Post-surgical pain arises from nociception (from sensory receptors on C fibres and A-delta fibres that respond to intense thermal or mechanical stimuli) and from the detection of inflammation by nociceptors (a consequence of trauma to peripheral tissues) [23].

Following incision, inflammatory mediators (prostaglandins, bradykinin, histamine, cytokines) are released at the periphery by damaged tissue triggering an inflammatory cascade [23]. These act directly on the primary afferent terminals and reduce their excitation threshold. This is known as peripheral sensitization [28]. Substance P (Sub P) and Calcitonin-Gene-Related Peptide (CGRP) are expressed within the superficial dorsal horn [28].

With modification in the response properties of central neurones, central sensitization can occur as well. After an injury or surgery central sensitization results in an enhanced responsiveness to activation, a decreased threshold, expanded receptive fields, and spontaneous activity that create increased pain after surgery [23]. Peripheral and central sensitization is meant to be protective but can become maladaptive, with damaging consequences.

A sign of central sensitization is allodynia where a non-painful stimulus, such as touch becomes painful. Another sign is secondary hyperalgesia where an increase in pain sensitivity occurs in non-injured areas outside the area of primary injury [71]. Peripheral and central sensitization remains critical in the development of pain chronicity [41]. When long-term potentiation of synaptic responses amalgamates with weakened nociceptive inhibitory modulation, enhanced nociceptive facilitatory modulation, and injury-induced proliferation of immunologically active microglia and astrocytes, central sensitisation is maintained and results in chronic pain [71].

Patients with poor inhibitory systems and enhanced excitatory processes experience higher postoperative pain, and are more prone to CPSP. Continuing translation of mRNA in the peripheral terminal of the primary afferent nociceptor plays a role in the transition from acute to chronic pain [34].

In the animal model hyperalgesic priming is used to exhibit the transition from acute to chronic pain. Hyperalgesic priming depends on the epsilon isoform of protein kinase C (PKC epsilon). Priming can be detected as a boosted and prolonged hyperalgesic response to the pro-inflammatory cytokine prostaglandin E2 (PGE2) switch that occurs in the intracellular signalling pathway mediating PGE2-induced hyperalgesia [34, 106].

Over a period of time, molecular memory is formed in primary afferent nociceptors [34]. Studies in the rat model confirm a switch in primary mechanical hyperalgesia to a G (i)-activated and PKC epsilon-dependent signalling pathway that is induced by stress or inflammation [106]. Priming in the rat model can be reversed by the translation inhibitors, rapamycin and cordycepin at the peripheral terminal of the primed nociceptor [34].

Acute insults produce hyperalgesic priming, a neuroplastic change in nociceptors that markedly prolongs inflammatory mediator-induced hyperalgesia. After an acute initiating insult, there is a 72 h delay to the onset of priming, for which the underlying mechanism remains unknown [35]. Spinally induced priming is detected not only when prostaglandin E2 (PGE2) is presented to the peripheral nociceptor terminals, but also when it is presented intrathecally to the central terminals in the spinal cord [35]. It has recently been shown that cytoplasmic polyadenylation element binding protein (CPEB) expressed by isolectin B4-positive nociceptors, a subset of nociceptors in which hyperalgesic priming occurs, are able to be co-immuno-precipitated with protein kinase C epsilon (PKCε) [34]. Both spinally and peripherally induced hyperalgesic priming can be prevented by intrathecal antisense oligodeoxynucleotide to the nuclear transcription factor CREB mRNA [34, 35].

The protease-activated receptor type 2 (PAR2) plays an important role in inflammatory, visceral, and cancer-evoked pain based on studies using PAR2 knockout [or PAR2(−/−)] mice [119]. Intraplantar injection of the novel highly specific PAR2 agonist, 2-aminothiazol-4-yl-LIGRL-NH2 (or 2-at) arouses a long-lasting acute mechanical hypersensitivity, facial grimacing, and causes robust hyperalgesic priming. This is shown by subsequent mechanical hypersensitivity and facial grimacing to prostaglandin E2 (PGE2). The promechanical hypersensitivity effect of 2-at is completely absent in PAR2 knockout mice, as is hyperalgesic priming as well. PAR2 activation is sufficient to induce neuronal plasticity. This leads to a chronic pain state, the maintenance of which is dependent on a BDNF/trkB/aPKC signalling axis [119].

Neuroplastic changes within different areas of the central nervous system may help to explain the transition from acute to chronic conditions [92].

