Preventing chronic post-surgical pain: therapeutic strategies

31 Mar 2015  |  Print

Preventing chronic post-surgical pain: therapeutic strategies

“Prevention is better than cure”

This familiar proverb can be traced all the way back to the English legal expert, Henry De Bracton, writing in the year 1240. He wasn’t thinking about post-surgical pain at the time – the concepts of surgery and pain control as we know them today were not conceived until hundreds of years later – but De Bracton’s words certainly ring true when it comes to chronic post-surgical pain (CPSP).

CPSP affects large numbers of patients. Exact figures are not available, but a recent analysis suggested an incidence of between 400,000 and 1.5 million patients per year in the US alone.[1] In up to 10% of cases, the associated pain can be severe.[2]

The physiological mechanisms that underlie CPSP are complex and not well understood. However, broadly speaking, perioperative pain is thought to sensitize the nervous system, and this hypersensitized state may then contribute to the development of chronic pain.[1]

Once CPSP is established, it is difficult to cure, and hence prevention is key. But how can we achieve this?

Preventive strategies

An important strategy that is sometimes ignored is simply not to perform the procedure at all. Inappropriate or unnecessary surgery should be avoided, and alternatives explored where necessary.[3] In addition, patients should be made aware of the risks associated with the proposed procedure, so that an informed decision can be made.

Once the surgery is scheduled, it is logical to try to reduce the perioperative nociceptive input to the spinal cord, with the aim of reducing the risk of sensitization.[1] This approach – known as preventive analgesia – attempts to reduce the impact of the nociceptive ‘barrage’ induced by activation of pain receptors during and after surgery.

If a given agent can reduce postoperative pain and/or analgesic use beyond its clinical duration of action (defined as 5.5 half-lives), then we can say this compound has demonstrated a preventive analgesic effect.[4]

Preventive effects of specific agents

The N-methyl-D-aspartate (NMDA) antagonists, particularly ketamine, have received increasing interest as preventive agents, owing to their potential inhibitory effect on pain sensitization.[5] For example, in a study of patients undergoing major abdominal surgery, remifentanil-induced post-operative hyperalgesia was prevented by low-dose ketamine.[6]

A recent meta-analysis included data from 14 trials examining the use of ketamine to prevent CPSP.[7] Of these, 12 used a pre-incisional loading dose plus an intraoperative infusion, and five continued the infusion for a further 1-3 days. Although most of the studies were small, the meta-analysis identified a modest but statistically significant reduction in the incidence of CPSP with ketamine: the relative risk of pain at 6-months post-surgery was 50% with ketamine versus placebo (odds ratio: 0.50; 95% confidence interval: 0.33-0.76).[7]

The anticonvulsants, gabapentin and pregabalin, have also been linked with preventive benefits against CPSP. However, in the same meta-analysis in which ketamine was found to have a positive effect, an examination of 15 studies of perioperative anticonvulsant use found no significant effect on long-term pain outcomes.[7] Trials of corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) also largely failed to demonstrate any benefit with regard to CPSP.[7]

A number of studies have examined the effects of regional anesthesia with regard to CPSP. A recent meta-analysis identified 23 randomized controlled trials that compared pain outcomes at 6 or 12 months with regional versus conventional anesthesia.[8] The key finding was that epidural anesthesia and paravertebral block may prevent CPSP after thoracotomy and breast cancer surgery, respectively. Importantly, one in every four to five patients treated could benefit from these effects.[8]

Another compound worthy of further study is nitrous oxide. Data from a follow-up study of a clinical trial have been reported, measuring the impact of intraoperative 70% nitrous oxide in 640 patients undergoing various different procedures.[9] Incidences of mild–moderate and severe pain at the surgical site were examined; significantly lower rates were observed in patients who had received nitrous oxide-based versus nitrous oxide-free general anesthesia. Importantly, the benefits were most apparent when only patients with severe CPSP (visual analog scale >5) were considered.[9]


Although several compounds have shown promise, there remains a great dealto do if we are to firmly establish their preventive benefits against CPSP. Further trials will be required. Ideally, such studies should focus on the surgical procedures that are associated with the highest rates of CPSP – such as amputation, thoracotomy, coronary artery bypass surgery, and breast surgery – and should measure standardized pain outcomes at multiple time points out to 1 year and beyond.[7]

There is also an urgent need for continued investigation into the pathogenesis of CPSP in order to identify novel therapeutic targets.[7]

Were he alive today, Henry De Bracton would surely agree that prevention is better than cure with regard to CPSP. However, a lot of work remains to be done if we are to optimize preventive strategies among our surgical patients.


  1. 1. Macrae WA. Chronic post-surgical pain: 10 years on. Br J Anaesth 2008;101:77-86.
  1. 2. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet 2006;367:1618-1625.
  1. 3. Ravindran D. Chronic postsurgical pain: prevention and management. Pain Europe. July 2013. Available at: Accessed February 2015.
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