Enhanced recovery after surgery: Pain management

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1 Received: 19 June 2017 Accepted: 13 July 2017 DOI: /jso REVIEW ARTICLE Enhanced recovery after surgery: Pain management Susan M. Nimmo MB ChB Hons, FRCA, FRCP, FFPMRCA, MSc Pain management 1 Irwin T.H. Foo MB BChir, MD, MRCP(UK), FRCA, FFPMRCA 1 Hugh M. Paterson BMedSci, MBChB, MD, FRCSEd 2 1 Department of Anaesthesia, Critical Care and Pain Medicine, Western General Hospital, Edinburgh, Scotland 2 Colorectal Surgery Unit, Western General Hospital, University of Edinburgh, Edinburgh, Scotland Correspondence Hugh M. Paterson, BMedSci, MBChB, MD, FRCSEd, Colorectal Surgery Unit, Western General Hospital, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, Scotland. hugh.paterson@ed.ac.uk Effective pain management is fundamental to enhanced recovery after surgery. Selection of strategies should be tailored to patient and operation. As well as improving the quality of recovery, effective analgesia reduces the host stress response, facilitates mobilization and allows resumption of oral intake. Multi-modal regimens combining paracetamol, non-steroidal anti-inflammatory agents where indicated, a potent opioid and a local anaesthetic technique achieve effective analgesia while limiting the dose and thereby side effects of any one agent. KEYWORDS analgesia, enhanced recovery, epidural, opioids, surgery 1 INTRODUCTION The report of the working party on pain after surgery, a joint publication from the Royal College of Surgeons of England and the College of Anaesthetists in 1990 raised the profile of effective assessment and management of acute pain following surgery. 1 It accepted that pain management improved the quality of recovery for patients and had the potential to mitigate some post-operative complications. Major improvements in acute pain management followed. Enhanced recovery after surgery programs further highlighted the importance of effective post-operative analgesia as part of the overall recovery process for patients. 2 Pain management is now rightly recognized as one of the three fundamental aspects of recovery from surgery along with mobilization and nutrition. Early post-operative mobilization of patients provides a significant challenge to achieving effective analgesia. A level of comfort commensurate with allowing patients to get up and walk needs to be combined with avoidance of side effects that might limit mobility and techniques where drips and pumps impede their ability to move. Similarly, recovery of gut function and the ability to recommence oral intake requires a level of comfort along with avoidance of nausea, vomiting, and ileus. Achievement of these sometimes opposing goals can be a challenge and requires balance and compromise. However, in tailoring our analgesic regimes to facilitate mobilization and enhanced recovery it is essential to remember that adequate analgesia is a treatment goal in its own right and it should not be acceptable to allow patients to suffer excessive pain in order to limit side effects of analgesia. 2 WHY IS PAIN ASSESSMENT AND MANAGEMENT SO IMPORTANT IN RECOVERY? Uncontrolled or poorly controlled pain is not just an unpleasant side effect of surgery, but drives the stress response along with the surgical injury itself, with the potential to cause a variety of complications. Pain limits mobilization, contributes to the development of post-operative cognitive dysfunction (POCD) and may lead to the development of chronic pain in susceptible individuals. It is readily apparent both from the literature and from clinical practice that the amount of pain suffered by an individual does not necessarily relate either to the size of an operation or to the amount of pain relief provided. This makes effective individualized pain assessment mandatory in the control of pain, since it is the pain the patient is actually suffering that we need to treat. We know that pain is a subjective experience, which in the context of surgery is due to injury, but which also has emotional components. 3 Pain scoring using verbal J Surg Oncol. 2017;116: wileyonlinelibrary.com/journal/jso 2017 Wiley Periodicals, Inc. 583

2 584 NIMMO ET AL. rating scales or visual analogue scales attempt to quantify this subjective sensation, but cannot be the sole factor on which pain management is based. Pain assessment must be holistic and include the level of function achievable: Can the patient take a deep breath and give an effective cough? Is the patient able to get out of bed and gently mobilize? Are the side effects of any analgesic agent limiting effective dosing or its use altogether? While for many patients achieving acceptable levels of analgesia and avoiding problematic side effects can be straightforward, this is not the case for all patients. Almost all acute surgical units will now have input from an Acute Pain Service, 4 dedicated to the optimization of pain relief and side effects. The Acute Pain Team has the ability to: write and implement protocols for pain relief; teach colleagues about pain assessment and management including enhanced recovery programs; and equally importantly, tailor management plans to individual patients where appropriate. 