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When Does Acute Pain Become Chronic?: Key Points
When Does Acute Pain Become Chronic?: Key Points
doi:10.1093/bja/aeq323
PAIN
Summary. The transition from acute to chronic pain appears to occur in discrete
Key points pathophysiological and histopathological steps. Stimuli initiating a nociceptive response
† The transition from acute vary, but receptors and endogenous defence mechanisms in the periphery interact in a
to chronic pain occurs in similar manner regardless of the insult. Chemical, mechanical, and thermal receptors,
Pain-related problems account for up to 80% of visits to Mechanism for acute pain generation:
physicians. The epidemiological significance of chronic pain
peripheral effects and spinal and central
after surgery is enormous.1 The prevalence of chronic pain
can range from 10.1% to 55.2% of the populations effects
studied.2 Current theories propose that a prolonged experi- The generation of acute surgical pain can be summarized
ence of acute pain in which long-standing changes are in the following way. Surgery-associated tissue injury is inter-
seen within and external to the central nervous system preted neuraxially in the same way as trauma-
(CNS) creates chronic pain with a histological and pathologi- associated injury. Pain sensation varies according to the
cal basis.3 Furthermore, chronic pain development after intensity, quality, and duration of stimuli. Surgery sets off a
surgery likely occurs as a result of complex biochemical cascade of inter-related events designed to fight infection,
and pathophysiological mechanisms that differ in type limit further damage, and initiate repair. It involves
among different surgical procedures. This article focuses on nociception, inflammation, and nerve cell remodelling.
how postoperative, traumatic, and neuropathic nociception Pro-inflammatory cytokines, chemokines, and neurotrophins
are generated and inter-related, with the goal of providing induce both peripheral and central nerve sensitization to
a deeper understanding of how long-term pain develops so heighten pain awareness in order to limit further injury to
that we can prevent and treat it more effectively, in the the affected area. In the generation of pain, multiple pain
hope of stimulating more research and inquiry. systems are known to be activated.
& The Author [2010]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: journals.permissions@oxfordjournal.org
BJA Voscopoulos and Lema
It is the activation of nociceptors in the periphery, and inhibitory and facilitatory descending pathways from
their ongoing activation, through processes such as periph- higher CNS centres.7
eral and ultimately central sensitization, that underlies one The CNS can alter the afferent nociceptive information it
mechanism of the transition to the chronic pain state. receives by a descending or modulatory system. This
Nociceptors are free nerve endings, with no extracellular system arises out of several regions of the CNS, including
matrix capsule or epithelial cell adjoined to the neurone, the somatosensory cortex, hypothalamus, PAG, pons,
and respond to stimuli that damage or threaten to damage lateral tegmental area, and raphe magnus. These structures
tissue.4 Nociceptors are present in skin, muscle, joints, and communicate with laminae I and V via the dorsolateral funi-
viscera, with varying degrees of density. It is this density of culus. Stimulation of these areas, or of their common outlet
population that allows for differential sensory ability, for path via the dorsolateral funiculus, inhibits nociceptive
example, the difference between the finger tip and the impulses promoting an analgesic effect.8 Descending
back.5 Nociceptors are the primary afferent terminals of inhibition largely involves the release of norepinephrine in
nerves that generate impulses to the spinal cord, and are the dorsal horn from the locus coeruleus, acting at
categorized by their receptive modality and by their response a2-adenoceptors, to inhibit primary afferent terminals and
to that stimulus.5 suppress firing of projection neurones.9 10 Descending facili-
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When does acute pain become chronic? BJA
Na+ channels, these neurones can exhibit ephaptic trans- of other tissues.18 – 26 Additionally, so-called ‘sleeping’
mission both between peripheral fibres and their cell bodies nociceptors can become activated after exposure to inflam-
within the dorsal root ganglion. Along with changes within mation and other endogenous mediators, and might rep-
nociceptive fibres, sympathetic efferents become able to resent as much as 15% of all C-fibres, contributing to a
activate nociceptive fibres via poorly characterized significant increase in peripheral input to the CNS.
a-adrenoceptors.15 In relation to this generation of spon-
taneous activity, the Nav 1.8 Na+ channel subtype is thought
to play a key role. Knockdown of this receptor in mice produces Neuroplasticity
a marked reduction in abnormal responsiveness.16 Neuroplasticity, or the physical remodelling of neuronal
Understanding the endogenous mediators and factors cytoarchitecture, occurs shortly after the onset of persistent
that contribute to sensitization in a synergistic fashion might acute pain and leads to the transition from acute pain into a
provide a better understanding of how acute pain may tran- chronic pain state. As a result of a peripheral lesion that per-
sition to a chronic physiological pain state (Fig. 1). Blocking sistently generates pain impulses to the spinal cord, inhibi-
these receptors might attenuate or prevent acute pain, or if tory interneurones responsible for modulating painful nerve
a chronic pain state has already developed, might ameliorate transmission impulses eventually die. Furthermore, glial
Plasma TNFa
extravasation IL6
Vasodilation LIF
Macrophage
Mast Tissue
cell damage
Pressure
Heat Bradykinin
5HT Histamine ?
