Chronic Post-surgical Pain Syndromes: Prediction and Preventive Analgesia

Incidence of CPSP

Having a well-developed definition and standard diagnostic criteria has assisted the visibility and recognition of CPSP, which had previously been underestimated. However, the diagnostic criteria for CPSP do not specify a clinically meaningful pain severity to define CPSP. Even with these more closely defined diagnostic criteria, variation in cut points for the severity constituting clinically significant pain and at timepoints chosen to study CPSP likely contributes to the wide range of reported incidence of CPSP in the literature. Studies have used different definitions to denote clinically meaningful CPSP, ranging from anything >0/10 on the pain scale to only considering pain >3 or >4/10 as significant. Frequency may be variable (constant vs. intermittent), and the quality of the pain may depend on its location and the exact mixture of its mechanistic basis. From mild to debilitating pain, this range of severity correspondingly results in varying degrees of negative impact on quality of life.

Thus the estimates for the incidence of CPSP vary substantially even among studies using the same procedure ( Table 24.2 ), ^, according to the methodologic differences in defining CPSP by pain intensity ( Table 24.2 ), and by time ( Fig. 24.1 ), and across study samples. The procedures with the highest reported incidence of CPSP include thoracotomy (5%–65%), mastectomy (11%–57%), and amputation (30%–85%). These procedures also have a higher prevalence of moderate to severe pain (5%–10%) than herniotomy (2%–4%) and seem to have more neuropathic characteristics (66%–68% for thoracotomy and mastectomy) than hip or knee arthroplasty (6%).

Although cross-sectional studies are the most common, some longitudinal studies have tracked the incidence of CPSP at later time points and generally show a decrease over time. For example, the incidence of CPSP after thoracotomy in the study by Montes et al. showed 38% at four months, 19% at 12 months, and 13% at 24 months. A similar mean trajectory of CPSP has been reported after hysterectomy and hernia repair ( Fig. 24.1 ). In contrast, other studies have suggested a relatively low but stable incidence beyond three months, as in the case of mastectomy, where both cross-sectional studies querying patients at six months to six years, and longitudinal studies out to 12 months, suggest a similar incidence of about 30% reporting pain of ≥3/10 or more. A more in-depth analysis, taking interpatient variability into account, suggests that there may be multiple pain trajectories within the first year after surgery, depending on severity, experienced by different subgroups of patients.

A large international study averaging across multiple surgical types showed an overall incidence of CPSP of 41% (95% CI 38–43) at six months and 35% (95% CI 32–39) at one year. However, patients with severe pain (NRS ≥6/10), who also reported greater pain interference with activities and mood than patients with more moderate pain, represented only 2% of patients in the same study (95% CI 1–3).

Neuroplasticity

Neuroplasticity is a term that describes the adaptability within the structure and function of the nervous system, a quality that fundamentally underlies several crucial tasks of the nervous system, such as learning and memory, and also includes self-preservation from noxious stimuli. The intense nociceptive and inflammatory stimuli from tissue injury that occurs during surgery is a message that the nervous system cannot evolutionarily afford to ignore. The nervous system response to tissue injury can be regarded as functional neuroplasticity. Increased pain immediately after surgery can drive adaptive behaviors that facilitate healing. However, these processes, when sustained or solidified into CPSP, represent a maladaptive change.

Surgical injury of tissues leads to a local release of inflammatory and other mediators and creates an acidic and often locally ischemic environment. These mediators activate peripheral nociceptors both directly through binding of mediators and by decreasing the threshold to activation by other stimuli, making normally painful stimuli more painful (hyperalgesia) and painful nonpainful stimuli (allodynia) at the site of injury (primary hyperalgesia and allodynia, limited to injury site). intense and maintained nociceptive input from the periphery also activates central nociceptive pathways, starting at the level of the dorsal horn, and modulating descending facilitation and inhibition from supraspinal centers, and cortex. This multi-level activation contributes to increased sensitivity at the primary site and sites distal to the injury (secondary hyperalgesia), otherwise known as central sensitization ( Fig. 24.2 ).

Changes in receptor and gene expression in the dorsal root ganglion contribute to this prolonged excitability of primary nociceptors (peripheral sensitization) and thus enhanced transmission of the nociceptive signal. Correspondingly, the continued transmission of this nociceptive input can cause transcriptional changes at the level of the spinal cord that underlie central sensitization. The N -methyl-d-aspartate (NMDA) receptor plays a pivotal role in the amplification of pain and central sensitization at the level of the spinal cord, as evidenced in pre-clinical and human models. The application of NMDA receptor antagonists to prevent hyperalgesia in experimental models provided hope for a similar outcome in humans. Some studies showed that NMDA receptor antagonism with agents such as ketamine might modify the incidence or intensity of CPSP in clinical application. Additionally, the response from surrounding immune, stromal, and glial cells in the periphery and spinal cord causally contributes to and sustains peripheral and central sensitization, influencing the extent and duration of pain and its transition to a more chronic state. In keeping with the idea of noxious nociceptive input from the periphery driving central sensitization, efforts to interrupt the intense nociceptive signal have long been viewed as a way to prevent pain amplification and nervous system plasticity (preventive analgesia, sometimes called preemptive analgesia).