3 THE PAIN PATHWAY The pain pathway is a complex system that converts a noxious signal into neural transmission, which is ultimately perceived as pain within the central nervous system. The nociceptive signal ascends via the dorsal horn, thalamic, and midbrain nuclei to the sensory cortex, where pain and its location are perceived. However, as a result of seminal work by Melzack and Wall, who described the Gate theory of pain published over 50 years ago, 5 we know that this pain signal can be both up- and down-regulated at a variety of points along the pathway, resulting in sensitization of the pain signal or descending inhibition. The balance of activity in these opposing pathways dictates the level of pain suffered by an individual in response to a painful stimulus and helps explain the variation in pain suffered between individuals. It also provides a mechanism whereby other patient factors, for example anxiety, previous pain experience, or catastrophizing, can influence not just the response to pain but the quantity of pain suffered. Loeser aptly illustrated this concept in his onion skin model 6 where nociception is the central driving process, but eventual pain suffered by the patient is a product of nociception filtered through layers of patient anxiety, personality, previous experience, environmental factors, and so on. Using functional magnetic resonance imaging to visualize pain intensity, Irene Tracy has elegantly demonstrated the effects that different patient factors such as anxiety can have on the level of pain suffered for a standard pain stimulus. 7 4 MULTI-MODAL ANALGESIA Due to the complexity of pain experience, no single analgesic agent can completely switch off the pain signal and provide complete analgesia. Effective analgesia for acute post-operative pain is optimally achieved by combining the agents we currently have available to maximize the analgesia while being able to limit the dose and thereby side effects of any one agent. It is also clear that different operations will provide different analgesic challenges, as will different patients, and these factors have to be accommodated within our pain management strategies. In the rest of this paper we will discuss analgesia for major abdominal surgery since this is the area in which the authors work. However, the general principles are applicable to a wider range of major surgeries. We will discuss the components of multi-modal analgesia in routine clinical use, and the evidence for the additional use of other agents, within the context of enhanced recovery. We will include in this discussion some newer innovations, not yet available in routine practice, which might be beneficial in improving pain management within enhanced recovery in the future. 5 OPIOIDS Opioid analgesia remains the mainstay of acute post-operative pain management. Potent opioids can provide a high quality of effective pain relief, but their use is frequently limited by side effects with particular impact on delivery of enhanced recovery, especially gastrointestinal side effects that delay recovery of gut function. Endogenous opioid pathways are part of the inhibitory control of pain and are variably activated by the acute pain stimulus itself. Opioid receptors are extensively distributed throughout the central nervous system. Stimulation of these G protein-coupled receptors inhibits neurotransmitter release and transmission of pain while activating descending pain inhibitory pathways. Three active opioid receptors are currently recognized with the mu (MOP) receptor being largely responsible for analgesia and the well-recognized side effects of opioids such as sedation, respiratory depression, nausea and vomiting, and pruritis. Variation in stimulation of the other opioid receptor subtypes might explain some of the differences in efficacy and side effects between different opioids. 8 Although peripheral opioid receptors are activated in areas of injury and inflammation, the role of blockade of these receptors in pain management is uncertain. Opioid receptors are also extensively present in the gastrointestinal tract within enteric nerve plexuses and play a physiological role in gut muscle activity and control of fluid and electrolyte absorption. Inhibition of these receptors by exogenous opioids reduces gut motility and propulsive contractions, while also decreasing absorption of fluid and electrolytes from the gastrointestinal tract. 9 Opioid induced inhibition of gastrointestinal motility is clearly a very important consideration in planning analgesia within an enhanced recovery program. Post-operative nausea and vomiting and intestinal ileus prevent resumption of oral intake, a key component of enhanced recovery. As a result, considerable effort has been made in looking for methods of reducing the opioid component of post-operative analgesia in order to limit this effect. These will be discussed, but it is important to remember that ileus is multi-factorial and limiting opioid analgesia is

