Current Pain and Headache Reports (2018) 22:9

https://doi.org/10.1007/s11916-018-0666-8

OTHER PAIN (A KAYE AND N VADIVELU, SECTION EDITORS)

Chronification of Pain: Mechanisms, Current Understanding,

and Clinical Implications
Daniel J. Pak 1 & R. Jason Yong 1 & Alan David Kaye 2 & Richard D. Urman 1

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of Review The development of acute to chronic pain involves distinct pathophysiological changes in the peripheral and
central nervous systems. This article reviews the mechanisms, etiologies, and management of chronic pain syndromes with
updates from recent findings in the literature.
Recent Findings Chronic post-surgical pain (CPSP) is not limited to major surgeries and can develop after smaller procedures
such as hernia repairs. While nerve injury has traditionally been thought to be the culprit for CPSP, it is evident that nerve-sparing
surgical techniques are not completely preventative. Regional analgesia and agents such as ketamine, gabapentinoids, and COX-
2 inhibitors have also been found to decrease the risks of developing chronic pain to varying degrees. Yet, given the correlation of
central sensitization with the development of chronic pain, it is reasonable to utilize aggressive multimodal analgesia whenever
possible.
Summary Development of chronic pain is typically a result of peripheral and central sensitization, with CPSP being one of the
most common presentations. Using minimally invasive surgical techniques may reduce the risk of CPSP. Regional anesthetic
techniques and preemptive analgesia should also be utilized when appropriate to reduce the intensity and duration of acute post-
operative pain, which has been correlated with higher incidences of chronic pain.

Keywords Hyperalgesia . Central sensitization . Peripheral sensitization . Chronic post-surgical pain . Preemptive analgesia .
Opioid

Introduction provide an up-to-date understanding of the etiologies and

treatment options.
Chronic pain is a debilitating condition that affects more than
75 million Americans and is the primary complaint for 20% of
all annual outpatient clinic visits [1, 2]. Pain syndromes are
also a leading cause of functional disability and have an enor-
Mechanisms of Acute Pain
mous economic burden, accounting for over $100 billion dol-
Acute pain is typically nociceptive in nature and is a result of
lars per year in costs to employers and taxpayers in the USA
noxious stimulation from tissue damage. Peripheral
[2]. This review focuses on the pathophysiological mecha-
nociceptors are activated by inflammatory molecules (i.e.,
nisms involved in the development of chronic pain syndromes
prostaglandins, histamine) and generate action potentials
from acute pain with evaluation of the most recent literature to
which are transmitted to second-order neurons in the spinal
This article is part of the Topical Collection on Other Pain cord and ascend the spinothalamic tract to the cerebral cortex.
Moreover, ascending projections to the medial thalamus, re-
* Richard D. Urman ticular activating system, and hypothalamus are likely respon-
[email protected]
sible for the unpleasant emotional component and arousal as-
1
Department of Anesthesiology, Perioperative and Pain Medicine, sociated with pain [3].
Brigham and Women’s Hospital, 75 Francis Street, The transmission of ascending pain signals is simulta-
Boston, MA 02115, USA neously inhibited by descending projections from supraspinal
2
Department of Anesthesiology, School of Medicine, Louisiana State structures such as the periaqueductal gray. These structures
University, New Orleans, LA 70112, USA release inhibitory neurotransmitters (i.e., noradrenaline and
9 Page 2 of 6 Curr Pain Headache Rep (2018) 22:9

serotonin) at the level of the dorsal horn to hyperpolarize Table 1 Risk factors for chronic pain syndromes
ascending neurons and provide endogenous analgesia. This Surgery
characterizes the “gate control” theory of pain processing. • Intraoperative nerve damage
• Open surgical approach vs. laparoscopic approach
• Surgery duration > 3 h
Pathophysiology of Chronic Pain • Volatile general anesthesia
Chronic opioid use, opioid-induced hyperalgesia (OIH)
Peripheral Sensitization • High-dose opioid use
Patient factors
While nociceptors typically have high thresholds for activa-
• Pre-existing pain syndromes
tion, repeated stimulation increases nociceptor excitability. As
• Genetic predispositions (i.e., polymorphisms of voltage-gated Na+,
inflammatory molecules, including bradykinin, prostaglan- Ca+ channels)
dins, and substance P, are released from a site of tissue injury, • Mood disorders, anxiety
excitatory receptors, such as transient receptor potential V1 • Personality disorders
(TRPV1) channels, are upregulated [3]. As a result, patients • Female
experience increased sensitivity to pain (hyperalgesia). • Obesity
Increased neuronal expression of voltage-gated sodium chan- • Young age
nels and decreased expression of potassium channels may also
contribute to peripheral sensitization in chronic pain
syndromes.