The concept of preemptive analgesia was described in 1983 as an early analgesic intervention initiated before a nociceptive stimulus, which may “preempt” the development of persistent pain. However, clinical studies comparing analgesics given before vs. immediately following an injury failed to strongly confirm the idea of preemption. The subsequent concept of preventive analgesia recognized the need to extend the time window of intervention to cover not only the initial intense nociceptive stimulation (during injury or hours after injury) but also the ongoing inflammation and aberrant firing of injured nerves at later time points (days after injury), when ongoing nociception has not yet abated. ^, The impact of regional anesthesia (nerve blocks), and pharmacologic agents such as ketamine, and lidocaine, have been often studied, with mixed but promising results in preventing CPSP. The definitions of these concepts are summarized in Table 24.3 .

Opioid-Induced Hyperalgesia

Opioids have long been commonly used as potent analgesics. However, when used chronically and at high doses, analgesic efficacy may diminish, disappear, or even lead to increased pain. This paradoxical phenomenon, where opioids lead to a hyperalgesic state, is called opioid-induced hyperalgesia.

Opioid-induced hyperalgesia (OIH) can be conceptualized as secondary hyperalgesia. The mechanism underlying OIH likely involves transcriptional changes leading to an imbalance between pro and antinociceptive pathways, including µ-opioid signaling, pronociceptive ion channel modulation, and microglial activation. Chronic exposure to opioids has been shown to result in µ-opioid receptor phosphorylation by G-protein coupled receptor kinases, which leads to β-arresting-2 recruitment, µ-opioid receptor endocytosis, and receptor unavailability. ^,

A systematic review of clinical studies suggests that high intraoperative doses of remifentanil are associated with small but significant increases in acute pain after surgery. Even lower dose and briefer exposures to remifentanil (0.1 mcg/kg/min for 30 min) have been associated with OIH. In pre-clinical studies, the hyperalgesic effect of a single dose of fentanyl can last for three weeks. OIH may potentially augment hyperalgesia from tissue injuries itself, making opioid-sparing strategies such as multimodal analgesia especially important in treating both acute postoperative pain and CPSP. Ketamine, an NMDA receptor antagonist, has been shown to decrease β-arresting-2 transcription in mice and to clinically decrease punctate hyperalgesia in humans who received remifentanil. Within a clinical context, it may be challenging to distinguish OIH from opioid tolerance, inadequate analgesia, and changes in underlying disease pathology. However, it may be suggested by altered sensory processing such as allodynia and hyperalgesia and worsening pain with further doses of opioids. Assessing specifically for signs of OIH early after surgery may allow a better determination of the extent to which OIH contributes to CPSP.

Nerve Injury

Peripheral nerves are among the tissues that can be injured by surgery. Peripheral nerve injury is often considered a central contributor to the mechanistic basis of CPSP. As outlined in the neuroplasticity section above, peripheral nerves contribute fundamentally to carrying an augmented message of pain after any tissue injury, whether the nerves themselves have sustained structural damage. However, pre-clinical studies have shown that a variety of damage to peripheral nerves may cause increased and spontaneous firing of action potentials, changes in gene expression including up and downregulation of neurotransmitters, and immune system activation after injury. These changes occur at the dorsal root ganglion level but reverberate to the dorsal horn and higher centers.

Neuropathic pain in the context of CPSP can be defined in various ways, although typically utilizing questionnaires such as the DN4, S-LANSS, and painDETECT, or by including similar questions in a surgery specific questionnaire. The presence of pain features of a certain quality (e.g. burning, tingling, stabbing) are indicators of nerve injury. Based on these definitions, the prevalence of neuropathic pain in CPSP varies from 6% to 68% among various surgeries, although the highest reported ranges appear after thoracic and breast surgery and lowest after hip or knee replacement. While more extensive nerve damage is associated with a higher incidence of CPSP, higher pain severity, and functional impairment, nerves are rarely injured in isolation, and causation cannot be inferred from this correlation.

Risk Factors for Developing CPSP

Although surgical injury, by definition, is the inciting event for CPSP, the surgical extent is not always the best predictor of greater incidence and severity of CPSP. Chronic pain is a complex interaction between nociception and an individual’s life. Many factors beyond the degree of tissue injury are formative to the individual experience of pain after surgery, including genetic, psychological, and social factors. The biopsychosocial model of pain, which includes biophysical differences between individuals (genetic variation, baseline nociceptive sensitivity, opioid dependence), and differences in psychosocial factors known to be involved in the processing of pain (anxiety, depression, coping strategies, social support), provides a comprehensive picture of the risk and predictive model for CPSP ( Fig. 24.3 ).