amount of
tissue damage, nerve damage and inflammation from operative and postoperative changes
may influence chronic postoperative pain development, but patient characteristics such as
age, sex and genetics have been proven to correspond to different degrees of chronic
postoperative pain development [6, 8, 14]. Younger age and female sex are associated
with increased risk of chronic postoperative pain. Genetic variations include several single
nucleotide polymorphisms within three genes involved in dopamine neurotransmission and
chronic pain; catechol-O-methyltransferase [COMT], GTP cyclohydrolase 1 [GCH1] and
DA receptor 2 (DRD2) seem to convey higher or lower risk of chronic postoperative pain.
Patients with a history of pre-existing pain, or with greater generalised pain sensitivity, also
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appear to be at higher risk [17].

Psychosocial factors conferring higher risk include pre-operative levels of state and trait
anxiety or depression; pain catastrophising; sleep disturbance; somatisation; positive and
negative effect; coping strategies; and expectations [18]. These can be assessed peri­
operatively with validated questionnaires such as the National Institutes of Health Patient­
Reported Outcomes Measurement Information System (PROMIS) short forms, or with
specialised psychosocial questionnaires such as the pain catastrophising scale. Social factors
may include socio-economic status and access to medical care, as well as relational social
support, with natural and interventional social networks and connections appearing to be
protective against pain severity [8]. The intensity of acute pain is one of the strongest
‘predictors’ of chronic postoperative pain, likely because acute pain itself is a product of all
these biopsychosocial variables, raising the question of whether acute pain is a correlate of
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chronic postoperative pain rather than a predictor [4, 6, 19].

Impact of regional anaesthesia on chronic postoperative pain

Regional anaesthesia, in the form of neuraxial or peripheral nerve blocks may play a
key role in the prevention of chronic postoperative pain in the peri-operative period
by modulating pain signalling created by a surgical incision (Table 2) [4]. Regional
anaesthesia and other multimodal analgesics block activation of the pain pathway. Although
most surgical injury occurs within the domain of peripheral nerves activating nociceptive
pain, inflammatory and neuropathic changes induced by surgery have the potential to
drive changes in both the peripheral and central nervous system, and contribute to the
development of chronic postoperative pain. The understanding of how RA influences
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these factors is still incomplete, but suggested mechanisms include dampening or blocking
nociceptive nerve impulses, regulating signals from glial cells, and minimising the synaptic
plasticity of neurons [20]. Local anaesthetics themselves have anti-inflammatory properties
which may also decrease sensitisation. Animal models and in-vitro studies have suggested
that local anaesthetics may reduce ectopic firing of neurons, reduce expression of cytokines
and other inflammatory mediators, and decrease neutrophil priming [20, 21]. Additionally,
RA indirectly reduces pain signals transmitted to the spinal cord and supraspinal and
cortical nociceptive centres, thus preventing central nervous system sensitisation. Reduction

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of central sensitisation with RA has been demonstrated in several animal models in the acute
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phase; notably, one study has shown a reduction in long-term pain vulnerability after RA,
which may act as a surrogate for reducing chronic pain development [20].

The prevalence of new persistent opioid use, defined as use at 3 months after surgery in an
opioid-naïve patient, has been reported as approximately 5% in the USA [22]. Risk factors
for persistent opioid use include genetics, prior history of opioid use or substance abuse,
more painful surgical procedures, pre-operative or postoperative opioid dose and duration,
underlying psychiatric disease such as a history of depression, extremes of age, lower socio­
economic status, lower educational level and a family history of substance-use disorder
[22]. Several of these risk factors overlap with risk factors for chronic postoperative pain.
One of the major benefits of RA is that it can provide pain control without relying heavily
on opioid medications. A recent prospective observational study showed that RA may
reduce postoperative opioid consumption, especially among patients with high baseline pain
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catastrophising [23]. High-dose intra-operative opioids, particularly remifentanil, can lead

to increased acute postoperative pain scores and analgesic consumption, likely secondary
to opioid-induced hyperalgesia [24]. While a substantial body of research has described
opioid-induced hyperalgesia in the acute postoperative phase of recovery, there are relatively
few studies addressing hyperalgesia within the context of chronic pain development [25].
In any case, RA may facilitate a decrease in reliance on high-dose intra-operative opioids,
making it an attractive alternative for pain control, especially advantageous in certain patient
populations.

Evidence for the role of regional anaesthesia in the prevention of chronic

postoperative pain
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There is a growing interest in the potential preventative impact of RA on chronic

postoperative pain, especially with ongoing development of new RA techniques [5, 26–
28]. Several studies have favoured the use of RA and local anaesthetics in decreasing the
incidence of chronic postoperative pain (Table 3 online Supporting Information, Appendix
S1).