IL1ß ATP H+
PGE2 NGF
Ca2+
(PKC)
PKA
PKC
TTXs
TTXr
(SNS/SNS2) Peripheral terminal
Fig 1 Peripheral mechanisms of nerve fibre sensitization. Understanding the ability of peripheral neurones to sensitize is complex given the
number of known ligand- and voltage-gated ion channels. However, many of these receptors use protein kinases A and C (PKA, PKC) signalling
pathways. Vanilloid type 1 receptor (VR1), 5-hydroxytryptamine receptors (5HT), Histamine type 1 (H1), Prostaglandin E2 (PGE2), Prostanoid
receptor EP subtype (EP), bradykinin receptors (B1/B2), interleukin-1 beta (IL-1b), interleukin-1 receptor (IL1-R), nerve growth factor (NGF),
tyrosine kinase A receptor (TrkA), adenosine triphosphate (ATP), purinergic receptor subtype P2X (P2X), hydrogen ion (H+), calcium (Ca2+),
protein tetrodotoxin-resistant voltage-gated sodium channel (TTXr), tetrodotoxin-sensitive voltage-gated sodium channel (TTXs), substance
P (Sub P), acid-sensing channel (ASIC). Used with Permission by Elsevier Limited. Modified from Costigan M, Woolf CJ. Pain: molecular mech-
anisms. J Pain 2000 (Suppl. 3):35 –44.
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BJA Voscopoulos and Lema
Whereas primary hyperalgesia occurs in the periphery, recognized that ‘chronic pain is the most common and
secondary hyperalgesia occurs within the CNS and precedes serious long-term problem after repair of an inguinal
long-term central sensitization. Most of the treatments for hernia,’ showing a heightened awareness of this important
postoperative pain have only minimal analgesic effects on issue in the last decade.33 44
secondary hyperalgesia. As secondary hyperalgesia is felt Surgery causes the release of inflammatory and other
to be a source for chronic postsurgical pain, developing mediators. Initially, these mediators activate nociceptors,
agents to better treat secondary hyperalgesia might be however during persistent pain nociceptors become sensi-
more effective in preventing chronic postsurgical pain, and tized. If this persistent pain resolves in the process of
treating acute postoperative pain.28 29 normal wound healing, this process of sensitization and
facilitation of synaptic transmission to the CNS reverts to
normal intrinsic nociceptor activity. For many surgery-related
Post-procedural pain reasons, such as prolonged inflammatory states with the
The factors contributing to post-procedural pain can broadly insertion of mesh materials or chronic nerve stretching in
be divided between patient and surgical factors. Patient bunionectomy, this process of sensitization and facilitation
factors include psychosocial status, pre-existing pain con- can cause phenotypic and pathophysiological changes in
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When does acute pain become chronic? BJA
without neuronal loss, increased neuronal expression of
Table 1 Predisposing factors for chronic post-procedural pain c-Fos, and increased number of dynorphin-immunoreactive
Preoperative pain at the site of surgery or other body regions
neurones in the spinal cord ipsilateral to the limb with
Psychosocial and mood factors
cancer.57 Differences were also found for microglial cells, in
Coping skills
which the marker complement receptor type 3 (Ox-42-IR)
Surgical factors
was increased only in the neuropathic pain model.57
1. Nerve damage (complicated aetiology likely than just nerve
Many patients with post-procedural pain report both
injury alone) sensory abnormalities and localized stimulus-evoked pain,
2. Factors predisposing to prolonged inflammatory states suggesting that both abnormal sensory nerve function and
(foreign materials) ongoing nociception play a role. Effective treatment for
3. Volume of surgeries performed per year for given operation these two interwoven yet distinctly different pain syndromes
4. Recurrence of operation is unlikely to be solved using a single therapeutic strategy for
5. Type of surgery one or the other.30 58
6. Length of surgery
Genetic predisposition
Epidemiology of chronic pain
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BJA Voscopoulos and Lema
analgesic techniques as a necessity. The process of central (nitric oxide, prostaglandins). Activated glial cells then upre-
sensitization is probably similar in this regard. gulate cyclo-oxygenase-2 (COX-2) to produce prostaglandin
