Steroids Do Not Reduce Persistent Pain after Cardiac Surgery: Should This Be the End of the Question or the Beginning of Newer Questions?

We read with interest the study by Turan et al.¹  on the use of methylprednisolone for persistent incisional pain after cardiac surgery. This substudy was done on 1,110 of the 7,500 patients included for the Steroid In caRdiac Surgery (SIRS) trial.²  The treatment group received 500 mg methylprednisolone (given as 250 mg doses at induction and cardiopulmonary bypass), and the placebo group received comparable placebo. The study failed to show any difference in the incidence of persistent incisional pain, measured as 0 to 10 numerical rating scale, both at 6 months (primary) and 30 days (secondary). Considering that this is the largest study ever published on the use of steroids for reducing persistent postsurgical pain (PPSP), it could be interpreted as an argument against the use of steroids in PPSP for future studies. However, we would like to highlight some important considerations with regard to this argument and say that this should probably lead to newer questions and hypothesis on the future use of steroids, rather than making it a death knell on the use of steroids for PPSP.

Like any other intervention, the use of steroids for reducing PPSP has to be considered from two different fronts. Mechanistically, there is a strong argument for modifying the inflammatory response associated with surgeries with a significant potential for PPSP, more so of the neuropathic type. The inflammatory mediators can sensitize and stimulate peripheral nerve endings, cause excitation of dorsal horn cells, and also cause activation of microglia and astrocytes, which are now appreciated to play an important role in neuropathic pain.^3,4  Among inflammatory mediators, neutralizing the responses to interleukin-6 can also alter the perception of pain, beyond the changes in thermal and mechanical sensitivity.⁵  Overall, there is increasing appreciation that chronic inflammation and nerve injury have strong pathophysiologic link, with one feeding to another in more than one way. Inflammation can be considered as a potent driver of PPSP, more so with nerve injury, and hence the neuropathic type of pain.

From an existing clinical evidence perspective, corticosteroids, being potent antiinflammatory agents, have shown perioperative benefits for various surgical outcomes such as improvement in postoperative nausea–vomiting, acute pain, and even overall surgical recovery.^6,7  Unfortunately, other than for postoperative nausea–vomiting prevention, the dose–effect relationship, choice of corticosteroid agent, and its necessary duration of treatment have not been established for specific surgical outcomes. Although most studies tend to use a single dose, the actual dosage (in equivalent doses) has a very wide range. For major abdominal surgeries, the doses ranged from 8 mg dexamethasone (40 mg methylprednisolone) to 30 mg/kg methylprednisolone.⁸  For cardiac bypass, the most common dose was 60 mg/kg, which is eight times the dose that was used in the SIRS trial. Dexamethasone has a much longer half-life than methylprednisolone (36 to 54 h vs. 18 to 36 h), and it was used in a dose of 1 mg/kg for the Dexamethasone for Cardiac Surgery trial.⁹ 

Thus, a failure to show a significant reduction in PPSP in the SIRS substudy could be attributed to several factors. The inflammatory response, including its intensity and temporal trend, and its correlation to persistence of pain could be different for different surgical categories. It is possible that surgeries with a higher proportion of neuropathic pain have a much closer link with inflammation, possibly as an autoimmune reactivity.¹⁰  Only a total of 10 patients had neuropathic pain in the SIRS substudy at 6 months.¹  Finally, as reported by the SIRS substudy investigators, other important factors such as differences in surgical and anesthetic techniques and postoperative analgesic management, which were not controlled, could have played an important role.¹ 

We believe that future studies must consider assessing the potential value of steroids in a different population, possibly with a much higher risk of neuropathic pain such as amputation, thoracic surgeries, or radical mastectomy procedures, perhaps as more than a single dose and using longer acting agents. Although the potential adverse effects of steroid remain a cause of concern, it is reassuring to know that studies (including large studies such as dexamethasone for cardiac surgery and SIRS) so far do not support this claim.

Supported by Canadian Institute of Health Research RCT mentoring grant (2015 to 2017) for protected research time (to Dr. Shanthanna). There were no external or internal funding resources specifically in support of this study or manuscript.

The authors declare no competing interests.