An important property of the nociceptive system is its plasticity. This is the ability to change in an experience-dependent manner; this is implicated in the transition from acute pain to chronic pathological pain. Disease-induced plasticity can occur at both structural and functional levels. It manifests as changes in individual molecules, cellular function, network activity, and synapses [70]. Synaptic plasticity may mediate pathophysiological alterations linked to chronic pain. It does this by virtue of shifting the balance between excitation and inhibition, with a particular emphasis on the spinal dorsal horn [70]. Synapse-to-nucleus communication can mediate long-term changes in nociceptive sensitivity [70].

Much has been written about the association of genetic polymorphisms and the development of chronic pain [15]. Epigenetic regulation governs gene expression in response to environmental cues. Recent animal model and clinical studies indicate that epigenetic regulation plays an important role in the development or maintenance of persistent pain and possibly the transition of acute pain to chronic pain [8].

Social defeat stress enhanced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 phosphorylation at the Ser831 site in the spinal cord greatly prolonged plantar incision-induced pain [76]. Spinal AMPA receptor phosphorylation contributes to the mechanisms underlying stress-induced pain transition [76].

A higher level of preoperative pain (intensity and duration) has frequently been identified as a risk factor for early severe acute postsurgical pain across a range of surgery types in the days and weeks after surgery, and of long term post-surgical pain [23, 74, 123]. Multiple sites of pain suggest widespread sensitization in the nociceptive system and potentially indicate individuals who are predisposed to the development of chronic pain. Female gender and a younger age have frequently been identified as risk factors for persistent postoperative pain [74]. In a review of 333,000 pain scores in those with severe pain events following surgery, females experienced greater mean pain scores on postoperative day 1 for a variety of surgical procedures [118]. Younger age is one of the most consistently reported factors associated with an increased risk of development of CPSP [107, 123]. Comorbid conditions have a relatively minor influence on pain outcomes [74].

The type of pain is an important determinant of whether the patient will develop chronic pain. For example, sensory abnormalities such as hyperaesthesia and hypoaesthesia may indicate that the patient had pre-existing neuropathic pain before the procedure, or developed neuropathic pain consequent to the procedure [23, 25].

Chronic pain unrelated to the surgical site may include fibromyalgia, irritable bowel syndrome, chronic headaches, and back pain. These may be characterized by an underlying state of pain amplification or central sensitization seen in patients suffering idiopathic pain disorders [72, 106].

Surgery-related factors increase the risk of CPSP as well. These include the following: [60, 106, 107]; site (e.g. major limb amputation, thoracotomy, mastectomy, sternotomy); extent of surgery [77, 108]; a low (compared to a high) volume surgical unit [108, 117]; pericostal (versus intracostal) stitches; and intraoperative nerve damage [77, 108]. Nerve damage can occur from surgical section, compression (in a suture or from clips, or following rib retraction), stretching, ischaemia, or infection [98, 108]. Other factors taken into account include the duration of surgery, and the specific surgical techniques used [1, 106].

Surgical techniques include open versus laparoscopic or arthroscopic surgery, the type of implant, and the newer developments in minimally invasive surgery. Minimally invasive surgery reduces the inflammatory response [63, 106]. Examples consist of natural orifice transluminal endoscopic surgery, single-incision laparoscopic surgery, imaging-assisted lesion localization for single-port video assisted thoracic surgery (lung resection), endoscopy-assisted surgery, minimally invasive mitral valve surgery, and robotic surgery [45, 66, 87, 123].

A recent systematic review of meta-analyses of randomised controlled trials in appendectomies showed that the laparoscopic approach shortened hospital stay from 0.16 to 1.13 days in seven out of eight meta-analyses [54]. Mini percutaneous nephrolithotomy in the treatment of renal and upper ureteral stones has been found to be related to less blood loss and shorter hospital stay [33]. In lumbar surgery, minimally invasive techniques have required smaller incisions. They have decreased approach-related morbidity by avoiding muscle crush injury by self-retaining retractors, and by preventing the disruption of tendon attachment sites of important muscles at the spinous processes [115]. A recent meta-analysis showed minimally invasive transforaminal lumbar interbody fusion to be associated with lower blood loss and infection rates [94]. In caesarean sections, the Misgav-Ladach incision was associated with a significant advantage in terms of reduction of post-surgical acute and chronic pain [44]. In open incisional hernia repair, the use of lightweight mesh seems to be associated with less chronic pain without the increase of recurrence [75]. Laparoscopic resection and transvaginal specimen extraction looks like a promising technique for some right-sided colon pathologies [61].