Breast surgery has been the most widely studied surgical intervention with regard to
the impact of RA on chronic postoperative pain. Up to 60% of breast surgery patients
may experience chronic postoperative pain, 14% of which is classified as severe [4, 29].
According to a recent Cochrane review, the use of local anaesthetics was associated with
an overall benefit in the case of breast surgery (18 pooled studies, OR 0.43, 95%CI 0.28–
0.68, p < 0.001) [5]. More specifically, subgroups examining paravertebral blocks (OR 0.61,
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95%CI 0.39–0.97), intravenous lidocaine (OR 0.24, 95%CI 0.08–0.69), and local infiltration
(OR 0.29, 95%CI 0.12–0.73), also showed a benefit [5]. Alternative approaches, including
intercostal, interscalene and intervertebral blocks showed mixed results. Most recently, Fujii
et al. described the potential benefit of pectoral nerve-2 (PECS 2) block in decreasing the
rate of moderate to severe chronic postoperative pain compared with the serratus plane
block (OR 0.23, 95%CI 0.07–0.80, p = 0.02) [26]. However, Al Ja’bari et al. found no
difference in the incidence of chronic postoperative pain with the PECS 2 block vs. no block

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[30]. Several ongoing studies addressing innovative blocks will likely continue to inform
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preventative treatment options for these patients.

Thoracotomy is associated with a relatively high incidence of chronic postoperative pain

compared with other surgical procedures, with estimates ranging as high as 30–40% [4].
In keeping with its relevance, there are also a sizable number of studies addressing chronic
postoperative pain after thoracotomy. Overall, studies favour RA for thoracotomy with an
OR of 0.52 (95%CI 0.32–0.84, p = 0.008) [5]. Epidural block showed the greatest tendency
for reduction in chronic postoperative pain while other modalities, including continuous
wound infiltration and intercostal nerve block, were less efficacious [19, 31]. Previous
studies investigating paravertebral blocks have suggest that they provide efficacy equivalent
to epidural for management of thoracic surgical pain, and paravertebral blocks may also
reduce the incidence and/or intensity of chronic postoperative pain [27, 32, 33].
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Pain control after caesarean section has become increasingly important, with the number
of caesarean sections increasingly worldwide, and a reported incidence of chronic
postoperative pain as high as 6–18% [34]. Transversus abdominis plane blocks are an
established RA technique which may reduce pain after caesarean section by blocking nerves
of the abdominal wall. Overall, reduction in chronic postoperative pain is associated with
RA use (OR 0.46 (95%CI 0.28–0.78, p = 0.004)) [5]. More recent studies have focused on
the role of adjunctive medications with RA and the role of RA with related gynaecological
procedures such as hysterectomies, so far with less promising results.

The role of RA for other surgical procedures, including cardiac surgery, laparotomy, hernia
repair, prostatectomy and hysterectomy, is informed by a smaller pool of randomised
controlled studies, making the case for chronic postoperative pain prevention by RA less
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clear. Additionally, phantom limb pain after amputation is a growing area of research,
with several ongoing studies which should help address the gap in knowledge for treating
these patients at particularly high risk for chronic postoperative pain (30–85% after limb
amputation) [2].

While the mechanistic rationale for RA use in chronic postoperative pain is clear, and
studies to date generally support its use, other studies fail to show a significant benefit.
There are several challenges in studying chronic postoperative pain which may account for
this. First, although an incidence of chronic postoperative pain up to 70–80% has been cited,
depending on the patient population sampled and surgical procedure, this estimate is likely
too high, with more conservative estimates in the 20–30% range. If this is the case, then
most patients entering a study of chronic postoperative pain will not actually develop it,
thus potentially shrinking the pool of relevantly studied patients substantially and leaving
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studies underpowered. Meta-analysis allows this problem to be abrogated to some extent,

with most meta-analyses suggesting a benefit [5]. The patient population studied in many of
the randomised controlled trials is also heterogeneous and not stratified based on a patient’s
biopsychosocial profile. Most studies applied the IASP definition of chronic postoperative
pain (greater than 3 months of pain), however, some studies had differing follow up times
(such as 6, 8, 12 and 55 months), measured outcomes (e.g. dichotomous pain vs. no pain,
pain scores, analgesic consumption), peri-operative medications and adjuvants used in nerve

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blocks (such as clonidine). Multiple studies assessed immediate postoperative pain control,
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which is important as acute postoperative pain is a predictor of development of chronic

postoperative pain, while others did not [35–37]. In addition, some studies did not report
block efficacy. Lastly, surgical technique and instrumentation have improved over time, and
therefore two surgeries, though the same (e.g. breast surgery), may have been performed
using different techniques.

