Persistent Postsurgical Pain
More than 45 million surgical procedures are performed in the United States each year.1 It has been estimated that acute postoperative pain will develop into persistent postoperative pain (PPP) in 10% to 50% of individuals after common operations.2 Since chronic pain can be severe in up to 10% of these patients, PPP represents a major clinical problem—affecting at least 450,000 people each year.
Postsurgical pain is defined as pain lasting more than 3 to 6 months after surgery. The pain differs in quality and location from pain experienced prior to surgery, and is usually associated with iatrogenic neuropathic pain caused by surgical injury to a major peripheral nerve.2 Although all types of surgery can lead to PPP, some surgeries are at higher risk of causing nerve damage, such as inguinal hernia repair, breast and thoracic surgery, leg amputation, and coronary artery bypass surgery (Table 1). Consequently, surgical techniques that avoid nerve damage should be applied whenever possible.
Despite improved understanding of the process, interpretation of pain signals, and the development of new analgesic techniques,3 undertreatment of postoperative pain continues to be a problem.4 Therefore, it is now recognized that aggressive perioperative interventions can reduce the intensity of acute postoperative pain, which reduces the risk of a patient developing PPP. Genetics may also play a role. The role of genetic factors should be studied, since only a proportion of patients with intraoperative nerve damage develop chronic pain.2 In addition, research is also suggesting that a patient’s emotional make-up can influence his or her risk of developing PPP.5-8 Based on all these factors, it now seems appropriate to apply a multimodal approach to preventing postoperative pain.9,10
This article will review strategies for the identification of patients at risk for PPP, as well as possible treatment strategies.
Mechanisms and Science
Pain is defined by the International Association for the Study of Pain as an “unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”11 It is both a psychological and sensory experience. Research has shown there are multiple brain regions that modulate both pain and emotion.12
Surgery, by nature, involves the cutting of tissues and nerves, which induces the injury response (inflammation, hyperalgesia) and alterations of peripheral and central nervous system (CNS) pain processing (central sensitization), which can lead to chronic pain (Figure 1).2 After peripheral nerve injury, increased sodium-channel (Na) expression on sensitized primary afferent nerves leads to spontaneous activity with increased glutamate release from the nerve endings. This excess of glutamate acts on glutamate receptors (N-methyl-D-aspartate [NMDA], α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid [AMPA], kainate, and metabotropic glutamate receptors [mGluRs]), thereby triggering intracellular changes. These changes contribute to sustained central sensitization, with increased spontaneous impulse discharges, reduced thresholds, increased response to peripheral stimuli, and expanded receptive fields of central neurons.13
Central sensitization is an amplification of pain signaling in the spinal cord from repeated stimulation from the periphery. Surgery increases synaptic activity in dorsal horn neurons. Humoral signals released from inflamed tissue act on the CNS and intracellular kinases. Within hours, altered gene transcription in the dorsal root ganglion (DRG) of sensory neurons and the spinal cord augment release of excitatory transmitters and reduce inhibitory transmitters. This results in neuronal excitability lasting days. When the noxious stimuli continue, then neuroplastic transformations occur and a positive feedback loop forms. Over time, neurons change structure, function, or chemical profile leading to pain as a disease (see Glossary of Terms).2,14,15
Patients differ in their response to pain and analgesics partly due to genetics. For example, catechol-O-methyltransferase (COMT) polymorphism is associated with the risk of developing chronic temporomandibular joint pain (TMJ).16Melanocortin-1 receptor gene in red headed/fair skinned persons confers greater female specific kappa-opioid receptor analgesia.17 Patients with complex regional pain syndrome (CRPS) have a high frequency of human leucocyte antigen (HLA)-DQ1 gene. Genetic polymorphism of GTP cyclohydrolase (rate-limiting enzyme for BH4 synthesis and key modulator of peripheral neuropathic pain and inflammatory pain) is associated with less pain following diskectomy.2,18
Pain is the result of the interaction between biological and psychological variables. Preoperative anxiety and pain are correlated with the development of more postoperative pain.5-8,19 For example, catastrophizing in limb amputees contributes to phantom limb pain.5
Fibromyalgia patients have abnormal pain perception with hypersensitivity to painful stimuli and decreased inhibition of descending CNS. In fact, researchers in Germany used functional neuroimaging (fMRI) to study the hypothesis of central pain augmentation in patients with fibromyalgia.20 They confirmed that fibromyalgia patients differ from controls in activation of the fronto-cingulate cortex, supplemental motor areas, and the thalamus over the course of pain stimulation, even during anticipation of pain.