Mixed evidence is found for the role of the anaesthetic (e.g. regional anaesthesia) and for analgesic regimens (e.g. pre-emptive analgesia, epidural analgesia), and for the experience of the surgeon [19, 106]. High intra-operative doses of remifentanil are associated with small but significant increases in acute pain after surgery [36]. Perioperative fluid management is important to improve outcomes, especially by avoiding fluid excess [66].

Postoperative risk factors include the following: unrelieved and severe pain; surgery performed in a previously injured area with pain or repeated surgery in the same area; preoperative chronic pain, high postoperative use of analgesics, co-morbid stress symptoms, capacity overloads, and radiation therapy and chemotherapy [3, 106, 108]. The severity of acute postoperative pain in the days and weeks after surgery remains one of the most consistent and strongest predictors of CPSP [23, 96]. Adequate postoperative analgesia allowing early mobilization is a prerequisite [66, 106]. However, red flags should be excluded. These include infection, bleeding, organ rupture, and the onset of a compartment syndrome. Better clarification is needed on the underlying cause of the postoperative pain (i.e., infection versus mechanical versus neuropathic [23, 106].

Prolonged postoperative opioid use occurs with legitimate preoperative opioid use, self-perceived susceptibility to pain medication, addiction, and preoperative depressive symptoms [17, 25]. Patients who are unable to self-implement a prescribed pain management regimen are at high risk for transitioning to chronic pain from unresolved acute pain [25]. For example, in ophthalmic surgery a recent systematic review has shown that female sex, longer duration of surgical procedure, second eye surgery as a consecutive procedure, type of surgery, general anaesthesia, lower satisfaction with anaesthesia, and postoperative nausea may contribute to increased postoperative pain intensity [73]. The type of surgery, the type of anaesthesia, and patient satisfaction with anaesthesia were factors associated with increased analgesic consumption as well [73].

There should be an ongoing assessment of pain, both at rest and with movement. Not only pain severity but pain qualities, duration, impact on functional capabilities, and underlying cause(s) need to be considered as well [99]. A longer assessment of postoperative pain that relies on the development of pain trajectories (e.g. from day 1 to day 5) is required [72].

Exposure to intense pain and stress during medical and nursing procedures can contribute to the transition from acute to chronic pain [72]. The presence of large areas of secondary hyperalgesia in the early postoperative phase has been found to be a major predictor of CPSP [28].

The most common emotions experienced by patients scheduled for major surgery are fear and anxiety. High preoperative anxiety, surgical fear and depression are predictors of severe postoperative pain (Table 19.3) [19, 72]. The fear of pain and pain anxiety play a significant role in the development of chronic pain and disability, although underlying mechanisms remain widely unknown [50]. The preoperative psychological state of a patient has been found to affect the outcome after total knee arthroplasty [67]. Poorly relieved long-lasting postoperative pain not only has a negative psychological impact but contributes to maintaining an underlying central sensitization process. This interferes with rehabilitation.

More recently, pain catastrophizing has been studied as a risk factor for CPSP (after knee arthroplasty and shoulder surgery) [19]. Catastrophizing continues to exert an effect many months to years after surgery [74]. Catastrophizing has been identified as the clearest predictor of chronic pain after total knee arthroplasty. Catastrophizing is associated with the severity of acute and chronic pain, altered central nociceptive processing (e.g. decreased conditioned pain modulation) exaggerated healthcare use, postoperative disability, and reduction in function [31, 38, 46, 74]. The critical elements needed to effectively treat or modify catastrophizing need to be better understood [74].

Less frequently identified factors include somatization, hypochondriasis, avoidant coping, psychological vulnerability, neuroticism, and a low expectation of return to work [59]. Many of these factors occur in the paediatric patient-related population as well [59].

Pain hypervigilance with a strong attentional bias toward pain, and emotional numbing measured after hospital discharge, predict subsequent CPSP and pain disability as well [23, 72]. Most changes in health-related quality of life occur during the first weeks and months after surgery [72].

Social and environmental factors have been associated with persistent postsurgical pain. These include solicitous responding from significant others, stressful life events, and social support [108]. Lower education and lower socioeconomic status have been identified as risk factors for CPSP as well [11, 123]. The evidence is mixed for other factors such as employment status, marital status, and for workers compensation [19, 123].

