PEPMEN trial: redefining pain management in minimally invasive esophageal surgery

The advent of minimally invasive esophagectomy (MIE) has been a triumph of modern surgical innovation. By minimizing surgical trauma, MIE is associated with reduced morbidity and faster postoperative recovery. However, effective perioperative pain management remains a critical and challenging cornerstone of postoperative patient care. The Paravertebral versus EPidural Analgesia in Minimally Invasive Esophageal ResectioN (PEPMEN) trial is a multicentered randomized controlled superiority trial investigating the hypothesis that paravertebral analgesia (PVA) provides patients undergoing MIE with a better quality of recovery than epidural analgesia (EA) due to similar pain control, but a lower incidence of unwanted side effects. The results delivered crucial insights into this ongoing debate.

Why does this matter?

Pain control in esophageal surgery is uniquely challenging due to the extensive surgical field and the interplay between thoracic and abdominal incisions. Adequate postoperative pain management is not only a matter of patient comfort but is furthermore a crucial part of the recovery process. For decades, EA has been the gold standard for postoperative pain management, especially for thoracic procedures. However, EA is sometimes technically demanding and is linked to a 30% failure rate in the clinical setting. In addition, recent evidence suggests that EA is associated with hypotension, urinary retention and ultimately delayed mobilization in critically ill patients, prompting the search for alternatives (1).

PVA has gained traction in recent years due to its relative ease of placement and favorable safety profile. Unlike EA, PVA selectively blocks nerves at the spinal level, avoiding many systemic side effects while still providing pain relief. Despite promising preliminary studies, PVA has struggled to replace EA as the default choice in esophageal surgery. The PEPMEN trial brings PVA into the spotlight (2).

Key findings

At its core, the trial aimed to determine whether PVA could match the robust pain relief provided by EA, with the primary outcome being Quality of Recover (QoR-40) on the third postoperative day (POD3). The results from the trial demonstrated that EA and PVA had similar QoR-40 scores and pain levels on the morning of POD3, helping the researchers conclude that PVA did not show superiority over EA. However, a key caveat is that EA provided superior pain control when compared to PVA on POD1 and POD2, with significantly higher QoR-40 scores and lower Numerical Rating Scale (NRS) pain scores in the PVA group. Despite the early advantages in pain control observed with EA, these findings suggest that PVA, while not as effective in the immediate postoperative period, still managed to limit undesired side effects such as hypotension, prolonged urinary catheterization and lower total opioid consumption. This is particularly relevant in the context of enhanced recovery after surgery (ERAS) protocols, which aim to minimize opioid use due to their association with adverse effects and potential for dependency. By delivering effective analgesia without relying on neuraxial blockade, PVA emerges as a viable alternative for centers where EA placement may be logistically challenging or contraindicated due to patient comorbidities.

One of the standout findings of this trial was that PVA demonstrated fewer systemic side effects, aligning with current trends favoring regional blocks over neuraxial techniques. These findings may pave the way for broader adoption of PVA, especially in patients where side effects like hypotension and delayed ambulation can have detrimental effects like myocardial injury after noncardiac surgery (MINS) (3,4). Balancing effective pain control versus rapid functional recovery and early mobilization are a critical consideration in individualizing postoperative care (5).

Strengths and limitations

The multicenter design and randomized nature of the trial provides robust and generalizable results. However, as with any trial, several limitations must be acknowledged. The specific techniques of analgesia placement, surgeon experience, and variations in postoperative care protocols may have influenced the outcomes. One of the limitations lies in the study design is that EA patients received a continuous epidural infusion containing a local anesthetic as well as an opioid, whereas PVA patients received only a local anesthetic infusion. This resulted in not only higher total opioid consumption in the EA group but also a differing mechanism of delivery. This may partially account for why patients in the EA group experienced lower pain and higher QoR-40 scores in the immediate postoperative period. This discrepancy makes direct comparisons between the two groups challenging. Future studies should aim to standardize opioid delivery and dosing to enable a more reliable head-to-head comparison between EA and PVA groups.

The Procedure-Specific Postoperative Pain Management (PROSPECT) guidelines provide recommendations for managing video-assisted thoracic surgery (VATS) with PVA or erector spinae plane (ESP) blocks, favoring their comparable analgesic effect and fewer hemodynamic side effects. Esophageal surgery has unique hurdles involving abdominal manipulation and intestinal anastomosis causing visceral post-operative abdominal pain. Though not clinically significant, this pain may be associated with poor postoperative outcomes. PVA relies on the local diffusion of anesthetic to achieve the desired pain control, the variability of spread may lead to patchy or incomplete visceral pain control. This raises the question of whether PVA should be combined with other blocks such as quadratus lumborum block to better manage pain. However, when infusing the patient with local anesthetic and supplementing with additional blocks, local anesthetic systemic toxicity becomes a growing concern for physicians. Alternatively, ESP blocks are technically easier to perform compared to PVA due to their superficial injection plain and more predictable spread of local anesthetic and have a similar dermatomal coverage. Future studies should aim to explore the efficacy of PVA vs. ESP blocks in similar surgeries.

Finally, long-term effects on chronic pain and quality of life critical to patients recovering from esophagectomy remain unexplored. Future studies should aim to follow patients that received specific blocks and assess the occurrence of chronic pain syndromes. This may reveal results that could further guide the patient centered approach of individualizing pain management protocols.

Implications for practice

The implications of the PEPMEN trial extend beyond the operating room. As healthcare increasingly prioritizes enhanced recovery pathways, minimizing opioid use and promoting early mobilization are paramount. Ultimately, both EA and PVA have proven to be effective pain management procedures with unique caveats. Patient specific factors such as risk of hypotension or history of chronic pain should guide the choice of analgesia. However, PVA, with its favorable risk-benefit profile, offers a compelling alternative for centers striving to optimize postoperative care in MIE.

A call for future research

The PEPMEN trial raises important questions for future investigation. Could patient-specific factors, such as comorbidities or surgical complexity, determine the optimal analgesic approach? How do these techniques influence long-term recovery, including respiratory function and chronic pain syndromes? Future studies should compare a standardized opioid administration approach to ensure a more direct comparison of analgesic effect in addition to exploring whether EA, PVA or even ESP blocks have a different impact on long-term chronic pain syndromes months after surgery. Addressing these questions will further refine our approach to pain management in esophageal surgery.

Conclusions

The PEPMEN trial is a landmark study that challenges traditional paradigms and invites the surgical and anesthesiology communities to reimagine pain management in MIE. As we integrate its findings into clinical practice, we take another step toward patient-centered, evidence-based care, a commitment that remains at the heart of modern medicine.

Acknowledgments

We sincerely thank Dr. Loay Allafy for providing valuable insights into the discussion of the limitations, in addition to the different regional blocks discussed in this editorial.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Surgery Journal. The article has undergone external peer review.

Peer Review File: Available at https://asj.amegroups.com/article/view/10.21037/asj-24-56/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://asj.amegroups.com/article/view/10.21037/asj-24-56/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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