As seen in the dorsal root reflex and axonal reflex, action E2 and release additional neuroactive substances (cytokines
potentials can be initiated in the central terminal, and con- interleukin-1, interleukin-6, TNF-a). These substances
ducted antidromically to the periphery. After surgical tissue increase the excitability of second-order neurones, and play
damage, this mechanism appears to be a significant factor a role in axonal sprouting, altered connectivity, and cell
in neurogenic inflammation.65 death.77 Hence, persistent glial cell activity producing these
There is evidence of a possible window in which perma- pro-inflammatory mediators plays a role in the development
nent changes occur in nociceptors after an insult.66 In refer- of a neuropathic pain state.78 79 Post-traumatic models,
ence to the development of neuropathic pain, this concept of inflammatory models, central demyelinating disorders, and
a window would be important in terms of the timing of the diabetes mellitus have all demonstrated a role for glial cell
delivery of treatment. activation.78 80 – 86 Activation of microglia can be followed
by increased expression of p38 mitogen-activated protein
N-methyl-D-aspartic acid receptors kinase (MAPK), which participates in a signalling cascade
controlling cellular responses to cytokines and stress and is
Prolonged firing of C-fibre nociceptors causes release of gluta-
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When does acute pain become chronic? BJA
Fig 2 Peripheral and central roles of prostaglandins and cyclo-oxygenase-2 (COX-2) in pain perception and sensitization. COX-2 plays both a
peripheral and central role in pain perception and sensitization. However, inflammation-evoked spinal hyperexcitability might be more related
to spinal COX-2 causing the metabolism of 2-arachidonoylglycerol (2-AG) to prostaglandin E2 subtype G (PGE2-G), and other endocannabinoids
to derivatives that bind prostaglandin receptors, than to spinal prostaglandin synthesis. Interleukin-1 beta (IL-1b), N-methyl-D-aspartate
receptor (NMDA), calcium (Ca2+), nitric oxide synthetase (NOS). Modified and used with permission from Raymond Sinatra MD, PhD.
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BJA Voscopoulos and Lema
Table 3 Summary of cannabinoid effects in pain development. Table 4 Summary of cyclo-oxygenase-2 effects in pain
CB1R, cannabinoid receptor subtype 1; CB2R, cannabinoid development. CNS, central nervous system
receptor subtype 2; RVM, rostral ventromedial medulla; CNS,
central nervous system; PNS, peripheral nervous system; PAG, Central upregulation by interleukin-1b
periaqueductal grey; FAAH, fatty acid amide hydrolysis Upregulation in CNS causes central sensitization via
prostaglandin E2
Derivatives of arachidonic acid Can metabolize anandamide and 2-arachidonoylglycerol into
Not stored in vesicles—rapidly synthesized de novo derivatives that bind prostaglandin receptors
Possess anti-nociceptive properties Cyclo-oxygenase-2 oxidizes 2-arachidonoylglycerol to form
CB1R expressed largely in CNS and PNS prostaglandin E2-G (pro-nociceptive agent)
CB2R expressed largely outside CNS and PNS
CB1R and CB2R are G protein-coupled
Act by retrograde synaptic inhibition inhibitors is more related to endocannabinergic mechanisms
Involved in PAG and RVM descending inhibitory pathways than to the inhibition of spinal PG synthesis91 (Table 4). These
CB1R mediates inhibitory tone on nociceptive activity early findings are encouraging. Of the commercially available
coxib compounds, rofecoxib and etoricoxib have good CNS
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When does acute pain become chronic? BJA
TRPV1 receptor to provide pain relief for 3–4 days after strong predictor of subsequent chronic pain.146 As severe
surgery.130 and persistent preoperative pain are reasonable predictors
Activation of the CB1 receptor in cultured primary sensory of chronic pain development, aggressive treatment of pain
neurones reduces responses mediated through the TRPV1 in the perioperative period should be a focus to prevent
receptor and plays a pivotal role in the development of chronic pain development.146 However, to date, the effective-
heat hyperalgesia and visceral hyper-reflexia in inflamma- ness of this approach has been equivocal.
