The description and initial early experiences with surgical treatment of peritoneal metastases in the early 1990s has gradually brought about the development of what we could define as a subspecialty of surgical oncology focused on peritoneal surface malignancies.1 This is evidenced not only by the expansion of the number of institutions across the world that offer cytoreductive surgery, but also the presence of dedicated working groups in leading surgical oncology societies internationally and a huge increase in publications related to cytoreductive surgery for peritoneal metastases.2 Yet relatively little of the scientific effort within the field has been dedicated primarily to the various aspects of perioperative management in this complex group of patients.

In this issue of Annals of Surgical Oncology, Boesl et al. bring a necessary and welcome focus on pain management in patients undergoing cytoreductive surgery coupled with hyperthermic intraperitoneal chemotherapy (HIPEC).3 The authors evaluated and compared the effect of continuous wound irrigation of local anesthetics coupled with an intraoperative dose of methadone with epidural analgesia on postoperative opioid consumption and length of stay. They focused on total and average daily opioid use as a primary outcome and found that it was decreased in the group of patients who received intraoperative methadone and continuous wound irrigation. The importance the authors gave to opioid use reduction by choosing it as a primary outcome should not surprise us considering the current proportions and impact of the opioid crisis and the increasing awareness of the link between initial opioid exposure as part of medical, and especially surgical, care and subsequent risk of prolong opioid use, dependance, and potential abuse.4 While the central finding of the study that demonstrated a nearly 50% reduction of total opioid consumption from 486.8 ± 86.6 to 252.8 ± 17.7 morphine milligram equivalents (MME) (OR 0.72, 95% CI 0.52–0.98; p = 0.04) is excellent news, we should not forget that overall opioid use in both groups was still quite high. In fact, both patients with an epidural as well as those receiving continuous wound irrigation were prescribed opioids via patient-controlled analgesia (PCA) following surgery. This likely reflects widely accepted prescribing habits that rely heavily on opioids for postoperative pain control for both in-hospital use as well as at the time of discharge. There is a well-documented and very significant difference in the frequency opioids are prescribed after common surgical procedures between the USA and the rest of the world (91% of US patients compared with 5% of non-US patients) despite clear and increasing evidence that the quality of analgesia is not superior, but rather inferior in patients prescribed opioids, while being associated with more side effects.5,6 We could argue that perhaps the most important take home message from the study by Boesl et al. is that opioid use can in fact be drastically lowered, even in major abdominal surgery such as cytoreductive surgery, but we need to acknowledge that the bar is still set too low. In a study published by our group, we have demonstrated that excellent postoperative analgesia, documented by average daily visual analogue scores, can be achieved with essentially no opioid use in patients undergoing cytoreductive surgery with HIPEC both in those that have an epidural plus a standardized, multimodal, non-opioid protocol containing acetaminophen, metamizole, and NSAIDs and those in whom the epidural was substituted by a 48-h lidocaine infusion. In fact, in our study the total opioid consumption during the first 5 postoperative days was only 1 (IQR 1–13.5) MME in the lidocaine group and 112.2 (IQR 36.6–137.85) MME in the epidural group, which included the opioids received through the epidural (unlike the current study by Boesl et al. in which the epidural opioids were not included in the analysis).7 Clearly identifying reduction of opioid use as a priority for optimizing perioperative management in patients undergoing cytoreductive surgery and HIPEC should therefore be the main goal, while the strategies to achieve it can, and should, be multiple. Standardization and a more consistent reliance on the multimodality principle in pain management, especially when coupled with other components of enhanced recovery after surgery, which is still early in its development in peritoneal surface malignancies, will be a very useful step toward achieving this goal.8,9

Another important step will be increasing our awareness regarding links between intraoperative analgesia management and postoperative pain levels, which may directly impact the need for opioids in the postoperative period. As part of the overall push for decreasing perioperative opioid use, opioid-free anesthesia (OFA) has emerged as a strategy that combines drugs and/or techniques that act at different levels of the nociceptive stimulus, modulating and balancing the response to surgical stress and blocking the central and peripheral nervous systems with the goal of drastically reducing perioperative use of opioids.10 The strategy is generally based on the combination of N-methyl-d-aspartate (NMDA) antagonists, sodium channel blockers, non-steroidal antiinflammatory drugs (NSAIDs), and α2-agonists. These combinations make it possible to provide effective intraoperative anesthesia and analgesia without opioids while simultaneously avoiding tolerance and hyperalgesia development that may cause a higher need for postoperative opoids.11 An important drawback of the study by Boesl et al. is that information regarding intraoperative exposure to opioids is not available, and therefore we are not able to evaluate the overall exposure to opioids in the two groups nor any possible differences in intraoperative exposure between them. This is an aspect that should routinely be included in studies evaluating pain control strategies in surgical patients going forward. While we have likely not yet reached widespread use of OFA in major oncological surgery such as CRS with HIPEC, early studies are emerging suggesting it is a feasible and likely beneficial approach.12

The study by Boesl et al. is also noteworthy because it reminds us of an effective, yet infrequently utilized, alternative approach to reducing pain during the early postoperative period involving the use of methadone. Methadone has several unique characteristics that may be advantageous for the patient undergoing highly aggressive surgery. It is a potent μ-opioid receptor agonist acting as an effective and cost-effective analgesic for acute, chronic, neuropathic, and cancer pain. Moreover, and contrary to other opioids, methadone has antihyperalgesic properties and inhibits the development of tolerance-minimizing opioid-induced hyperalgesia and acute opioid tolerance, thus fitting in with the main tenets of OFA. A primary concern related to its use is the potential for prolonged respiratory depression. Methadone has a long and variable half-life and a large volume of distribution with a potential risk of accumulation leading to sedation, respiratory depression, and even death.13 However, extensive studies dating back to the 1980s conducted in orthopedic and general surgery demonstrated that methadone provides excellent and prolonged intraoperative and postoperative analgesia with a fully acceptable safety profile confirmed subsequently in more recent studies.14,15,16 Additionally, methadone metabolism seems to be less susceptible to drug interactions than has been previously hypothesized. Despite these advantageous properties, intraoperative methadone is still underutilized by many healthcare providers not familiar with methadone’s complex pharmacology, thus the study by Boesl et al. is a refreshing reminder to reconsider its role. The same goes for continuous wound irrigation systems that were coupled with methadone in the study. These systems have a strong rationale and have been previously shown in a systematic review of randomized controlled studies to be associated with a reduction in the incidence of opioid consumption and opioid-related side effects, in addition to confirming their safety profile.17

Surgical oncologists should read the article with interest and embrace opioid reduction as a worthy goal for their patients, while realizing that the best chance of achieving it will be by working out, together with their anesthesiology colleagues, a standardized, multimodal, opioid-free management plan that starts in the operating room and truly makes use of multiple modalities including regional anesthesia. Breaking the old habit of automatically ordering a PCA pump for all will be hard but worth it.