Total knee arthroplasty (TKA) is one of the most commonly performed orthopaedic procedures, with over a million surgeries conducted worldwide each year. The demand for TKA continues to rise due to an aging population and increasing prevalence of osteoarthritis, which is one of the primary reasons patients undergo the procedure.

Postoperative pain is a major concern following TKA, with many patients experiencing moderate to severe pain that can hinder early mobilisation, delay rehabilitation, and negatively impact overall recovery. Effective pain management is critical in improving surgical outcomes and patient satisfaction. Previously, opioid medications were frequently prescribed to manage postoperative pain, but concerns over opioid-related adverse effects and the risk of long-term dependence have led to a shift towards multimodal analgesic strategies.

Multimodal analgesia involves the use of multiple analgesic agents and techniques to achieve effective pain control while minimising opioid consumption. Commonly used medications in multimodal analgesia include paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), local infiltration analgesia, and glucocorticoids such as dexamethasone. Dexamethasone has traditionally been administered postoperatively for its anti-nausea properties, but recent interest has focused on its potential role in pain relief. However, the analgesic benefits of dexamethasone in TKA remain unclear due to inconsistent findings in previous studies.

Investigating the Potential of Dexamethasone

Dexamethasone, a synthetic glucocorticoid, exerts its effects primarily through its anti-inflammatory properties. The drug is known to suppress the release of proinflammatory cytokines, induce anti-inflammatory cytokines, inhibit prostaglandin synthesis, and potentially reduce the excitability of nerve cells involved in pain transmission. These mechanisms suggest that dexamethasone may be effective in reducing postoperative pain and opioid consumption, but robust clinical evidence is needed to support its widespread use in TKA patients.

Earlier studies investigating the analgesic effects of dexamethasone have been limited by small sample sizes and methodological shortcomings, leading to uncertainty regarding its true efficacy. A previous systematic review recommended conducting larger, well-designed clinical trials using higher doses of dexamethasone than those typically given for nausea prevention. The objective of such trials would be to determine whether dexamethasone significantly reduces postoperative pain and opioid requirements while maintaining an acceptable safety profile.

DEX2-TKA Trial

The DEX2-TKA trial was designed to evaluate the efficacy of dexamethasone as an adjuvant to multimodal analgesia in TKA patients. This randomised, blinded, multicentre clinical trial aimed to compare the effects of one versus two doses of 24 mg intravenous dexamethasone on postoperative pain and opioid consumption.

Participants in the trial were randomly assigned to receive either a single dose of dexamethasone or two doses administered 24 hours apart. Both groups received standard multimodal analgesia, including paracetamol, ibuprofen, and local infiltration analgesia. The primary outcome measured was total morphine consumption within the first 48 hours postoperatively, as morphine use serves as an indirect marker of overall pain experience.

The key hypothesis of the trial was that dexamethasone would reduce opioid consumption and postoperative pain, with the expectation that two doses would be more effective than a single dose in achieving sustained pain relief.

Outcome of the Study

The results of the DEX2-TKA trial demonstrated that dexamethasone, regardless of whether it was administered in one or two doses, significantly reduced postoperative morphine consumption compared to patients who did not receive dexamethasone. However, the group that received two doses of dexamethasone achieved a greater reduction in opioid consumption, meeting the predefined minimal important difference (MID) of a 10 mg morphine reduction. This reduction translated to a 25% decrease in morphine use despite the use of a multimodal analgesic regimen.

Pain relief, as measured by the visual analogue scale (VAS), showed significant improvement in both groups at 24 hours postoperatively. However, at 48 hours, only the group that received two doses of dexamethasone maintained a significant reduction in pain scores. These findings suggest that while a single dose of dexamethasone provides early postoperative pain relief, an additional dose may be required to sustain analgesic benefits over a longer duration.

Additionally, dexamethasone was associated with a lower incidence of opioid-related side effects, including nausea, vomiting, dizziness, and sedation. These findings further support the use of dexamethasone as part of a multimodal analgesic strategy to improve patient comfort and reduce opioid-related complications.