Additional multimodal analgesics for prevention of chronic postoperative

pain
Regional anaesthesia is but one important part of the multimodal analgesic approach
to preventing acute and chronic postoperative pain. Other pharmacological antagonists
target receptors along the nociceptive pathway that is activated in response to surgical
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incision (Table 2) [12, 38]. These targets include voltage-gated sodium channels (local
anaesthetics, RA) and α2-δ calcium channels (gabapentinoids), which primarily target
peripheral neurons; N-methyl-D-aspartate (NMDA) glutamate receptors and α−2 adrenergic
receptors, which target spinal cord neurons; and cyclooxygenase (COX) enzymes and other
inflammatory pathways (NSAIDs, celecoxib and paracetamol), which act both peripherally
and centrally [14]. As with RA, other multimodal analgesics focus on preventing activation
of peripheral neurons, thus decreasing noxious inputs from reaching the central nervous
system to reduce acute and chronic pain. The concept of multimodality makes use of
additive, and possibly synergistic, interactions of blocking these various pharmacological
targets, partly through minimising the side effects seen with use of higher doses of any one
agent [14,39].

N-methyl-D-aspartate receptors are central to the phenomenon of ‘windup’ in the spinal

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cord, which is thought to be an important aspect of the central sensitisation involved

in chronic pain development after an injury. N-methyl-D-aspartate receptors also appear
to be important in the phenomenon of acute opioid tolerance [40]. Ketamine is the
most widely studied NMDA receptor antagonist for pain relief, with several systematic
reviews and meta-analyses published. The vast majority of these studies acknowledge
the benefits of ketamine as an adjuvant for acute pain and chronic non-cancer pain
management, but its specific role in chronic postoperative pain is less well established
[41–43]. One analysis showed a reduction in pain at 3 and 6 months after surgery using
intravenous ketamine when administered for at least 24 h [42]. Further research is needed
to address the prevailing limitations of small sample sizes, heterogeneous populations and
variability in timing and route of administration [41, 44]. Other NMDA receptor antagonists,
including dextromethorphan, magnesium, memantine and nitrous oxide have shown some
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benefit in acute postoperative pain, but their role in chronic postoperative pain is largely
unknown [44]. One recent positive randomised control trial showed that women treated with
memantine had a reduction in pain (p = 0.017) and a reduction in the need for neuropathic
pain treatment (p = 0.040) 3 months after mastectomy [45].

Local anaesthetics can be utilised as a pain control adjunct when administered locally (e.g.
wound infiltration or RA) or systemically. The systemic effects of intravenous lidocaine

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have shown lasting pain control benefits by reducing inflammatory and neuropathic
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nociception and reducing central sensitisation [21]. The mechanism of action is unlikely
to be explained exclusively by its primary action of blocking voltage-gated sodium channels,
and may include additional activity at hyperpolarisation-activated cyclic nucleotide-gated
channels, transient receptor potential ion channels, and certain G-protein-coupled receptors
[21, 46]. There is evidence for benefit of intravenous lidocaine for breast and abdominal
surgery, and a recent meta-analysis found that lidocaine infusions reduced the incidence of
chronic postoperative pain between 3 and 6 months after surgery (OR 0.29; 95%CI, 0.18–
0.48; p < 0.001) with a similar effect size when analysing breast and non-breast surgical
procedures [21, 47]. Interestingly, studies investigating the benefits of intravenous lidocaine
for acute postoperative pain have not been as promising [48, 49].

Gabapentinoids, including gabapentin and pregabalin, despite their name, appear to reduce
pain by inhibiting the α2-δ subunit of voltage-gated calcium channels (Cav α2-δ).
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These channels regulate neuronal excitation and are upregulated in the process of central
sensitisation, thus forming a rational target for pain prevention [44]. Early studies suggested
that both gabapentin and pregabalin were effective at reducing chronic postoperative pain
[42, 50]. Notably, full efficacy for analgesia appears to require relatively high doses,
which are also associated with significant side effects, such as sedation, gait and vision
changes [44]. Moreover, recent meta-analyses have not supported evidence for gabapentin or
pregabalin in the peri-operative period or in the prevention of chronic postoperative pain [51,
52].