tory conditions.131 Furthermore, anandamide might inhibit Physical activity or physical therapy is most effective when
TRPV1-mediated responses in a non-CB1/CB2 receptor- acute pain is managed optimally.147 Perhaps allowing the
dependent manner in primary sensory neurones in inflam- nervous system to learn, or relearn, functional skills is the
matory conditions.131 Emerging pharmacological treatments reason why staying active may be so important in the treat-
are promising, as this receptor is thought to play important ment, and prevention, of non-specific low back pain where
roles in neurone sensitization induced by inflammation and neuroplastic changes have occurred.148 Other interesting
nerve injury.132 133 possibilities in preventing neuroplastic changes in the
dorsal horn include pharmacological block of 5--
Genetics hydroxytryptamine-3 (5-HT3) receptors, which has been
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BJA Voscopoulos and Lema
diabetic peripheral neuropathy, microglial cells appear to thoracotomy pain syndrome.168 169 Similar findings have
play a prominent role as demonstrated by an increased been noted in breast surgery in which attempts to preserve
density in the dorsal spinal cord and thalamic nuclei in dia- the intercostobrachial nerve are associated with a lower inci-
betic mice.103 Cannabidiol has anti-nociceptive effects in dence of pain.170 In hernia and gallbladder surgery, laparo-
mice. Specifically, cannabidiol started concomitantly with scopic approaches vs open approaches have lower
the evolution of the diabetic neuropathic state was associ- incidence of chronic post-surgical pain.171 – 174 In breast
ated with a lesser microglial density in the dorsal spinal surgery, less-experienced lower volume units had a higher
cord and blunted elevation in phosphorylated p38 MAPK. incidence of chronic post-surgical pain than more experi-
This reduction in microglial accumulation and activation in enced centres.175 Patients operated for a recurrence of ingu-
the dorsal spinal cord was associated with limited develop- inal hernia are at higher risk for persistent pain.176
ment of a neuropathic pain state, even after the discontinu- Though efforts are made to simplify the issue of chronic
ation of cannabidiol, although it did not alter the course of post-surgical pain by surgical factors such as nerve
the diabetic condition. When the neuropathic state was damage, it is important to note that these issues probably
already established, both CB1 and CB2 agonists demon- represent a more complicated aetiology. In a study examin-
strated an anti-nociceptive effect until their discontinu- ing post-thoracotomy pain, neurophysiological tests before
Anaesthetic factors
Surgical factors Though little is known about the long-term consequences of
Working closely with surgeons to modify surgical approaches anaesthesia techniques and their possible links to chronic
could prove beneficial in the prevention of chronic pain devel- pain development, halogenated anaesthetics used routinely
opment. Lightweight mesh and non-invasive fixation could in anaesthesia activate peripheral pro-nociceptive ion chan-
be more effective for the prevention of chronic pain with nels, and in doing so enhance neurogenic inflammation.184
laparoscopic hernia repair.167 Though larger randomized A few studies dealing with pre-emptive analgesia to
studies are needed, these concepts are in line with the reduce central sensitization focused on the use of epidural
current understanding of inflammatory pain in the develop- analgesia. They followed patients through the postoperative
ment of chronic pain. Intra-operative nerve damage as period and found decreases in the incidence of postoperative
seen in thoracotomies and mastectomies plays a key role pain.38 43 185 186 Several studies have shown that the use of
in the development of chronic neuropathic pain, and care an epidural block before surgery could reduce the incidence
should be taken to minimize such neuronal damage.146 For of long-term post-thoracotomy pain at 6 months after oper-
example, anterior thoracotomies are not as likely to ation.187 188 For example, Richardson has shown that
develop intercostal nerve dysfunction or resultant post- regional anaesthetic techniques can reduce the incidence
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When does acute pain become chronic? BJA
of chronic post-thoracotomy pain.189 Likewise, there have patients could be candidates for analgesic therapy as early
been several studies that have shown benefit for regional as 1 week before surgery utilizing some type of changing
anaesthetic techniques to reduce chronic post-surgical pain therapeutic regimen and continuing, uninterrupted, several
after hysterectomy, Caesarean section, and iliac crest bone weeks after discharge from the facility.
harvesting. However, there have also been studies that Though the evidence in this regard is conflicting, given the
have not shown this benefit.135 188 One possibility for the dis- clear relationship of the severity of acute postoperative pain
cordance between reports is the length of analgesic treat- leading to chronic post-surgical pain and what is known
ment time needed to prevent pain signals from inducing about peripheral and central sensitization, it appears reason-
neuroplastic changes within the spinal cord.33 able that better designed studies tailored to individual
patients will show effective multimodal drug treatment in
Predicting postoperative pain the prevention of chronic post-surgical pain.
Recently developed preoperative quantitative sensory testing
(QST) could possibly be used as a clinical tool to predict post- Conclusions
operative pain, and predict the majority of variance in acute The question of whether acute pain causes chronic pain has
postoperative pain.190 This assessment can perhaps guide not been completely resolved, but some type of stimulus or
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BJA Voscopoulos and Lema
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