Central Sensitization pain (CPSP), defined as pain that lasts at least 2 months fol-
lowing surgery excluding other causes (i.e., worsening dis-
Persistent transmission of pain signals from the peripheral ease, chronic infection), is also not restricted to major surger-
nervous system also induces central nervous system sensitiza- ies and is often seen after less invasive procedures [11].
tion. Excitatory sensory neuropeptides such as substance P Patients undergoing surgeries that are high risk of intraop-
and glutamate interact with neuronal G protein-coupled mem- erative nerve injury may be more susceptible to developing
brane receptors to lower the action potential thresholds of CPSP [12]. Thoracic (intercostal nerves) and breast
second-order neurons in the dorsal horn [4, 5]. A reduction (intercostobrachial nerve) surgeries can lead to the develop-
in descending GABA and glycine-mediated inhibitory signals ment of chronic neuropathic pain, and measures should be
further increases ascending neuron excitability [6, 7]. taken by the surgeon to reduce the risk of nerve damage. For
N-methyl-D-aspartate (NMDA) receptors play a crucial instance, anterior thoracotomies lower the risks of intercostal
role in central sensitization as well. Upregulation of these nerve damage [3, 13] and the performance of breast surgeries
receptors from persistent pain states enables transmission of at high-volume centers with experienced breast surgeons are
ascending pain signals with normally subthreshold stimuli, associated with lower incidences of post-operative pain [14].
creating a “wind-up” phenomenon [8]. Phenotypic reorgani- Laparoscopic approaches have also been demonstrated to re-
zation of sensory neurons is also suspected in central sensiti- duce CPSP compared to open approaches in gallbladder sur-
zation, with rodent studies demonstrating receptor field ex- gery [15]. However, despite attempts to utilize nerve-sparing
pansion and termination of sensory neurons in the superficial surgical techniques, it is evident that nerve injury is not the
laminae of the dorsal horn normally occupied by nociceptive only causative factor for CPSP. In a study of post-thoracotomy
neurons [9]. Therefore, non-painful stimuli such as light touch pain, Maguire et al. demonstrated no significant association
and pressure evoke painful sensations (allodynia). between intraoperative nerve injury and post-operative pain at
3 months [16]. Similarly, avoiding transection of the
intercostobrachial nerve during breast surgeries may not al-
Etiologies of Acute to Chronic Pain ways prevent CPSP [17]. Surgery duration is also an impor-
Syndromes tant factor to consider, with patients undergoing procedures
lasting greater than 3 h being at higher risk of developing
Chronic Post-surgical Pain (CPSP) subsequent pain syndromes [18]. This may, however, be mere-
ly indicative of the complexity of the surgery and extent of
Surgery is one of the most common sources of acute to chron- intraoperative tissue injury [12]. In short, patients should al-
ic pain syndromes (Table 1) [10]. Surgery-associated tissue ways be thoroughly educated of these post-operative risks, as
injury can lead to persistent inflammatory states that facilitate even elective surgeries such as vasectomies have reported
peripheral and central sensitization. Chronic post-surgical rates of CPSP up to 15% [19].
Curr Pain Headache Rep (2018) 22:9 Page 3 of 6 9