The activation of α−2 adrenoceptors spinally results in analgesia and may show important
synergism with spinal opioids, but wider antagonism results in sedation and reduction
of sympathetic tone [53]. The most commonly used α−2 adrenoceptor agonists are
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dexmedetomidine and clonidine. Despite their potential for spinal analgesia, there are
relatively few human studies investigating chronic postoperative pain specifically. One study
showed that dexmedetomidine infusions during breast surgery reduced chronic pain intensity
3 months postoperatively [54]. The few studies investigating clonidine did not include
chronic postoperative pain as a primary outcome [44]. Despite the uncertainty of chronic
pain benefits, enhanced recovery after surgery protocols frequently utilise these agents due
to their acute opioid sparing effects [55]. They have also been used successfully as RA
adjuncts with local anaesthetics when administered perineurally to hasten the onset and
prolong the duration of sensory and motor blockade [56].

Both COX inhibitors and paracetamol help reduce the intensity of acute pain. The
inflammatory state from surgery leads to upregulation of several mediators, including
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cyclooxygenase-2 (COX-2) and prostaglandins, which can drive both peripheral and central
sensitisation [57]. No randomised controlled trials have shown significant reductions in
chronic postoperative pain for either COX-2 inhibitors or paracetamol, although both agents
are considered an integral part of the multimodal approach to the treatment of acute
postoperative pain [15, 44].

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Future of multimodal analgesia with regional anaesthesia and chronic

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postoperative pain
The ability of RA to target many areas of the surgically induced pain pathways makes
it a powerful tool in reducing neural activation from surgical injury, making it the
centrepiece of a well-rounded multimodal approach. A clearer understanding of when
to apply it, and for whom it is most likely to be beneficial, will allow more targeted
prevention of chronic postoperative pain. Larger randomised controlled trials that include
high-risk patients are needed to better assess the efficacy of RA in the prevention of
chronic postoperative pain. Future studies should also assess the impact of a variety of
factors, including biopsychosocial variables which may be assessed pre-operatively, on
the preventative efficacy of chronic postoperative pain. Successful approaches to decrease
chronic postoperative pain incidence should start at the time of pre-operative planning
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and extend into the recovery period (Fig. 1). These strategies include a combination of
techniques, ranging from modifying surgical technique to be less invasive, the thoughtful
use of multimodal analgesic techniques including RA, and behavioural interventions to
improve coping with pain. Published studies suggest that reducing acute pain, avoiding
opioid-induced hyperalgesia and identifying at-risk individuals play important roles in
preventing chronic postoperative pain. Moreover, testing RA techniques on a carefully
selected sample of patients at high risk of developing chronic postoperative pain would
be useful, and potentially reveal which mechanistic target for chronic postoperative pain
prevention is most important in humans. The milieu of multimodal protocols makes testing
a single therapy challenging and, as RA becomes more widely adopted, it may be ethically
difficult to argue for a control group that does not receive it in some form or other.
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Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgements
No external funding or competing interests declared.

References
1. Werner MU, Kongsgaard UEI. Defining persistent post-surgical pain: is an update required?British
Journal of Anaesthesia2014; 113: 1–4. [PubMed: 24554546]
2. Schug SA, Lavand’homme P, Barke A, Korwisi B, Rief W, Treede RD. The IASP classification
of chronic pain for ICD-11: chronic postsurgical or posttraumatic pain. Pain2019; 160: 45–52.
[PubMed: 30586070]
Author Manuscript

3. Crombie IK, Davies HT, Macrae WA. Cut and thrust: antecedent surgery and trauma among patients
attending a chronic pain clinic. Pain1998; 76: 167–71. [PubMed: 9696470]
4. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention.
Lancet2006; 367: 1618–25. [PubMed: 16698416]
5. Weinstein EJ, Levene JL, Cohen MS, et al.Local anaesthetics and regional anaesthesia versus
conventional analgesia for preventing persistent postoperative pain in adults and children. Cochrane
Database of Systematic Reviews2018; 6: CD007105.
6. Schug SA, Bruce J. Risk stratification for the development of chronic postsurgical pain. Pain
Reports2017; 2: e627. [PubMed: 29392241]

Anaesthesia. Author manuscript; available in PMC 2021 August 17.

 Chen et al. Page 10

7. Fillingim RB, Bruehl S, Dworkin RH, et al.The ACTTION-American Pain Society Pain Taxonomy
(AAPT): an evidence-based and multidimensional approach to classifying chronic pain conditions.
Author Manuscript

Journal of Pain2014; 15: 241–9.