A patient’s gene expression profile can change rapidly in the post-injury period. Over 1000 genes are activated in the dorsal root ganglion alone after nerve injury [15]. Genetic variation can influence pharmacokinetics (drug transporters and drug-metabolizing enzymes) and pharmacodynamics (opioid receptor and catechol-O-methyltransferase enzymes). A few candidate gene polymorphisms have been linked to pain susceptibility, including catechol-O-methyltranferase (COMT). This enzyme affects nociceptive and inflammatory pain, and its variants (particularly the Val158Met variant) have been linked to temporomandibular joint pain syndromes [15].

Variants of the guanosine triphosphate cyclohydrolase 1 (GTP-cyclohydrolase 1) that is involved on the synthesis of tetrahydrobiopterin affects cancer pain severity and the development of persistent peripheral neuropathic low back pain [108]. A recent meta-analysis has shown the A118G allele variant of opioid receptor mu 1 (OPRM1) to have the most potent influence on pain management of postoperative patients [102]. Other candidate genes are the transient receptor potential cation channel, subfamily 5 member 1 gene, and the melanocortin-1 receptor gene [108].

The SCN9A gene has been looked at as a marker of pain sensitivity. Mutations in this gene that codes for the alpha-subunit of voltage gated sodium channel (Nav1.7) that results in alterations of pain perception. These are found in rare pain disorders such as erythromelalgia and in paroxysmal extreme pain disorder [15]. Five hereditary sensory and autonomic neuropathy syndromes have been described [108]. SCN9A polymorphisms have been described in individuals who are insensitive to pain as well [15].

The induction of inflammatory or neuropathic pain states is known to involve molecular activity in the spinal superficial dorsal horn and dorsal root ganglia, including intracellular signalling events which lead to changes in gene expression [40].

The incorporation of genetic knowledge is expected to lead to the development of more effective means to prevent and manage CPSP using tools of personalized pain medicine [21]. There is a large variability in CPSP amongst patients undergoing similar surgery [21]. Heritability estimates suggest that about half of the variance in CPSP levels is attributable to genetic variation [21]. Analysing patients’ DNA sequences, blood and salivary pain biomarkers, as well as their analgesic responses to medications will facilitate developing insights into CPSP pathophysiology, and inform predictive algorithms to determine a patient’s likelihood of developing CPSP even prior to surgery [21]. As genetic testing allow prediction as to which patients may have greater problems with pain control, more logical medication strategies would be selected as well [62].

Epigenetics is the study of heritable modifications in gene expression and phenotype that do not require changes in genetic sequence to manifest their effects [15]. Epigenetic mechanisms are essential for long-term synaptic plasticity and modulation of gene expression. This is because epigenetic modifications are known to regulate gene transcription [40]. Epigenetic modifications potentially play an important role in inflammatory cytokine metabolism, in steroid responsiveness, and in opioid sensitivity [15]. DNA methylation, histone acetylation, and RNA interference can alter epigenetic processes. Long-lasting epigenetic modifications could contribute to the transition from acute to chronic pain states by supporting maladaptive molecular changes [40]. At present there is an inability to prevent the epigenetic changes that occur following injury and surgery.

There is an increased postoperative morbidity associated with opioid-only strategies. Adverse effects of opioids include nausea, vomiting, sedation, pruritus, constipation, urinary retention, and respiratory depression) [23]. Opioid medications tend not to be effective in relieving movement-evoked pain. Opioids enhance central sensitization. Multimodal analgesia uses more than one analgesic modality to achieve effective pain control while reducing opioid-related adverse effects [116].

Opioid adverse effects (sedation, postoperative nausea and vomiting, urinary retention, ileus, respiratory depression) can delay discharge [116]. The long-term consequences of perioperative opioids (development of chronic postsurgical pain syndromes, hyperalgesia, and immunomodulation) are increasingly being recognized [109]. There is emerging evidence that opioids may influence cancer outcomes by directly stimulating tumour growth and inhibiting the body’s immune response [62]. For patients with severe postoperative pain that is non-neuropathic requiring around-the-clock analgesia, data show that cyclooxygenase-2 inhibition may reduce opioids and improve long-term outcomes [25].

Combining opioids with non-opioid analgesics limits their dose and boosts recovery [66]. Many clinical studies have reported an opioid sparing effect using a wide variety of non-opioid adjuvants (i.e. paracetamol, local anaesthetics, non-steroidal anti-inflammatory drugs [NSAIDs], cyclooxygenase-2 inhibitors, paracetamol, ketamine, clonidine, dexmedetomidine, adenosine, gabapentin, pregabalin, glucocorticoids, esmolol, neostigmine, and magnesium) [81, 108, 109]. Implementing a multi-modal regimen at the outset can diminish the unwanted adverse effects of opioid analgesics and reduce intraoperative and long-term tolerance [23].