3 NIMMO ET AL. 585 not a guarantee of a patient recovering post-operative gut function promptly. Other factors contributing to post-operative ileus include the surgical injury and bowel handling, sympathetic activation as part of the stress response, and interstitial edema resulting from excessive intravenous fluid therapy. In addition, it is unclear how much opioid sparing is necessary or beneficial and it is likely that this varies markedly between different individuals. Opioid sparing is not a therapeutic goal of itself, but must be considered in the context both of the reduction in opioid side effects and the introduction of additional side effects related to the opioid sparing medication. 6 WHICH OPIOID? Morphine, fentanyl, and oxycodone are all potent opioids in routine clinical use for management of acute post-operative pain with a similar pattern of efficacy and side effects. Owing to genetic variation in opioid receptors and in the metabolic pathways for the different agents, it is clear that individual patients achieve a better balance of efficacy versus side effects with specific agents, and it is often a case of assessing this post-operatively and making an opioid switch if appropriate. Morphine is generally the first line opioid used. Morphine is metabolized via the glucuronyl transferase system, with production of active metabolites (mainly morphine-6-glucuronide). This metabolite accumulates in significant renal impairment so that morphine is best avoided for post-operative analgesia in patients with pre-existing renal impairment or those developing acute kidney injury. Oxycodone and fentanyl have no significant active metabolites but since their metabolism is via the cytochrome system there is considerable interindividual variation in metabolic handling and a much higher likelihood of other drugs facilitating or inhibiting their metabolism. There is little or no evidence in the literature to facilitate choice of individual potent opioid, but clinical experience suggests that fentanyl is better tolerated in elderly patients in terms of sedation and dysphoria. 7 ROUTES OF OPIOID ADMINISTRATION Opioids may be administered by almost any route. Most common immediately post-operatively is intravenous analgesia usually as patient controlled analgesia. This has the benefit of allowing patients to have control in titrating their own pain relief. However, connecting patients to pumps post-operatively can have a detrimental effect by reducing mobility. New systems of transdermal PCA may avoid this problem, but are not yet widely available or in routine clinical use. 10 As patients resume oral intake, analgesia should also be converted to the oral route. If potent opioids are still required a combination of a regular modified release preparation and an as required prescription of immediate release drug should provide background pain relief and allow for the inevitable variations in the level of pain throughout the day and with activity. Reducing and stopping opioid therapy in timely fashion as acute pain resolves is important in reducing side effects, and also in avoiding longer term opioid dosing. Epidemiological studies suggest that a significant number of patients appropriately given potent opioids for acute pain management fail to discontinue these in the longer term. 11 Intrathecal opioids will be discussed below with regional analgesia. However, this provides a route of opioid dosing which significantly reduces the dose of opioid required while maximizing duration of analgesia. 8 OTHER OPIOIDS Tramadol is a mu opioid receptor agonist but also inhibits serotonin and noradrenaline re-uptake hence facilitating descending pain inhibitory pathways. 12 It is a less potent analgesic than morphine and is not always adequate immediately post-operatively but, due to its dual action, has less negative gastrointestinal effects than the pure opioid agonists. This may be beneficial within an enhanced recovery program and tramadol can be used for step down analgesia in this context. It is however associated with nausea and vomiting and may cause confusional states in the elderly. Tapendatol is a similar agent, with mu receptor activity and descending pain pathway facilitation by inhibition of noradrenaline reuptake only. 13 It is considered equipotent to the other potent opioids and appears to have a better side effect profile than tramadol. However, it is not currently licensed for use in acute pain in the UK, and experience of its use within an enhanced recovery program is lacking. Analgesia requires blockade of central opioid receptors and the negative gastrointestinal effects of opioids are largely mediated by peripheral gastrointestinal opioid receptors. Targinact (modified release oxycodone and modified release naloxone) cleverly combines stimulation of the former with inhibition of the latter. Naloxone has high first pass hepatic metabolism, therefore if given in a controlled release fashion insufficient agent will reach the central opioid receptors to reverse analgesia, but the naloxone will reverse the effects of oxycodone in the gut. Studies in chronic pain have demonstrated improvements in the severity of constipation when patients on chronic opioid therapy are switched to this combination preparation. 14 A recent study of Targinact versus oxycodone in patients undergoing laparoscopic colorectal resection within an enhanced recovery program did not show an improvement in recovery of gut function defined by toleration of oral diet, low post-operative nausea and vomiting score, and passage of either flatus or stool. While passage of stool was significantly earlier in the Targinact group, there is insufficient evidence to promote use of this agent in enhanced recovery PERIPHERAL OPIOID RECEPTOR ANTAGONISTS Alvimopam and methylnaltrexone have shown promising results in terms of earlier recovery of gut function following surgery. 16 These agents do not cross the blood brain barrier and therefore while inhibiting the gastrointestinal effects of opioids, they do not compromise overall analgesia. Neither of these agents is currently licensed for use in the UK.