8. Schreiber KL, Belfer I, Miaskowski C, Schumacher M, Stacey BR,Van De Ven T. AAAPT
diagnostic criteria for acute pain following breast surgery. Journal of Pain2020; 21: 294–305.
9. Kent ML, Tighe PJ, Belfer I, et al.The ACTTION-APS-AAPM Pain Taxonomy (AAAPT)
multidimensional approach to classifying acute pain conditions. Pain Medicine2017; 18: 947–58.
[PubMed: 28482098]
10. Nugraha B, Gutenbrunner C, Barke A, et al.The IASP classification of chronic pain for ICD-11:
functioning properties of chronic pain. Pain2019; 160: 88–94. [PubMed: 30586076]
11. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature2001; 413: 203–10.
[PubMed: 11557989]
12. Costigan M, Scholz J, Woolf C. Neuropathic pain: a maladaptive response of the nervous system to
damage. Annual Review of Neuroscience2009; 32: 1.
13. Woolf CJ, Ma Q. Nociceptors-noxious stimulus detectors. Neuron2007; 55: 353–64. [PubMed:
17678850]
Author Manuscript

14. Katz J, Ze S. Transition from acute to chronic postsurgical pain: risk factors and protective factors.
Expert Review of Neurotherapeutics2009; 9: 723–44. [PubMed: 19402781]
15. Thapa P, Euasobhon P. Chronic postsurgical pain: current evidence for prevention and
management. Korean Journal of Pain2018; 31: 155–73.
16. Peters ML, Sommer M, de Rijke JM, et al.Somatic and psychologic predictors of long-term
unfavorable outcome after surgical intervention. Annals of Surgery2007; 245: 487–94. [PubMed:
17435557]
17. van Reij RRI, Joosten EAJ, van den Hoogen NJ. Dopaminergic neurotransmission and genetic
variation in chronification of post-surgical pain. British Journal of Anaesthesia2019; 123: 853–64.
[PubMed: 31558312]
18. Schreiber KL, Kehlet H, Belfer I, Edwards RR. Predicting,preventing and managing persistent
pain after breast cancer surgery: the importance of psychosocial factors. Pain Management2014; 4:
445–59. [PubMed: 25494696]
19. Katz J, Jackson M, Kavanagh BP, Sandler AN. Acute pain after thoracic surgery predicts long-term
Author Manuscript

post-thoracotomy pain. Clinical Journal of Pain1996; 12: 50–5.

20. Rivat C, Bollag L, Richebe P. Mechanisms of regional anaesthesia protection against hyperalgesia
and pain chronicization. Current Opinion in Anesthesiology2013; 26: 621–5. [PubMed: 23995064]
21. Hermanns H, Hollmann MW, Stevens MF, et al.Molecular mechanisms of action of systemic
lidocaine in acute and chronic pain: a narrative review. British Journal of Anaesthesia2019; 123:
335–49. [PubMed: 31303268]
22. Brummett CM, Waljee JF, Goesling J, et al.New persistent opioid use after minor and major
surgical procedures in US adults. Journal of the American Medical Association: Surgery2017; 152:
e170504. [PubMed: 28403427]
23. Zinboonyahgoon N, Vlassakov K, Lirk P, et al.Benefit of regional anaesthesia on postoperative
pain following mastectomy: the influence of catastrophising. British Journal of Anaesthesia2019;
123: e293–e302. [PubMed: 31331591]
24. de Hoogd S, Ahlers SJ, van Dongen EP, et al.Is intraoperative remifentanil associated with acute or
chronic postoperative pain after prolonged surgery? An update of the literature. Clinical Journal of
Pain2016; 32: 726–35.
Author Manuscript

25. de Hoogd S, Ahlers S, van Dongen EPA, et al.Randomized controlled trial on the influence of
intraoperative remifentanil versus fentanyl on acute and chronic pain after cardiac surgery. Pain
Practice2018; 18: 443–51. [PubMed: 28741894]
26. Fujii T, Shibata Y, Akane A, et al.A randomised controlled trial of pectoral nerve-2 (PECS 2)
block vs. serratus plane block for chronic pain after mastectomy. Anaesthesia2019; 74: 1558–62.
[PubMed: 31535722]
27. Li XL, Zhang Y, Dai T, Wan L, Ding GN. The effects of preoperative single-dose thoracic
paravertebral block on acute and chronic pain after thoracotomy: a randomized, controlled,
double-blind trial. Medicine2018; 97: e11181. [PubMed: 29901652]

Anaesthesia. Author manuscript; available in PMC 2021 August 17.

