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Optimal analgesia for major open surgery

Effective analgesia after major surgery is not only a humanitarian requirement, but is regarded as fundamental to the overall anaesthetic process, having a key role in achieving the best patient outcomes. The adoption of multimodal analgesia, since its description in 1993,1 was driven by the need to avoid both the short-term effects of opioids and mitigate against the possible impact they may have on longer-term intrinsic immunological mechanisms protecting against infection and long-term cancer growth and recurrence. Opioid-sparing analgesia also facilitates early mobilisation and enteral feeding with subsequent early return of bowel function. Optimising analgesia is recognised as a key component of an effective enhanced recovery after surgery (ERAS) programme, which by reducing the surgical stress response, allowing early mobilisation and return to normal gut function, has led to improvements in outcomes for a number of surgical specialties worldwide, especially colorectal surgery.2 Furthermore, the concept of ‘procedure-specific analgesia’ is fundamental as it can be unwise to extrapolate analgesic techniques from one surgical procedure to another. 
To achieve effective opioid-sparing analgesia several other treatment of modalities have been described including: 
  • Local anaesthetic nerve blockade 
  • Systemic analgesics 
  • Non-analgesic methods (such as acupuncture, transcutaneous electrical nerve stimulation (TENS) and hypnosis) The last method is outside the scope of this article and is not considered further. 
Opioid analgesia
Opioid use remains widespread despite well-known adverse effects including sedation, respiratory and cough depression, dysphoria, post-operative nausea and vomiting (PONV), a delayed return to normal gastrointestinal (GI) function and urinary retention. More recently there has been a focus on other issues surrounding perioperative opioid use such as tolerance, opioid-induced hyperalgesia and the immunosuppressive effects of opioids.3,4
There is no doubt that opioids are very effective analgesics and should not be withheld from patients if other methods provide inadequate analgesia. Indeed, the use of opioids in the immediate post-operative period probably has little deleterious effect. The aim should not be total avoidance but conscientious use as part of a multi-modal approach.1 There remains an important role for opioids in patient-controlled analgesia (PCA), particularly in patients for whom regional analgesia may not be possible. Patients must have a satisfactory pain score prior to commencing PCA to achieve adequate effect. Patient education remains an important aspect of opioid use. The prolonged use of opioids should be avoided and increased doses may be required for patients already using regular opioids. The use of opioids is not restricted to systemic use but commonly as an adjunct to epidural and intrathecal techniques.
Morphine is considered the gold-standard opioid, with others such as codeine and tramadol frequently used. Codeine is renowned for causing constipation and its variable metabolism should be considered in certain populations such as paediatrics.5 Tramadol has effects on opioid receptors alongside inhibition of serotonin and noradrenaline reuptake. This results in effective analgesia but is also causes side effects that many patients find intolerable, such as confusion or agitation. 
Opioid-induced hyperalgesia is currently topical relating largely to perioperative remifentanil and medium to long-term opioid use in chronic pain. It remains unclear as to the clinical significance of this effect; however, strategies such as the concurrent use of N-methyl-D-aspartate (NMDA) antagonists are thought to attenuate this effect.
Regional anaesthetic techniques
Central neuraxial blockade – epidural and spinal  
Epidural analgesia is considered the gold standard for open abdominal surgery due not only to its excellent opioid-sparing effects but also other described benefits. These include improved post-operative pulmonary function (with a reduced incidence of pulmonary complications) and attenuation of aspects of the stress response to surgery. The reduced sympathetic and pituitary activation results in reduced adverse metabolic effects (such as hyperglycaemia and protein breakdown). However there is no effect on the cytokine-mediated inflammatory response. Epidural analgesia also reduces the incidence of ileus and PONV, thromboembolic events and blood loss, with an earlier return to diet and some evidence to suggest a reduction in the rates of myocardial infarction, renal failure and mortality.6
In order to be effective, several considerations must be taken in account. 
The level of insertion must be appropriate for the surgery taking place including likely positions of any surgical drains, with thoracic insertion most likely to be effective for open surgery.