4 586 NIMMO ET AL. 10 SIMPLE ANALGESICS Regular paracetamol either orally or intravenously, if the oral route is not available, can provide a useful contribution to analgesia and has been shown to be opioid sparing. 17 There are few absolute contraindications to paracetamol and it is a component of most enhanced recovery analgesia protocols. More contentious is the use of non-steroidal anti-inflammatory agents (NSAIDs). These act by inhibiting cyclo-oxygenase and thereby reducing prostaglandin synthesis. Prostaglandins are part of the inflammatory soup which sensitizes and stimulates nociceptors at the site of injury. NSAIDs may also have central analgesic effects. NSAIDs can be divided into nonselective (eg, Ibuprofen) and selective COX 2 inhibitors (eg, celecoxib). COX 2 is the enzyme induced by pain and inflammation whereas COX 1 makes important contributions to gastrointestinal and platelet function. Both COX 1 and COX 2 have housekeeping roles in the kidney. Hence, COX 2 inhibitors have a better efficacy to side effect profile, in particular causing less gastric symptoms and less bleeding than COX 1 inhibitors. Both groups can provide a useful contribution to analgesia and are opioid sparing, hence lending themselves to being a component of enhanced recovery analgesia protocols, and many units use these agents routinely in the peri-operative phase. However, NSAIDs bring concerns. Recently, both selective and non-selective COX inhibitors have been implicated in an increase in cardiovascular and cerebrovascular morbidity and mortality, and while this is less likely to be an issue with short-term perioperative use this remains uncertain in the current literature. As increasingly elderly patients with significant co-morbidities undergo major surgery the potential risk of ischaemic tubular injury (acute tubular necrosis) and acute renal failure increases. 18 Furthermore, a number of recent papers have suggested a link between perioperative NSAID use and an increase in anastomotic leak rate. Definitive studies are awaited. 19,20 Thus it is the authors practice to consider the use of NSAIDs in enhanced recovery in terms of risks versus benefits for each individual patient, rather than prescribing them as a routine part of the enhanced recovery protocol. 11 GABAPENTINOIDS These agents have a proven role in the management of chronic neuropathic pain. They are thought to provide analgesia by reducing the sensitivity of presynaptic neurones by blocking the alpha 2 delta subunit of voltage sensitive calcium channels. They may also have effects on noradrenergic descending inhibitory pain pathways. A systematic review of the use of perioperative gabapentinoids by Tiippana et al 21 concluded that their use was beneficial in reducing pain and opioid consumption. Optimal dose and duration of treatment was unclear. However, gabapentinoids can cause sedation and dizziness and both these symptoms are undesirable for enhanced recovery. Some studies have failed to show analgesic benefit. 22 Inclusion of gabapentinoids within enhanced recovery analgesia protocols requires further investigation and currently they cannot be universally recommended. 12 NMDA RECEPTOR ANTAGONISTS Ketamine is an NMDA receptor antagonist and in low doses can provide useful analgesia for post-operative pain and be opioid sparing. It also has beneficial effects in opioid tolerant patients and those with acute neuropathic pain. At low dose side effects are often minimal but ketamine can cause significant dysphoria, hallucinations and nightmares in some patients. There is no published evidence to support routine use of ketamine in enhanced recovery analgesic protocols and its use should be decided on an individual patient basis. 23 Magnesium is also thought to exert its analgesic effect via NMDA receptor blockade. It also has some anti-inflammatory activity and reduces calcium conduction. A meta-analysis in demonstrated both analgesia and opioid sparing with perioperative use and no serious adverse effects. Once again however, there is no work specifically within the context of enhanced recovery, where the potential disadvantage of sedation that can result from magnesium use may outweigh the additional analgesic benefits. 13 ALPHA 2 AGONISTS Similarly, alpha 2 agonists such as clonidine and dexmedetomidine have been shown to provide post-operative analgesia with opioid sparing and a beneficial effect on post-operative nausea and vomiting. However, they can cause sedation, hypotension, and bradycardia. 25 Their contribution within an enhanced recovery program has not been investigated and use of alpha 2 agonists is again at the discretion of individual units. 