 Chen et al. Page 11

28. Theodoraki K, Papacharalampous P, Tsaroucha A, Vezakis A, Argyra E. The effect of transversus

abdominis plane block on acute and chronic pain after inguinal hernia repair. A randomized
Author Manuscript

controlled trial. International Journal of Surgery2019; 63: 63–70. [PubMed: 30769214]

29. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain2011;
152: S2–S15. [PubMed: 20961685]
30. Al Ja’bari A, Robertson M, El-Boghdadly K, Albrecht E. A randomised controlled trial of
the pectoral nerves-2 (PECS-2) block for radical mastectomy. Anaesthesia2019; 74: 1277–81.
[PubMed: 31273773]
31. Liu FF, Liu XM, Liu XY, et al.Postoperative continuous wound infusion of ropivacaine has
comparable analgesic effects and fewer complications as compared to traditional patient-controlled
analgesia with sufentanil in patients undergoing non-cardiac thoracotomy. International Journal of
Clinical and Experimental Medicine2015; 8: 5438–45. [PubMed: 26131121]
32. Yeung JH, Gates S, Naidu BV, Wilson MJ, Gao SF. Paravertebral block versus thoracic epidural for
patients undergoing thoracotomy. Cochrane Database of Systematic Reviews2016; 2: CD009121.
33. Borys M, Hanych A, Czuczwar M. Paravertebral block versus preemptive ketamine effect on
pain intensity after posterolateral thoracotomies: a randomized controlled trial. Journal of Clinical
Author Manuscript

Medicine2020; 14: 793.

34. Nikolajsen L, Sørensen HC, Jensen TS, Kehlet H. Chronic pain following Caesarean section. Acta
Anaesthesiologica Scandinavica2004; 48: 111–6. [PubMed: 14674981]
35. Althaus A, Arranz Becker O, Moser KH, et al.Postoperative pain trajectories and pain
chronification – an empirical typology of pain patients. Pain Medicine2018; 19: 2536–45.
[PubMed: 29800281]
36. Brandsborg B, Dueholm M, Nikolajsen L, Kehlet H, Jensen TS. A prospective study of risk factors
for pain persisting 4 months after hysterectomy. Clinical Journal of Pain2009; 25: 263–8.
37. Macrae WA. Chronic pain after surgery. British Journal of Anaesthesia2001; 87: 88–98. [PubMed:
11460816]
38. Colloca L, Ludman T, Bouhassira D, et al.Neuropathic pain. Nature Reviews Disease Primers2017;
3: 17002.
39. Wall PD. The prevention of postoperative pain. Pain1988; 33: 289–90. [PubMed: 3419835]
40. Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent
Author Manuscript

on N-methyl-d-aspartic acid receptor activation; implications for the treatment of post-injury pain
hypersensitivity states. Pain1991; 44: 293–9. [PubMed: 1828878]
41. Cohen SP, Bhatia A, Buvanendran A, et al.Consensus guidelines on the use of intravenous
ketamine infusions for chronic pain from the American Society of Regional Anesthesia and
Pain Medicine, the American Academy of Pain Medicine, and the American Society of
Anesthesiologists. Regional Anesthesia and Pain Medicine2018; 43: 521–46. [PubMed: 29870458]
42. Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I. Pharmacotherapy for the prevention of
chronic pain after surgery in adults. Cochrane Database of Systematic Reviews2013; CD008307.
43. Klatt E, Zumbrunn T, Bandschapp O, Girard T, Ruppen W. Intra- and postoperative intravenous
ketamine does not prevent chronic pain: a systematic review and meta-analysis. Scandinavian
Journal of Pain2015; 7: 42–54. [PubMed: 29911604]
44. Richebe P, Capdevila X, Rivat C. Persistent postsurgical pain: pathophysiology and preventative
pharmacologic considerations. Anesthesiology2018; 129: 590–607. [PubMed: 29738328]
45. Morel V, Joly D, Villatte C, et al.Memantine before mastectomy prevents post-surgery pain: a
randomized, blinded clinical trial in surgical patients. PLoS One2016; 11: e0152741. [PubMed:
Author Manuscript

27050431]
46. Reddi D, Curran N. Chronic pain after surgery: pathophysiology, risk factors and prevention.
Postgraduate Medical Journal2014; 90: 222–7; quiz 6. [PubMed: 24572639]
47. Bailey M, Corcoran T, Schug S, Toner A. Perioperative lidocaine infusions for the prevention of
chronic postsurgical pain: a systematic review and meta-analysis of efficacy and safety. Pain2018;
159: 1696–704. [PubMed: 29757886]
48. Chang YC, Liu CL, Liu TP, Yang PS, Chen MJ, Cheng SP. Effect of perioperative intravenous
lidocaine infusion on acute and chronic pain after breast surgery: a meta-analysis of Randomized
Controlled Trials. Pain Practice2017; 17: 336–43. [PubMed: 26913591]

Anaesthesia. Author manuscript; available in PMC 2021 August 17.

