High dose glucocorticoids: will this change the face of multimodal postoperative analgesia and enhanced recovery?

Effective postoperative analgesia remains a problem. Depending on the type of surgery, pain intensity at rest and during mobilisation can be very high.1,2 Inadequate analgesia is associated with increased morbidity, protracted recovery, prolonged hospitalisation and chronicisation of pain.3 When enhanced recovery programs aim to be successful, adequate pain relief after surgery and during mobilisation and physiotherapy, is crucial. For many decades, opioids have been the cornerstone of peri-operative analgesia. However, it has become clear that opioids have significant adverse effects that can themselves hamper patient recovery and cause additional serious adverse effects with a significant health burden.4 Effective pain relief after surgery needs to be procedure specific and multimodal. Indeed, different types of surgery have different pathophysiological mechanisms by which pain is generated: location of the surgical incision, minimally invasive surgery or not, visceral pain, injury of larger nerves, etc. The procedure specific postoperative analgesia (PROSPECT) group has developed procedure specific guidelines for analgesia based on high level scientific evidence.5–9 Additionally, it has been widely accepted that good analgesia is multimodal, meaning that it will incorporate more than one modality of pain treatment that will act synergistically, target surgical mechanism, reduce opioid requirements and hence improve pain relief and stimulate early recovery.10 Dexamethasone is used in anaesthesia mainly as an antiemetic agent,11,12 however, strong evidence is available suggesting that it also is a promising adjunctive analgesic in various surgical interventions.6,7,13,14 A recent meta-analysis and trial sequential analysis re-confirmed the analgesic potential of dexamethasone in the setting of caesarean delivery.15 Dexamethasone, when administered in doses up to 8 mg in the peri-operative period, does not result in abnormal glycaemic control in either nondiabetic or well controlled diabetic patients undergoing noncardiac surgery.16 In this issue, Koppen et al. publish a meta-analysis and trial sequential analysis of randomised controlled trials evaluating the use of the systemic administration of glucocorticoids in total hip and total knee arthroplasty.17 The objective of the analysis was to identify the benefits and drawbacks of this intervention. The primary outcome of the analysis was the 24-h morphine use, with 5 mg defined as the minimal clinically important difference. Secondary outcomes included pain intensity scores at rest and mobilisation, with a visual analogue score of 10 mm or more difference as being important. The authors identified 32 trials that were included in the analysis, involving 3521 patients. Risk of bias was high in 23 trials due to problems with allocation concealment, blinding and selective outcome reporting. A 5 mg morphine reduction was confirmed. The effect on pain scores was minimal, with glucocorticoids reducing visual analogue scale pain scores at rest and mobilisation but never by more than the 10 mm defined as the threshold of clinical significance. With glucocorticoids nausea, vomiting and fatigue were reduced. Glucose levels were unaffected by the treatment. Serious adverse events were rare in both the control and treated patients. The authors clearly explain the strengths and weaknesses of their systematic review. A large heterogeneity of included studies and a high risk of bias, together with a large variability in the dose are probably the most important weaknesses. Despite the high risk of bias in many trials, the results of the present meta-analysis are clear: a glucocorticoid given as analgesic adjunct reduces opioid consumption and minimally reduces pain scores. However, this can be explained, as do the authors, by the fact that in many studies the glucocorticoid was part of a two, three, or four analgesic drug multimodal protocol for the individual study. Indeed, in a multimodal approach every addition with a minimal benefit is important to achieve the final goal: effective analgesia that enhances recovery and improves return to normal life whilst at the same time opioid use is reduced. However, any drug that fails to document an additional analgesic benefit has to be avoided as all the drugs, including dexamethasone, may also induce adverse effects. The conclusions of a meta-analysis are based on available published material. Unfortunately, many studies dedicated to postoperative pain treatments suffer from considerable flaws. Firstly, many studies are not procedure specific. They evaluate “abdominal surgery” or “orthopaedic surgery” or “laparoscopic surgery” without explicitly looking at specific surgical procedures. Secondly, studies are not homogeneous in terms of frequency and duration of pain measurements at rest and/or at mobilisation. Ideally, frequent evaluations of pain, both at rest and during activity, should be performed.18 And activity should be predefined and assessed via – best – validated questionnaires.18 However, the most important flaw of many current postoperative pain studies, is the absence of “basic analgesia / multimodal analgesia” that could be considered as the standard of care for a given surgical procedure. Most of the time a treatment group is compared to a control group that receives only placebo with morphine on demand as a rescue. Any new analgesic treatment should be compared to the standard of care for a given surgical procedure. It might be that a certain intervention is of no additional benefit when the previously established “standard of care” is used. Combining new analgesics with one another or with a previously used combination of analgesics, requires that a clear benefit should be documented versus the standard of care. Most of the studies, included in the present analysis of the glucocorticoid pain adjunct, have indeed used multimodal analgesia in both the control and intervention groups. To conclude, the systemic peri-operative administration of a glucocorticoid during major arthroplasty surgery as part of a multimodal approach to postoperative pain, seems to result in an opioid sparing effect and small reductions in pain intensity scores. Therefore, we can recommend the use of glucocorticoids especially since major adverse effects are reported to be similar to those in the control arm of the meta-analysis. Further research is required to determine the optimal dose of glucocorticoid, to assess if glucocorticoids mays also improve postoperative fatigue and quality of life after surgery, or if they help to achieve enhanced recovery after surgery and a decrease in hospital length of stay. As for pain control, all these parameters should be evaluated focusing on specific surgical procedures. Larger trials are also required to assess the adverse-effect profile.