14 LOCAL ANAESTHETICS Local anaesthetic should always be included as part of a multi-modal package of analgesia for enhanced recovery. 26 Local anaesthetic can be administered via the neuraxial route, nerve blocks, wound infiltration, or as an intravenous infusion, and achieves varying degrees of analgesia and opioid sparing with a very favorable side effect profile. The route of administration of local anaesthetic will depend on practitioner and patient preference and the surgery performed. Epidural analgesia is still considered the gold standard for major open abdominal surgery and equivalent operations. 27 Epidural analgesia has the potential to provide complete pain relief, both at rest and on mobilizing, and provides both cutaneous and visceral analgesia. Effective epidural analgesia established prior to surgery reduces the stress response and, through a combination of reduced opioid requirement and sympathetic blockade allowing unopposed parasympathetic stimulation of peristalsis, reduces both the incidence and severity of post-operative ileus. Unlike systemic analgesic

5 NIMMO ET AL. 587 techniques, epidural analgesia also provides effective pain relief for patient mobilization (dynamic analgesia). Since the analgesia is targeted at the site of injury systemic side effects such as sedation can be markedly reduced, leaving patients able to co-operate with their enhanced recovery activities. Epidural analgesia usually utilizes an infusion of local anaesthetic combined with an opioid, to maximize analgesia while attempting to reduce the side effect profile. Epidural analgesia is not without its problems however, and some of these impinge on successful achievement of enhanced recovery. There is a failure rate of up to a third in some series, either in not establishing or not maintaining an adequate block for its intended duration. 28 Failure to recognize and effectively manage inadequate epidural blockade can result in severe pain episodes for patients. Local anaesthetic may produce a motor block which compromises the patient's ability to mobilize. The sympathetic block resulting from epidural local anaesthetic causes vasodilatation and hence significant hypotension in some patients, which again may prevent the patient from mobilizing effectively. Excessive intravenous fluids sometimes given in an effort to improve blood pressure with epidural induced hypotension may contribute to post-operative ileus. There are also concerns about anastomotic perfusion following colorectal resection in the face of hypotension or vasopressor use to correct this. However, there is no convincing evidence linking epidural analgesia with an increased anastomotic leak rate. On a more mundane level, connecting patients to pumps and additional levels of monitoring makes effective mobilization harder to achieve. Optimal management of epidural analgesia by Acute Pain Teams allows these complications to be minimized. They should not compromise enhanced recovery, as illustrated by Kehlet's group in Denmark who first described enhanced recovery programs advocating the use of epidural analgesia. 29 Catheterization of the epidural space can also be associated with serious neurological sequelae, the risk of which precludes epidural catheterization for some patients. In 2009 a National Audit project carried out by the Royal College of Anaesthetists (NAP3) provided useful data on the likelihood of these complications occurring. 30 Around epidural blocks per annum were being placed at this time for perioperative analgesia and a few for conditions such as rib fractures and acute pancreatitis. Severe complications included permanent neurological damage (neuraxial haematoma or abscess) and death. Given that epidural analgesia is generally reserved for highrisk patients undergoing major surgery, it is not always clear that the epidural analgesia is the cause of complications. However assuming that all possible complications documented in this audit relate to the epidural analgesia used then the rate of severe complications is estimated as 1 in 5800 cases. Where assessors decided that the epidural was unlikely to be the cause, complication rate was estimated at 1 in cases. Hence, careful weighing up of the risks and benefits of the technique must be undertaken when epidural analgesia is considered, and its use is precluded in patients at risk of epidural haematoma or abscess. Patients who are likely to benefit most from effective epidural analgesia are the elderly, those with significant cardiorespiratory co-morbidities, patients undergoing major open surgery, patients tolerant to opioids from therapeutic or recreational use, patients previously noted to be seriously intolerant of opioid analgesia, and patients suffering from or at risk of the