 Chen et al. Page 12

49. Kranke P, Jokinen J, Pace NL, et al.Continuous intravenous perioperative lidocaine infusion for
postoperative pain and recovery. Cochrane Database of Systematic Reviews2015; 6: CD009642.
Author Manuscript

50. Clarke H, Soneji N, Ko DT, Yun L, Wijeysundera DN. Rates and risk factors for prolonged opioid
use after major surgery: population based cohort study. British Medical Journal2014; 348: g1251.
[PubMed: 24519537]
51. Martinez V, Pichard X, Fletcher D. Perioperative pregabalin administration does not prevent
chronic postoperative pain: systematic review with a meta-analysis of randomized trials. Pain2017;
158: 775–83. [PubMed: 28296652]
52. Verret M, Lauzier F, Zarychanski R, et al.Perioperative use of gabapentinoids for the management
of postoperative acute pain: a systematic review and meta-analysis. Anesthesiology2020; 133:
265–79. [PubMed: 32667154]
53. Fairbanks CA, Stone LS, Kitto KF, Nguyen HO, Posthumus IJ, Wilcox GL. alpha(2C)-Adrenergic
receptors mediate spinal analgesia and adrenergic-opioid synergy. Journal of Pharmacology and
Experimental Therapeutics2002; 300: 282–90.
54. Jain G, Bansal P, Ahmad B, Singh DK, Yadav G. Effect of the perioperative infusion of
dexmedetomidine on chronic pain after breast surgery. Indian Journal of Palliative Care2012;
Author Manuscript

18: 45–51. [PubMed: 22837611]

55. Kaye AD, Chernobylsky DJ, Thakur P, et al.Dexmedetomidine in enhanced recovery after surgery
(ERAS) protocols for postoperative pain. Current Pain and Headache Reports2020; 24: 21.
[PubMed: 32240402]
56. Hussain N, Grzywacz VP, Ferreri CA, et al.Investigating the efficacy of dexmedetomidine as an
adjuvant to local anesthesia in brachial plexus block: a systematic review and meta-analysis of 18
randomized controlled trials. Regional Anesthesia and Pain Medicine2017; 42: 184–96. [PubMed:
28178091]
57. Pak DJ, Yong RJ, Kaye AD, Urman RD. Chronification of pain: mechanisms, current
understanding, and clinical implications. Current Pain and Headache Reports2018; 22: 1–6.
[PubMed: 29340793]
Author Manuscript
Author Manuscript

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Figure 1.
Timing, events and risk factors contributing to the development of chronic postoperative
pain; with assessment and treatment to prevent chronic postoperative pain. A combination
of modifying surgical technique, adjusting for biopsychosocial patient factors, and using
multimodal analgesic techniques inclusive of regional anaesthesia may be more effective at
preventing chronic postoperative pain.
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Table 1

Nociceptive, inflammatory and neuropathic pain classifications [4, 12, 13]. Distinct pain processing classifications have been described, all of which
represent important aspects of surgical pain. Nociceptive pain refers to the perception of a noxious stimulus and involves activation of high threshold,
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mostly unmyelinated C-fibres and some myelinated Aδ-fibres within peripheral sensory neurons (nociceptors) in response to mechanical, chemical or
noxious stimuli of non-neuronal tissue. Inflammatory pain is the result of the release of inflammatory mediators and cytokines primarily by non-neuronal
cells which are called to the area after tissue injury. Neuropathic pain is caused by injury to a neuron, which leads to spontaneous firing of action
potentials (ectopic activity) by the injured and surrounding neurons (Aβ, Aδ and C fibres), activation of NMDA receptors leading to ‘wind-up’
phenomenon, induction of central sensitisation, and heightened pain sensitivity. Peripheral sensitisation is a reduction in threshold of activation of
nociceptors that innervate inflamed tissue. Central sensitisation is an increase in excitability of neurons in the central nervous system.

Evolutionary Neuronal
Pain classification Definition Example response plasticity Sensitisation
Nociceptive Activation of high threshold peripheral sensory neurons Surgical incision of innervated tissue Adaptive Reversible Peripheral
in response to potential oractual injuryto non-neuronal
tissue
Inflammatory Activation of local or infiltrating immune orstromal cells, Heat, pain, redness and swelling in the area of a Adaptive Generally Peripheral and central
release of inflammatory mediators in response to non­ surgical wound reversible
neuronal injury
Neuropathic Injuryto neuronal structures Cutting, electrocautery or devascularisation ofa Maladaptive Variably Peripheral and central
nerve in surgical field reversible

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Table 2

Targets and risk factors for chronic postoperative pain that may be amenable to intervention. Regional anaesthesia targets several areas on the pain
pathway activated by surgical incision [4]. Multimodal analgesic therapy, ranging from pharmacological targets to behavioural modulation, may augment
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a primary regional anaesthesia role in the blockade at many mechanistic levels to prevent chronic postoperative pain.