Chronic Opioid Use pain syndromes or vice versa [14, 27]. Nonetheless, personality
disorders (i.e., neuroticism) may represent deficiencies in cop-
Opioid use, though effective for acute pain, can induce ing skills essential for managing pain symptoms.
hyperalgesia and paradoxically contribute to the development
of chronic pain [20]. This is more commonly associated with
higher dosages and can lead to a dangerous cycle of increasing Prevention and Management
opioid utilization and worsening pain. Although the exact
mechanism of opioid-induced hyperalgesia (OIH) is unclear, Anesthetic Technique and Preemptive Analgesia
it is generally believed to be a result of increased NMDA re-
ceptor activation and dorsal column neuron sensitization [21]. Anesthetic technique is an important consideration for
In the context of hyperalgesia and allodynia with no evidence preventing CPSP. While general anesthesia blunts the aware-
of disease progression, clinicians should consider opioid rota- ness of surgical trauma, halogenated gases activate peripheral
tion or tapering the patient’s opioid dosage while providing nociceptive receptors that may paradoxically increase post-
NMDA modulators, such as ketamine. Differentiating OIH operative inflammation and peripheral sensitization [28].
from drug tolerance can be difficult. OIH typically presents The severity of acute post-operative pain has also been corre-
with more diffuse pain that is less defined in quality as well lated with the development of chronic pain [29]. Hence, re-
as withdrawal-like symptoms [21]. Furthermore, patients who gional anesthetic techniques should be utilized when appro-
exhibit tolerance usually experience improvement in their pain priate (Table 2). By blocking the propagation of nociceptive
with increasing opioid doses while those with OIH have wors- nerve impulses, preemptive analgesia may decrease risks of
ening pain. central sensitization. The use of pre-operative epidural anal-
gesia has been demonstrated to decrease the incidence and
Patient Factors intensity of chronic pain syndromes following thoracotomies
[3]. Similar benefits of perioperative regional anesthesia have
Individual patient characteristics play a substantial role in the been shown in patients undergoing hysterectomies, cesarean
development of chronic pain. Patients with pre-existing pain sections, limb amputations, and iliac crest bone harvesting [3].
syndromes or sensitivities (such as fibromyalgia, irritable Efforts to quantify baseline pain thresholds and tolerance
bowel syndrome, migraines, and irritable bladder syndrome) have demonstrated varying predictive strengths for identifying
are implicated with having an underlying genetic predisposi- those susceptible to developing CPSP, which can help guide
tion to the development of CPSP [3, 22]. Genetic polymor- the utilization of aggressive pre-operative and post-operative
phisms of catechol-O-methyltransferase (COMT), voltage- analgesia [11, 30]. Although the optimal timing of when to
gated sodium channels, voltage-gated calcium channels, and institute regional and systemic analgesia is unclear for CPSP
μ-opioid receptors have all been identified as potential gene prevention, pre-emptive analgesia instituted prior to surgical
targets for the treatment of chronic pain [3, 23, 24]. Other incision is preferable [31, 32].
genetic polymorphisms of CYP2D6 hepatic enzymes may
affect an individual’s metabolism and response to opioid and
non-opioid medications [24]. Moreover, female sex, young Ketamine
age, and obesity are risk factors for developing chronic pain
with reports that these patients tend to experience longer du- Administering perioperative ketamine, an NMDA receptor
rations and greater intensity of pain [25]. antagonist, as a single bolus (0.15–0.5 mg/kg) or low-dose
Psychosocial vulnerabilities are important for clinicians to infusion (2–4 mcg/kg/min) has been shown to be effective
be cognizant of as well, because pain perception is intimately
Table 2 Prevention and management of chronic pain syndromes
affected by an individual’s previous experiences, memories,
and mood. The limbic system of the brain, which contextual- Regional anesthesia
izes an individual’s pain experience, interacts with the • Neuraxial nerve block
rostroventromedial medulla, which modulates descending • Peripheral nerve block
pathways that inhibit nociceptive inputs [26]. Catastrophizing • Local wound infiltration
and anxiety can lead to hypervigilance and predispose patients Ketamine
to the development of chronic pain [11]. Furthermore, mal- Gabapentinoids
adaptive response to pain not only amplifies a patient’s percep- COX inhibitors
tion of the stimulus but also one’s ability to modify behavior in Intravenous lidocaine
a positive manner. Personality disorders and mood disorders TRPV1 agents
have been associated with higher rates of CPSP, though it is Cognitive behavioral therapy
difficult to distinguish whether these disorders lead to chronic
9 Page 4 of 6 Curr Pain Headache Rep (2018) 22:9