development of chronic pain. Increasingly laparoscopic surgery is replacing an open approach for many abdominal procedures. This has in many cases converted a large operation into a much smaller one in terms of the stress response and pain. Epidural analgesia is probably not required for the majority of these patients, since in the absence of ileus most can be managed on oral analgesia from around 24 h following surgery. However, it is still desirable to have the benefits of epidural analgesia, opioid sparing dynamic analgesia, stress response reduction and reduction of ileus over a shorter time scale, and this can be achieved with spinal analgesia using a combination of local anaesthetic and intrathecal opioid. 31 Spinal analgesia is more consistently effective than epidural analgesia, and has a better safety profile, although still contraindicated in patients at risk of haematoma or abscess formation within the spinal canal. The local anaesthetic component will provide some stress response reduction and sympathetic block, also intra-operative analgesia, but is unlikely to contribute much to post-operative analgesia due to the time scales involved. Most laparoscopic abdominal surgery will take longer than the working duration of spinal bupivacaine. However, intrathecal opioids can provide prolonged analgesia with doses around one tenth that given intravenously. Side effects of intrathecal opioids are the same as for systemic administration. However, pruritis can be much worse using the intrathecal route. More importantly, late onset respiratory depression has been documented, particularly with more hydrophilic opioids such as morphine. It is therefore essential that patients receiving intrathecal opioids are appropriately monitored for sedation and respiratory depression, and that staff are trained to assess and appropriately manage this. Diamorphine, which is still available for therapeutic use in the UK, is significantly less likely to cause this problem since it is highly lipophilic and there is less risk of significant concentrations of the drug reaching the respiratory centre via CSF diffusion. In the authors unit intrathecal diamorphine is used routinely to good effect and with a side effect profile that is similar to systemic opioid use. A number of alternative local anaesthetic techniques have been described and have become increasingly popular due to concerns over the efficacy and risk of neuraxial techniques. Abdominal wall blocks can be established pre or post-operatively and continued for several days by placing catheters and either running an infusion of local anaesthetic or giving regular bolus doses. The success of these blocks is improved with the use of ultrasound to guide placement, alternatively they can be placed under direct vision at the time of surgery. A rectus sheath block using local anaesthetic placed between the rectus muscle and posterior rectus sheath bilaterally blocks the ventral rami of the seventh to twelfth intercostal nerves and provides effective analgesia for a midline incision. 32 Transversus abdominis plane blocks aim to place local anaesthetic within the plane between transversus abdominis and internal oblique muscles blocking the anterior rami of the lower thoracic and upper

6 588 NIMMO ET AL. lumbar spinal nerves. These can provide effective analgesia for unilateral incisions or bilateral blocks to cover a more extensive area of the abdominal wall. 33 Wound catheters placed directly within the layers of the surgical wound, ideally pre-peritoneally, provide opioid sparing analgesia for some patients. All of these blocks provide good analgesia if correctly sited and have been shown to improve quality of analgesia and be opioid sparing. Intuitively, placing catheters more peripherally should be safer and certainly the serious issues of haematoma and abscess formation within the vertebral canal are avoided. However, complications from these blocks can arise and less information is available than for epidural analgesia in terms of risks versus benefit. Similarly, failure rate is less well documented. Some studies have attempted to compare epidural analgesia with abdominal wall blocks. 34 Niraj et al demonstrated non inferiority of four quadrant TAP blocks versus epidural for a small series of laparoscopic colorectal resections. Epidural analgesia is probably not needed for the majority of laparoscopic abdominal operations so the clinical relevance of this comparison is questionable. A comparison of epidural versus wound catheters for patients undergoing hepatectomy demonstrated earlier mobilization and discharge home for patients in the wound catheter group but at the expense of inferior analgesia. 