Targets and risk-factors Intervention

Peripheral nerve injury ● Nerve protective surgery
Peripheral nerve activation ● Regional anaesthesia
● Cavα2-δ ligands(gabapentin, pregabalin)

Local inflammatory response and neurogenic inflammation ● Regional anaesthesia

● Anti-inflammatory (COX-2, NSAIDs, paracetamol)
Peripheral nerve sensitisation and continued ectopic activity ● Regional anaesthesia
● Cavα2-δ ligands(gabapentin, pregabalin)

Changes in gene expression at dorsal root ganglion ● Regional anaesthesia

● Corticosteroids (dexamethasone)
● Anti-inflammatory (COX-2, NSAIDs)
Central sensitisation ● Regional anaesthesia
● NMDA receptor antagonists (ketamine, magnesium, dextromethorphan, memantine)
● Corticosteroids
● α-2 adrenoreceptoragonists(clonidine, dexmedetomidine)
● Opioid receptor agonists
Descending facilitation from the brainstem ● Regional anaesthesia
● Anti-inflammatory (COX-2, NSAIDs, paracetamol)
Limbicsystem and hypothalamus ● Behavioural interventions
● Antidepressants
● Anxiolytics
Cortical pain processing ● Regional anaesthesia
● Assessment and pre-screening
● Support network
● Proper expectations

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Genomic DNA leading to predisposition to chronic pain ● Assessment and pre-screening
● Discussion regarding multimodal analgesia
● Proper expectations

NMDA, N-methyl-D-aspartate; COX-2, cyclooxygenase-2; NSAIDs, non-steroidal anti-inflammatory drugs.

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Table 3

Recent studies assessing the incidence of chronic postoperative pain when comparing regional anaesthesia( RA) and local anaesthesia (LA) with
conventional therapy and their effects on prevention of chronic postoperative pain, by surgical type. Study list was curated with major contributions from
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Weinstein et al. 2018 and the addition of recent randomised controlled trials published between 2018 and 2020 [5]. Only randomised controlled studies
with at least 3 months of follow-up are included. Conventional therapy is defined as a study group that did not use RA or LA. Published meeting abstracts
were excluded. A detailed reference list may be found in online Supporting Information Appendix S1.

Type of surgery Studies Studies that favouredRA or LA, Studies that favoured RA or LA, not Studies that showed no RA or LA techniques shown to favour
(n) significantly different significantly different difference or favoured prevention of chronic postoperative pain
conventional therapy
Breastsurgery 15 ● Kendall 2017 ● Karmakar2014 ● Al Ja’bari 2019 ● Intravenous lidocaine infusion
● Strazisar2014 ● Lee2013 ● Albi-Feldzer2013 ● Continuous wound infusion
● Grigoras 2012 ● Ibarra 2011 ● Baudry 2008 ● Lidocaine cream
● Strazisar2012 ● Terkawi 2015 ● Fassoulaki 2001 ● Paravertebral block
● Kairaluoma 2006 ● Fassoulaki 2005
● Fassoulaki 2000
Thoracotomy 8 ● Borys 2020 ● Comez 2015 ● Liu 2015 ● Epidural
● Lu 2008 ● Can 2013 ● Katz1996 ● Paravertebral block
● Ju 2008
● Senturk2002
Caesarean section 5 ● Shahin 2010 ● McKeen 2014 ● Loane 2012 ● Intraperitoneal installation
● Bollag 2012 ● TAP block
● Lavand’homme 2007 ● Continuous wound infusion
Iliac bone graft 4 ● Singh 2007 ● Barkhuysen 2010 ● Continuous wound infusion
● Blumenthal 2005 ● Multiple wound infiltrations
● Gundes 2000 ● Local wound infiltration
Amputation 1 ● Karanikolas 2006 ● Epidural
Cardiacsurgery 2 ● Vrooman 2015 ● Dogan 2016 ● Lidocaine patch
Laparotomy 2 ● Lavand’homme 2005 ● Katz2004 ● Epidural
Inguinal hernia 3 Mounir2010 Kurmann 2015 Local wound infiltration

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● ● ●
repair ● Theodoraki 2019

TAP, transversus abdominis plane.

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