Prediction and Prevention of Persistent Postsurgical Pain

Alan David Kaye

Nicole Rose Rueb

Lindsey K. Xiong

Stewart J. Lockett

Victoria L. Lassiegne

Elyse M. Cornett

Introduction

Persistent postsurgical pain (PPSP) is chronic pain that lasts at least 3 months after surgery. The pain cannot be attributed to any other cause, such as infection or cancer, and must be distinctly characterized from any pain before the surgery.¹,² PPSP can occur after a variety of procedures, including herniorrhaphy and cesarean sections, thoracotomies, radical mastectomies, and hysterectomies.³ PPSP occurs in 10%-50% of patients. Severe PPSP affects as many as 2%-10% of all adults undergoing surgery. Possible etiologies of PPSP include persistent inflammation or damage to peripheral nerves resulting in neuropathic pain.

Inflammatory pain is defined as pain that occurs in response to tissue injury and inflammation. Inflammatory pain results from the release of inflammatory mediators leading to a lower threshold of nociceptors resulting in increased neuronal excitability. Neuropathic pain is caused by nerve injuries leading to aberrant transmission to the spinal cord and to the brain. Two of the most important determinants for the development of PPSP include iatrogenic nerve injury leading to neuropathic pain and the patient’s severity of preoperative pain.⁴ Severe preoperative pain is associated with sustained nociceptive input leading to changes in the central nervous system. The sustained nociceptive input may be enhanced by opioids leading to an exaggerated postoperative pain response.⁵ Other risk factors for the development of PPSP include severity of postoperative pain, multiple surgeries, younger age, female, surgery site, and genetic and psychological influences.²

Predictors of the development of PPSP cannot be limited to one clear cause and is difficult to predict related to psychological, emotional, behavioral components, and genetic influences.⁶ Methods to reduce the incidence of PPSP can take place preoperatively, perioperatively, and postoperatively. Preoperatively, patients with a high risk of developing PPSP should be identified and receive individualized pain management.⁷ Perioperatively, techniques to avoid nerve damage should be implemented whenever possible. Postoperatively, acute pain management must be addressed since there is a correlation between a patient’s intensity of acute postoperative pain and their predilection to develop PPSP.⁴ Prior research on PPSP has focused on pharmacotherapy and drug modality, including patient-controlled analgesia and spinal delivery methods. However, PPSP is often inadequately treated. Research focus has shifted to evaluating patient individualized increased response to pain and patient inadequate response to analgesics. Methods of assessing preoperative pain include quantitative sensory testing (QST), which assesses quantifiable pain responses to mechanical, thermal, or electrical stimuli.⁵ The QST measures pain thresholds to best quantify hyperalgesia.⁸ QST may be a valuable source in predicting postoperative pain.⁶

Persistent postsurgical pain can lead to prolonged rehabilitation, poor surgical outcomes, and an increased risk of cardiovascular and pulmonary complications.⁷ Proper preoperative screening for the susceptibility of PPSP and implementation of individualized therapies may lead to improvements in short-term and long-term morbidities caused by PPSP.⁵ The following chapter explains risk factors for developing PPSP, prevention, and intervention.

Risk Factors of Persistent Postsurgical Pain

Risk factors for PPSP include genetic, demographic, psychosocial, pain, medical comorbidities, and surgical factors.⁹

Demographic Risk Factors

Younger age is associated with an increased risk of PPSP across multiple surgical types, including breast, cardiac, and hernia repair.⁹,¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵ Few studies site female sex as a risk factor for postoperative pain.⁹,¹⁶,¹⁷,¹⁸ However, more recent analyses show equivocal data on gender as a significant risk factor for PPSP, warranting further research.⁹,¹³,¹⁵,¹⁹,²⁰,²¹

Genetic Risk Factors

The most extensively studied genetic target for PPSP is the COMT gene, which encodes catechol-O-methyltransferase enzyme and has been studied repeatedly in relation to experimental pain, chronic pain, and acute postoperative pain.⁹,²²,²³,²⁴,²⁵,²⁶ However, only a few studies have shown a significant association between COMT gene polymorphisms and PPSP, and this was only in the presence of another risk factor, pain catastrophizing.²⁵,²⁷,²⁸,²⁹

Medical Comorbidities

Preoperative medical comorbidities, their number, and severity may be important predictors of PPSP across multiple surgical types, with an emphasis on increased numbers especially important for predicting outcomes.³⁰,³¹,³²

Psychosocial Factors

Psychosocial factors, including depression, trait, and state anxiety; pain catastrophizing; and stress have often been implicated in the development of PPSP. However, meta-analyses have shown equivocal outcomes on the size of their effect.³³,³⁴,³⁵,³⁶,³⁷,³⁸ Pain catastrophizing, as a key risk factor, is defined as the propensity to magnify the threat of pain and feel helpless in the context of painful stimuli.³²,³³,³⁴,³⁹,⁴⁰,⁴¹,⁴² In a meta-analysis, Theunissen and colleagues discerned that 55% of included studies found preoperative anxiety and pain catastrophizing as statistically significant predictors for PPSP, with no studies supporting a reversed effect and all studies with larger sample sizes indicating a positive correlation.⁹,³³ In conjunction with a more recent meta-analysis by Giusti and colleagues, researchers posit a weak, albeit statistically and clinically significant association between depression, state anxiety, trait anxiety, self-efficacy, and pain catastrophizing and PPSP.³³,³⁵,³⁷

Pain as a Risk Factor

Pain has been repeatedly identified as the strongest predictor of PPSP across multiple surgery types. Preoperative pain, its duration, location, and intensity is a major risk factor for the development of acute postsurgical pain (APSP) and PPSP.⁴,⁹,¹²,¹⁴,¹⁷,²¹,²⁶,³⁴,³⁸,⁴³ In multiple hernia repair studies, preoperative pain has been associated with an increased incidence of
PPSP.¹²,⁴⁴,⁴⁵ Similar correlations were found in amputation populations with preamputation pain and postamputation phantom limb pain and in preoperative breast pain and phantom breast pain after mastectomy.⁴⁶,⁴⁷,⁴⁸ Furthermore, an emphasis on APSP and its relationship to PPSP across different surgical types has been reflected in the literature.⁹,¹⁴,⁴³,⁴⁹,⁵⁰ The connection between general preoperative pain, preoperative pain related to the surgical site, APSP, and PPSP is complex as preoperative pain may be attributable to multiple risk factors, including other medical comorbidities, and APSP may be due to increased pain susceptibility either as a consequence of poor pain management preoperatively or postoperatively.⁹,³⁴,³⁶,⁴⁹ Furthermore, Willingham and colleagues found that medical complications postoperatively were the strongest independent predictors of PPSP and associated with a twofold increase in risk of developing PPSP, further suggesting postoperative pain chronification into PPSP.¹⁵

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