35 Whether this is a problem or not will depend on individual patients. 15 INTRAVENOUS LIDOCAINE Recent work has suggested that intravenous infusions of lidocaine may be beneficial especially in abdominal surgery due to its analgesic, antihyperalgesic, and anti-inflammatory effects. 36 There is evidence to suggest that lidocaine infusions decrease post-operative pain, reduce the use of opioids, facilitate the recovery of gut function and shorten the duration of hospital stay. 37 However, the optimal dose of lidocaine and duration of infusion is yet to be established and there remains concern regarding the safety of lidocaine infusions in clinical practice. In the authors unit, intravenous lidocaine infusions have been used in over 2000 patients (mainly colorectal) with only seven reported cases of minor side effects and no major cardiovascular or neurological complications. Large published case series also confirm the safety of this technique. 38 A recent Cochrane review 39 concluded that the effectiveness of intravenous lidocaine infusions was best demonstrated in abdominal surgery (especially laparoscopic surgery) where there was a moderate reduction in pain scores up to 24 h postoperatively. This is likely to be due to the inhibition of visceral nociceptive reflexes and spinal neurones by lidocaine. In the context of enhanced recovery and laparoscopic abdominal surgery, it is likely that intravenous lidocaine infusions limit the amount of opioids used and may have a direct beneficial effect in reducing ileus. Wongyingsinn et al have demonstrated equivalent benefits on gut function with intravenous lidocaine and epidural analgesia in patients undergoing laparoscopic colorectal resection. Patients having a rectal resection had better analgesia in the epidural group. 40 Systemic lidocaine has a narrow therapeutic index and a number of factors that may affect the plasma concentration (eg, low plasma protein levels, cardiac output, and acid-base status), hence monitoring for local anaesthetic toxicity is essential. Intravenous lipid emulsion for treating local anaesthetic toxicity should be readily available where this analgesic modality is used. 41 It is noteworthy that measurements of plasma local anaesthetic levels following abdominal wall blocks can demonstrate toxic levels and it is interesting to speculate, as has been done with epidural analgesia in the past, how much of their efficacy relates to a systemic effect LIPOSOMAL BUPIVACAINE An extended release formulation of bupivacaine encapsulated in liposomes has FDA approval for surgical site infiltration and has the potential to provide prolonged analgesia, up to 24 h, with a single injection. It is not currently available in the UK LOCAL ANAESTHESIA: SUMMARY Local anaesthetic can therefore be administered by a variety of routes and can provide analgesia and beneficial effects in stress response reduction and improvement in gut function with reduced ileus. Choice of technique will be dictated by patient factors, the extent of surgery and expertize in the various techniques described. It is important to achieve and maintain skills in a range of techniques so that appropriate routes of administration can be chosen for individual patients. 18 OTHER ISSUES 18.1 Peri-operative cognitive impairment It is increasingly recognized that perioperative cognitive impairment, which includes delirium and POCD, is harmful to the patient's postoperative recovery. Delirium is defined as a non-specific organic cerebral syndrome characterized by concurrent disturbances of consciousness and attention, perception, thinking, memory, psychomotor behavior, emotion, and the sleep-wake schedule. Its onset is typically during the first 3 days after surgery and fluctuates throughout the day, and tends not to persist beyond 1 week. 44 There are different subtypes of delirium ranging from the hyperactive type, easily recognized by staff as the disruptive patient (approximately 15% of cases) to the hypoactive type (approximately 35% of cases), which may simply be mistaken by staff for sleepiness and easily missed. However, a large proportion of delirious patients demonstrate a mixture of these two subtypes. 45 Delirium is common and its incidence depends on the type of surgery and patient characteristics, for example, the incidence in hip fracture patients varies from 4% to 53.3% and in elective surgery between 3.6% and 28.3%. 46 The risk factors for delirium can be conveniently divided into predisposing factors (such as cognitive impairment, age greater than 65 years, multiple co-morbidities, polypharmacy, frailty, impaired functional status, malnutrition, and sensory