Clinical Practice

The reduction in opioid consumption observed in the DEX2-TKA trial has important clinical implications. Lower opioid use decreases the risk of adverse effects such as respiratory depression, constipation, and nausea, all of which can delay recovery. Additionally, minimising opioid exposure reduces the risk of opioid dependence, a growing concern in postoperative pain management.

These findings highlight the need for multimodal analgesia in optimising postoperative pain control. The use of dexamethasone as an adjunct to other non-opioid analgesics provides a promising approach to improving pain relief while limiting opioid reliance. Furthermore, defining clinically meaningful differences in opioid reduction and pain scores helps ensure that research findings are relevant to real-world clinical practice.

Safety Considerations

The safety profile of dexamethasone has been extensively studied in various surgical populations. Research suggests that dexamethasone does not increase the risk of wound infections, and its impact on blood glucose levels in non-diabetic patients is minimal. Additionally, studies in cardiac surgery patients have found no significant increase in major adverse events associated with dexamethasone use.

Despite its favourable safety profile, clinicians should remain aware of potential rare adverse effects, such as transient hyperglycaemia, mood changes, and an increased risk of infections in immunocompromised patients. While the DEX2-TKA trial did not identify any significant safety concerns within the first 48 hours postoperatively, further studies are needed to assess long-term outcomes and potential risks associated with repeated dexamethasone administration.

Strengths and Limitations

One of the primary strengths of the DEX2-TKA trial was its rigorous study design, which included predefined statistical analyses and blinding of participants, healthcare providers, and assessors. The multicentre nature of the study enhances its external validity, making the findings more generalisable to diverse patient populations. Additionally, the use of 48-hour morphine consumption as the primary outcome provides a robust measure of overall pain experience.

However, the study also had some limitations. The findings were limited to the first 48 hours postoperatively, and the long-term effects of dexamethasone on pain relief and functional recovery remain unknown. Additionally, the study did not include quality of recovery measures, which could have provided further insights into postoperative rehabilitation and patient satisfaction.

Furthermore, the results may not be directly applicable to patients receiving different doses of dexamethasone or those undergoing different anaesthetic techniques. The absence of systematic blood sugar monitoring is another limitation, as hyperglycaemia is a known side effect of glucocorticoids, particularly in diabetic patients. Additionally, the study findings may not be applicable to patients with a body mass index (BMI) greater than 40 or those with high preoperative opioid use, as these populations were not adequately represented in the trial.

Conclusion

The DEX2-TKA trial provides strong evidence that high-dose dexamethasone (24 mg, given as one or two doses) effectively reduces opioid consumption and postoperative pain in TKA patients. The findings support the use of dexamethasone as part of a multimodal analgesic strategy, with two doses offering superior pain relief beyond 24 hours.

Dexamethasone also reduces opioid-related side effects without increasing major complications, making it a valuable addition to perioperative pain management protocols. However, further research is necessary to explore long-term outcomes, optimise dosing regimens, and incorporate patient-centred measures to refine pain management strategies for TKA patients.

References

Gasbjerg, K. S., Hägi-Pedersen, D., Lunn, T. H., Laursen, C. C., Holmqvist, M., Vinstrup, L. Ø., Ammitzboell, M., Jakobsen, K., Jensen, M. S., Pallesen, M. J., Bagger, J., Lindholm, P., Pedersen, N. A., Schrøder, H. M., Lindberg-Larsen, M., Nørskov, A. K., Thybo, K. H., Brorson, S., Overgaard, S., … Mathiesen, O. (2022). Effect of dexamethasone as an analgesic adjuvant to multimodal pain treatment after total knee arthroplasty: randomised clinical trial. BMJ (Clinical Research Ed.), 376, e067325. https://doi.org/10.1136/bmj-2021-067325

De Oliveira, G. S., Jr, Almeida, M. D., Benzon, H. T., & McCarthy, R. J. (2011). Perioperative single dose systemic dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology, 115(3), 575–588. https://doi.org/10.1097/ALN.0b013e31822a24c2

Dieleman, J. M., De Wit, G. A., & Nierich, A. P. (2017). DExamethasone for Cardiac Surgery (DECS) Study Group. Long-term outcomes and cost effectiveness of high-dose dexamethasone for cardiac surgery: a randomised trial. Anaesthesia, 72, 704–713.