for treating acute pain and preventing OIH [12, 33]. The an- stimuli, effectively providing pain relief. Other similar
algesic mechanism is via antagonism of NMDA-mediated vanilloid derivatives (resiniferatoxin) attenuate inflammatory
wind-up and activation of supraspinal descending inhibitory hyperalgesia and chronic pain when administered intrathecal-
pathways. Several studies have demonstrated a reduction in ly, though the clinical application of this approach is still novel
post-operative pain and opioid consumption beyond the [41].
drug’s expected duration of action [34]. Ketamine administra-
tion in patients with acute neuropathic pain from spinal cord
Behavioral Therapies
injury also reduces the incidence of allodynia [35•]. Yet, the
evidence for ketamine as a preventative agent is somewhat
Preemptive cognitive behavioral therapies (CBT) help to de-
equivocal, with recent studies calling into question the effec-
crease anxiety prior to and during acute pain episodes by
tiveness of intraoperative ketamine in decreasing CPSP fol-
teaching effective coping mechanisms and relaxation tech-
lowing cardiac surgery [36•].
niques. Enabling patients to feel more in control with their
therapies and pain-driven behaviors allows them to actively
Gabapentinoids
manage their distress. This has been demonstrated to reduce
pain intensity and opioid use in post-surgical patients [42].
Gabapentinoids, such as gabapentin and pregabalin, are also
Furthermore, preemptive CBT can be particularly efficacious
effective as preemptive analgesics. Both are anticonvulsant
in high-risk individuals preparing for surgery. By providing
agents that have high affinity to α-2-δ subunit-containing
education and reassurance that post-operative discomfort is
voltage-gated calcium channels and provide analgesia by
expected and normal, fear-avoidance behaviors can be tem-
inhibiting the release of excitatory neurotransmitters in as-
pered. Also, since unemployment is an important prognostic
cending pain pathways. Gabapentinoids have been widely
factor for disability in patients with acute and chronic pain,
used as first-line agents for the treatment of neuropathic pain
behavioral interventions to encourage early rehabilitation and
syndromes. In a meta-analysis examining the efficacy of
resume work responsibilities is crucial for regaining function-
gabapentin, four of eight studies found that perioperative
ality [43••].
gabapentin administration reduced the incidence of CPSP
Once chronic pain has developed, a multidisciplinary team
[37]. Gabapentin has also been found to increase range of
approach integrating physicians (i.e., primary care physicians,
motion and improve functionality compared to placebo in
pain physicians, psychiatrists) and non-physicians (psycholo-
patients undergoing total knee arthroplasties [38].
gists, physical therapists, complementary therapists) is often
necessary to address the multitude of ways pain impacts one’s
Cyclooxygenase Inhibitors
quality of life. Individual treatment plans address a patient’s
specific needs with continuity of care. Prospective studies
Inflammatory reactions during acute pain episodes induce
have demonstrated the potential superiority of multidisciplin-
cyclooxygenase-2 (COX-2) and upregulate the expression of
ary approaches for pain management compared to various
prostaglandins, which contribute to peripheral and central sen-
unimodal approaches in improving physical functioning, dis-
sitization. Non-steroidal anti-inflammatory drugs (NSAIDs),
ability, employment, long-term pain intensity, and mood dis-
particularly COX-2 selective inhibitors, have been found to
orders [1, 44, 45••]. In fact, Rasmussen et al. demonstrated an
play a critical role for suppression of nociceptive hyperalgesia
almost 50% reduction in lumbar disc surgery in patients un-
[39]. Oral COX-2 inhibitors also have excellent penetration
dergoing non-surgical multidisciplinary treatment for sciatica
across the blood-brain barrier and should be considered as
[46].
first-line therapeutic and preventative agents.

Other Medication Therapies

Conclusion
Perioperative intravenous lidocaine administration reduces
post-operative pain and opioid requirements in patients under- The development of acute to chronic pain is a progressive and
going abdominal surgery [40]. While lidocaine infusions have complex process. Repeated acute injury, opioid-induced
been linked to reducing acute post-operative pain and likely hyperalgesia, neuroinflammation, comorbid psychiatric con-
playing a role in preventing central sensitization, its long-term ditions, and modification of pain processing systems have
protective effect against CPSP has yet to be elucidated. been linked to the development of chronic pain states.
TRPV1 channels are also a target of interest given that they Prolonged inflammation and degenerative conditions from
populate the terminals of nociceptors and are modulated by tissue damage following an injury or surgery can lead to a
inflammatory molecules. Topical capsaicin binds to these cascade of neural dysfunction that ultimately results in periph-
channels to desensitize peripheral nociceptors from noxious eral and central nervous system sensitization. Patients can also
Curr Pain Headache Rep (2018) 22:9 Page 5 of 6 9

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