Effective postoperative pain management is critical for optimizing recovery following cardiac surgery. Inadequate analgesia is linked to impaired respiratory mechanics and adverse hemodynamic responses (e.g., hypertension, tachycardia) and to pulmonary complications such as atelectasis and pneumonia; poorly controlled pain can delay functional recovery and is associated with persistent postsurgical pain. Contemporary guidance endorses multimodal, opioid-sparing strategies in cardiac surgery as a core element of enhanced recovery after surgery (ERAS) and opioid-sparing strategies (Echeverria-Villalobos et al., 2020; Grant et al., 2023; Loria et al., 2022; Othenin-Girard et al., 2025). Multimodal analgesia has emerged as an essential component of ERAS cardiac recommendations. Optimizing postoperative pain control includes concurrent use of primarily non-opioid analgesics around the clock in scheduled dosing. This strategy reduces reliance on opioids, as the medications have additive, if not synergistic, analgesic effects.

Scheduled around the clock dosing of non-opioids often provides better postoperative pain control compared to pro re nata (PRN) administration in several surgical populations (Blitz et al., 2022; Inoue et al., 2021). However, in routine practice, PRN administration remains common, and implementation of standardized multimodal care is heterogeneous (Lui et al., 2023; Yoon et al., 2025). Metamizole (dipyrone, Optalgin®) is widely used in many countries as a non-opioid analgesic, authorized in the European Union for moderate to severe pain. Oral paracetamol is FDA-approved for the temporary relief of mild to moderate pain. This distinction in labeled pain indications aligns with differences in clinical utilization patterns and pharmacologic classification (FDA, 2025; EMA, 2025; Erlenwein, 2016). The existing literature demonstrates that metamizole provides adequate analgesia comparable to NSAIDs and is non-inferior—and in some surgical contexts, occasionally superior—to paracetamol for postoperative pain control (Erlenwein, 2016; Jeyaraman et al., 2024). In a recently randomized coronary artery bypass graft (CABG) trial, scheduled metamizole reduced the need for additional co-analgesics without attenuating aspirin’s antiplatelet effect (Luz et al., 2025; Petermichl et al., 2025).

Safety considerations remain primary priority, as cardiac surgery itself triggers a marked inflammatory response—locally within the pericardial space and systemically. This is most pronounced in the first 24–48 h after cardiac pulmonary bypass (CPB), which can be accompanied by leukocytosis/neutrophilia (Squiccimarro et al., 2022; El-Diasty et al., 2024).

Cardiac surgery associated acute renal failure (CSA-AKI), usually evolves within the first 48–72 h, and is associated with short and long adverse outcomes (Scurt et al., 2024a; Lindhardt et al., 2024).

Concerning hematologic safety, metamizole-associated agranulocytosis is very rare but life-threatening side effect, which require awareness and vigilance during treatment (patient education and prompt complete Blood Count (CBC) testing if systemic symptoms like high fever, chills, sore throat, difficulties swallowing occur) (Chatzimanouil et al., 2023; European Medicines Agency, 2024; Robich, 2020). Evidence on renal safety relative to other NSAIDs is mixed and context-dependent (Scurt et al., 2024a; Chatzimanouil et al., 2023).

This retrospective real-world study evaluated scheduled versus PRN metamizole use as part of a postoperative multimodal analgesia protocol in post cardiac surgery patients. Primary outcomes were pain intensity, opioid consumption by morphine milligram equivalents (MME), and safety parameters [white blood cells (WBC)/neutrophils and serum creatinine], to determine optimal metamizole use in this population.

This retrospective study evaluated the impact of implementing a standardized scheduled around the clock metamizole dosing protocol as part of a multimodal analgesia approach following cardiac surgery. Our findings demonstrate that scheduled metamizole administration was associated with lower opioid consumption, while maintaining adequate pain control and preserving renal and hematologic safety.