The choice of drugs administered into the epidural space is crucial. It most often includes a local anaesthetic combined with an opioid; however, other adjuvants such as alpha-2-adrenoreceptor agonists (for example, clonidine) or adrenaline improve or hasten the analgesic effect. 
The post-operative environment must include staff trained in the effective management of epidurals to correctly titrate the rate of ongoing epidural infusion and recognise, and effectively treat, common side effects, particularly hypotension or motor block. 
Establishing the epidural is best undertaken early to demonstrate that it is working effectively before returning a patient to a ward. 
Failed or inadequate blockade is commonplace and its early recognition is vital so that topping up with anaesthetic and/or opioid, re-siting or switching to alternative analgesia can be instituted.
Excessive fluid administration in the event of hypotension should be avoided, and the use of vasoactive drugs in a critical care environment is certainly more logical and may be preferable to avoid potential for detrimental effects on the cardiovascular and respiratory systems and any surgical anastomoses from fluid overload.
Mobilisation can be impaired in the post-operative period due to leg weakness, hypotension and attachment to drips, etc. 
There remain conditions in which an epidural may not be suitable for patients. Those with a known coagulopathy or concurrently receiving coagulation-modifying drugs should be considered on an individual basis and guidelines regarding  this matter are widely available.7 Patient refusal, concurrent septicaemia (increasing the risk of epidural abscess), and cardiac conditions in which patients are dependent on a higher systemic vascular resistance (for example, severe aortic stenosis) are also contraindications. 
A more common adverse occurrence is accidental dural puncture, which can lead to severe headache with the rare possibility of more serious complications such as subdural haematoma.8
Intrathecal (or spinal) analgesia, which is a one-shot technique, although regarded as safer than epidural, may be unsuitable for major open surgery due to its limited duration of action offering little in the way of ongoing post-operative analgesia. For some small open incision surgical techniques, it may be suitable providing excellent short-term analgesia without the problems of prolonged reduced mobility and hypotension.
Peripheral local anaesthetic administration
In the context of major open abdominal surgery, many methods of peripheral administration can aid post-operative analgesia. Most are generally regarded as safer than neuraxial blockade due to the reduced risk of hypotension and motor block alongside fewer more serious complications such as neurological injury. The dose of local anaesthetic required for effective analgesia can be high, increasing the risk of local anaesthetic toxicity.
Transversus abdominis plane (TAP) blocks can block dermatomes T10 to L1 when using a large volume of local anaesthetic and are more effective when performed pre-operatively by the anaesthetist.9 This distribution of block is unlikely to confer a benefit for open surgery requiring an above-umbilical incision. When injected surgically at the level of the subcostal margin, analgesia can be improved for upper quadrant abdominal surgery.10 Multi-hole catheters can also be considered to prolong the duration of block.11 Rectus sheath blocks can offer a higher level of analgesia than the TAP block and may also include the use of infusion catheters.
Continuous wound infiltration catheters themselves have shown to confer a number of benefits for open surgery including comparable analgesia to epidurals and accelerated recovery post-operatively although study results vary in this regard.12,13
Systemic analgesia
Paracetamol (acetaminophen) remains popular, offering effective, non-opioid analgesia with an excellent safety record when used appropriately. The intravenous preparation allows administration in patients unable to take enteral medication.
Non-steroidal anti-inflammatory drugs have an important role in analgesia but evidence varies between preparations as to their safety profile with regard to bleeding, cardiovascular complications, renal failure, wound healing and anastomotic leakage after colonic surgery. Both selective (for example, parecoxib, celecoxib) and non-selective (for example, diclofenac) are thought to increase the risk of anastomotic leak but the non-selective drugs more so.14
Lidocaine is effective when used as an intraperitoneal or intravenous infusion. Both techniques have recently begun to gain popularity in light of favourable study results when compared with epidural but remain controversial.  Used as part of ERAS programmes, both techniques can improve analgesia with an opioid-sparing effect and faster GI recovery with a low side-effect profile. Lidocaine is also thought to have an intrinsic anti-bacterial and anti-inflammatory effect with evidence to suggest its use may contribute to reduced cancer 
Gabapentinoids reduce post-operative pain, opioid consumption and PONV, although they can cause sedation, visual disturbances and dizziness, and there is currently a lack of evidence to support their use for open abdominal surgery with pregabalin having a better pharmacological profile than gabapentin. The optimal dose of pregabalin remains unresolved with 150–300mg pre-operatively being most commonly used although higher doses confer a higher rate of adverse effects.17 These drugs may also help to prevent the onset of chronic post-surgical pain.