7 NIMMO ET AL. 589 deficits) and precipitating factors of which major surgery, poorly controlled pain and the use of opioids are over-represented. 47 Delirium is not just a nuisance for the patients and staff but carries important clinical consequences: it increases the incidence of postoperative complications, for example, falls and pneumonia, and is associated with increased mortality, institutionalization and deteriorating cognition. 48 POCD on the other hand, is subtle and can only be detected with neuropsychological tests applied before and after surgery. However, it has become synonymous with the phrase Granddad was never the same after his operation. In the landmark study performed by the International Study of Post-operative Cognitive Dysfunction group (ISPOCD) in patients over the age of 60 years and undergoing major surgery, approximately one in four exhibited cognitive deterioration 1 week after surgery and this persisted in 1 in 10 patients at 3 months. 49 The most consistent risk factor for POCD is age and for late POCD (tested 2 weeks or more after surgery) includes pre-existing mild cognitive impairment, previous cerebrovascular accident, and post-operative delirium. Again, as with delirium, POCD is associated with negative consequences: impaired performance of activities of daily living, premature loss from the workforce and increased mortality. 50 There is evidence to support the role of enhanced recovery techniques which focus on early mobilization, multi-modal, opioid sparing analgesia, and early discharge to reduce the incidence of both post-operative delirium and POCD.Optimizedperioperative care, for example, minimal use of bladder catheters, and early removal if used, and early discharge from hospital are believed to be the main reasons for the reduction in cognitive disturbances. 51 agents has been found to be effective. 53 Similarly, a case-controlled series of more than 100 patients demonstrated a reduction in CPSP after abdominal surgery in patients managed with epidural analgesia CONCLUSIONS Effective analgesia allowing patients to mobilize and to recommence oral fluids and diet is a cornerstone of enhanced recovery after major surgery (see Table 1), and the combination of which can produce excellent results. 55 Multi-modal analgesia combining paracetamol, non-steroidal anti-inflammatory agents where indicated, a potent opioid and a local anaesthetic technique provides an adequate level of analgesia while limiting the severity of side effects and is of proven benefit. The addition of further agents may benefit selected patients and should be considered where standard management is either actually or predicted to be less effective. The benefit of adding these agents to multi-modal analgesia packages routinely is not yet proven; demonstrating opioid sparing alone is not proof of efficacy. Side effects introduced by use of these agents may be detrimental to enhanced recovery practice and must be carefully monitored and managed as appropriate. However, as new agents emerge into clinical practice there are exciting prospects of more specifically tailoring analgesia for the individual patient, informed in the future by predictive pharmaco-genetic information. 56 Given the ageing population and associated co-morbidities of patients presenting for surgery, other pain related issues such as post-operative cognitive dysfunction and chronic pain must be considered, and accommodated, in pain management plans within the enhanced recovery program Chronic pain Chronic post-surgical pain (CPSP) is now recognized as a serious consequence of many types of surgery. 52 A variety of risk factors have been identified, the most consistent of which is severe acute postoperative pain. Although patient and surgical factors are also recognized, there is as yet no sure way of predicting the occurrence of CPSP. Where the incidence of CPSP is known to be high, for example in breast surgery, thoracotomy, and amputation, the use of regional analgesic techniques, ketamine and other anti-neuropathic TABLE 1 ERAS and pain management- key points Effective pain management is an essential component of enhanced recovery Assessment of analgesia should include level of function and side effects in addition to severity of pain Analgesia should be multimodal including simple analgesics, opioids and a local anaesthetic component, choice of which will range from intravenous infusion to epidural administration Since there is considerable variation in pain suffered, analgesia should be tailored to provide the best balance of efficacy versus side effects for individual patients ORCID Hugh M. Paterson REFERENCES 1. The Royal College of Surgeons of England. The College of Anaesthetists. Commission on the Provision of Surgical Services. 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