Interestingly, a slight but statistically noteworthy increase in hospital length of stay was observed following protocol implementation, with the mean duration increasing from 10.45 nights (SD = 8.41) pre-protocol to 11.21 nights (SD = 7.68) post-protocol, the independent t-test indicated a mean increase of 0.76 nights, with a 95% CI [−0.90, −0.62] and p < 0.0001. While this might initially appear counterintuitive given improved analgesia and opioid sparing, several potential explanations exist. These include changes in institutional discharge policies unrelated to the pain management protocol, case mix variations in patient complexity, trends in cardiac surgery practice during the study period, or unmeasured confounding factors. This finding contrasts with previous trials demonstrating that multimodal analgesia protocols are typically associated with reduced length of stay (Williams et al., 2019; Li et al., 2018). Further investigation with prospective design and more rigorous control for confounding variables is needed to clarify this unexpected finding and determine whether it represents a true effect of the protocol or reflects limitations in the retrospective design.

Several limitations should be acknowledged. The retrospective, single-center design may limit generalizability to other institutions with different patient populations, practice patterns, and healthcare systems. The unequal group sizes reflect real-world implementation constraints but may introduce statistical limitations and reduce power to detect differences in certain subgroup analyses. With respect to surgical urgency, the current dataset does not include a structured variable distinguishing elective from emergent procedures. Based on institutional practice patterns, the majority of cardiac surgeries performed during the study period were elective; however, because urgency was not systematically coded in the electronic medical record, this distribution cannot be quantified retrospectively with high precision. Similarly, although comorbidities such as diabetes, chronic kidney disease, and other chronic conditions are documented at the individual patient level, these variables were not extracted during the initial dataset construction and are therefore unavailable for comparative analysis in the present retrospective cohort. Designed prospective study with more granular comorbidity characterization would enhance external validity.

Pain assessments were based on routine clinical documentation with inherent variability in measurement techniques, documentation practices, and potential reporting bias. Although we adjusted for confounders where possible, unmeasured factors such as changes in surgical technique, anesthetic management, or other aspects of perioperative care might influence outcomes.

Additionally, while no serious safety concerns emerged in this study, rare adverse events such as agranulocytosis cannot be definitively ruled out based on a single-center retrospective analysis with limited sample size. The relatively short follow-up period precluded assessment of long-term outcomes including chronic post-sternotomy pain, persistent opioid use, and delayed complications. In our dataset, documentation of opioid-related clinical adverse effects (e.g., nausea/vomiting, constipation, delirium, respiratory depression) was incomplete and therefore not suitable for reliable analysis. It should also be noted that chest wall regional analgesia techniques (such as paravertebral blocks or erector spinae plane blocks) are not routinely performed in our institution for cardiac surgery, which may limit the applicability of our findings to centers where regional anesthesia is a standard component of multimodal analgesia protocols. The relative contribution of metamizole within a more comprehensive multimodal approach that includes regional techniques remains to be determined.

In conclusion, our findings provide real-world evidence that scheduled metamizole as part of a multimodal analgesia protocol effectively reduces opioid consumption after cardiac surgery while maintaining adequate pain control and without compromising renal or hematologic safety.

These results support the integration of around-the-clock metamizole into postoperative analgesia and opioid sparing strategies in cardiac surgical populations where this medication is available and approved for use, particularly in patients for whom traditional non-opioid options may be contraindicated. Given the limitations of retrospective observational studies, prospective randomized controlled trials are warranted to confirm these findings and establish optimal dosing strategies, define appropriate safety monitoring protocols, and assess long-term outcomes including chronic pain, quality of life, and functional recovery. A prospective randomized trial would yield higher-quality evidence, incorporating a design powered on the observed between-group difference in opioid consumption (mean difference of MME), inclusion of patient-centered secondary outcomes (such as opioid-related adverse effects, NRS thresholds, and length of stay), and predefined surveillance for the hematologic and renal safety of metamizole. Future research should also investigate the comparative effectiveness of metamizole versus other non-opioid analgesics in cardiac surgery, evaluate its role in specific subpopulations (such as those with chronic kidney disease, advanced age, or baseline hematologic abnormalities), examine cost-effectiveness within comprehensive care pathways, and assess its integration with regional anesthesia techniques. The potential inclusion of metamizole in standardized ERAS protocols for cardiac surgery should be formally evaluated through multicenter collaborative research, particularly in regions where this medication is approved for clinical use. Such evidence would help inform international guidelines and optimize perioperative postoperative pain management strategies. Ongoing pharmacovigilance remains essential to continue monitoring the safety profile of metamizole in this vulnerable population, with particular attention to rare but serious adverse events and their early detection and management.