NMDA antagonists (ketamine and magnesium) are useful adjuncts in acute pain with effects on acute tolerance and hyperalgesia with central desensitisation. There is evidence to demonstrate the efficacy of morphine and ketamine mixtures in PCA but ketamine also has a role intraoperatively when used as a bolus or infusion. Optimal dose and duration of infusion remains unclear but even low doses reduce morphine consumption with a low adverse-effect profile and demonstrable anti-inflammatory response. Ketamine may be useful for patients who are opioid-tolerant and for reducing chronic pain, but there remains a lack of procedure-related evidence for its use at present. Magnesium has been shown to improve post-operative pain scores and reduce ileus but prolongs neuromuscular blockade.
Alpha-2-agonists (clonidine and dexmedetomidine) have an analgesic effect through reduction of sympathetic outflow and noradrenaline release within the central and peripheral nervous systems interrupting pain pathways, including the release of the substance P. Clonidine is often used as part of a nerve block or intrathecal preparation for its analgesic effect; however, its adverse effect profile (sedation, hypotension, bradycardias) make it otherwise less popular.
Glucocorticoids can have an opioid-sparing effect alongside reducing PONV, length of stay and modifying the stress response to surgery. The use of glucocorticoids is currently controversial in surgery for malignant disease due to conflicting evidence regarding disease recurrence. There is insufficient evidence at present to suggest glucocorticoids should be omitted during cancer surgery.  In orthopaedic surgery, there has been considerable success with the use of high-dose methylprednisolone, with concerns of hyperglycaemia and wound infections not being major issues.  
Optimal analgesia involves consideration of the most appropriate method for particular patients at an early stage of the perioperative process. A multi-modal approach reduces the need for systemic opioids and their adverse effects, with an epidural considered as the best option to offer suitable patients. There is an ever-growing arsenal of analgesic adjuncts with variable evidence to support or contest their use. The PROSPECT working group provides a fundamental way in which to view post-operative analgesic therapy, as it focuses on areas of procedure-specific analgesia ( including a very good resource for guiding anaesthetic practice based upon the latest evidence.
As ERAS pathways evolve, together with the concept of anaesthetists practising as perioperative physicians, the involvement of patients at an earlier stage of their perioperative journey should be encouraged, in order that they can be fully informed of what to expect pre- and post-operatively in terms of pain management. As a result, patients feel more empowered to inform staff if they feel their pain is not under control. Finally, the ability to deep-breathe, cough effectively and mobilise early should be explained as vital targets for patients and if this is not possible, urgent intervention may be required.
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7 Association of Anaesthetists of Great Britain and Ireland. Regional anaesthesia and patients with abnormalities of coagulation. (accessed March 2017).
8 Royal College of Anaesthetists, Third National Audit Project of the Royal College of Anaesthetists (NAP3). Major complications of central neuraxial block. (accessed March 2017).
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13 Jouve P et al. Epidural versus continuous preperitoneal analgesia during fast-track open colorectal surgery: A randomized controlled trial. Anesthesiology 2013;118(3):622–30.
14 Gorissen KJ et al. Risk of anastomotic leakage with non-steroidal anti-inflammatory drugs in colorectal surgery. Br J Surg 2012;99(5):721–7.
15 Kahokehr A et al Intraperitoneal local anesthetic improves recovery after colon resection: A double-blinded randomized controlled trial. Ann Surg 2011;254(1):28–38.
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