Patient-controlled analgesia (PCA) empowers patients to play a role in their own postoperative pain management. PCA routes include PCA-intravenous or subcutaneous (morphine, fentanyl with adjuvants such as clonidine, dexmedetomidine, and ketamine), PCA-oral, patient-controlled regional analgesia, or patient controlled epidural analgesia (PCEA) [92]. A recent Cochrane review provides moderate to low quality evidence that PCA is an efficacious alternative to non-patient controlled systemic analgesia [83]. A recent meta-analysis has shown that evidence of a clinically relevant analgesic effect of peripherally applied opioids for acute postoperative pain is lacking; this may depend on the presence of preoperative inflammation [88].

Postoperative nausea and vomiting (PONV) can delay the time to discharge and resumption of activities of daily living [91]. Multi-modal opioid sparing analgesia should be provided and the Apfel risk score and a risk based multi-modal PONV prophylaxis followed [91]. Pharmacogenetics in PONV-related studies is attracting attention [86].

Surgery and its associated requirements such as positioning and tourniquet have specific risks. Patients with pre-existing neuropathy may be at an increased risk of postoperative neurological dysfunction [13]. Animal studies of posttraumatic nerve injury pain demonstrate that there is a critical time frame before and immediately after nerve injury in which specific interventions can reduce the incidence and intensity of chronic neuropathic pain behaviours-so called “preventative analgesia” [18].

Several studies using quantitative sensory testing and specific questionnaires have reported a major neuropathic component in CPSP [72]. Following surgical nerve repair, cofactors like poor capacity of nerve regeneration (a suspected genetic origin), decreased pain tolerance (due to altered endogenous pain processing) and a particular psychological profile played a major role as shown in the 33 % of patients who developed CPSP [72].

In animal models, perineural local anaesthetic, systemic intravenous local anaesthetic, perineural clonidine, systemic gabapentin, systemic tricyclic antidepressants, and minocycline have each been shown to reduce pain behaviours days to weeks after treatment [18]. The translation of this work to humans also suggests that brief perioperative interventions may protect patients from developing new chronic postsurgical pain [18]. Patients with a neuropathic component, first-line treatments such as topical lignocaine, tricyclic antidepressants, and alpha-2-delta calcium channel modulators are used before opioids [25]. A recent Cochrane review found no evidence from randomised controlled studies supporting the use of topical lignocaine for neuropathic pain, although individual studies indicated that it was effective for relief of pain [27]. More intraoperative data on handling of tissue and nerves needs to be collected.

Some of the psychological strategies that are in use include cognitive-behavioural therapy, acceptance commitment therapy, hypnosis, electro-myographic biofeedback, and coping strategies (Table 19.4). Modern treatment approaches focus on the extinction of aversive memories, and the restoration of the body image and normal brain function. Such approaches include brain stimulation, mirror training, virtual reality applications, or behavioural extinction training [37]. A recent systematic review has found that the effectiveness of therapeutic play intervention in children’s perioperative anxiety, negative behaviours, and postoperative pain is inconclusive [51].

In multimodal (or “balanced”) analgesia, the patient is administered a combination of opioid and non-opioid analgesic drugs that act at different sites within the central and peripheral nervous systems in an effort to minimize opioid use and decrease opioid-related adverse effects (Table 19.1) [109]. Individualized pharmacologic treatments require a complete characterization of a patient’s pain profile, in terms of frequency of pain over the course of a 24-h day and over time thereafter, frequency and duration of pain flares, and presence of neuropathic pain [25]. In the elderly, postoperative pain may be complicated by a number of factors, including a higher risk of age-related and disease-related changes in physiology and disease-drug and drug-drug interactions. Early studies evaluating approaches to facilitating the recovery process have demonstrated the benefits of multimodal analgesic techniques [47]. Recent advances have been due to new ways to use old drugs in a variety of settings, often as components of a multimodal approach to pain relief [104].

Multimodal analgesia uses a combination of delivery routes (i.e. enteral, parenteral, epidural, intrathecal). These are administered at variable time points (i.e. preoperative, intraoperative, and postoperative) to optimize outcomes in the treatment of acute pain and in the prevention of chronic pain [82].