European Journal of Cardiovascular Medicine

Postoperative pain continues to be a major clinical concern as it negatively affects mobilization, increases morbidity such as pulmonary complications, delays recovery, and can contribute to the development of chronic postsurgical pain (Apfelbaum et al., 2003; Kehlet et al., 2021). Historically, opioids have been the mainstay of postoperative analgesia, but their use is limited by a range of well-documented side effects including respiratory depression, nausea, vomiting, constipation, pruritus, sedation, and the risk of persistent opioid dependence (Beverly et al., 2021; Myles et al., 2023). In response, perioperative pain management has undergone a significant paradigm shift toward multimodal analgesia (MMA)—a strategy that employs additive or synergistic combinations of pharmacologic and non-pharmacologic analgesics with different mechanisms of action to achieve effective pain relief while minimizing the adverse effects associated with high doses of a single medication (Joshi & Ong, 2019; Bhatia et al., 2019).

Multimodal analgesia aims to optimize the use of non-opioid agents, reserving opioids only for breakthrough pain, thereby reducing total opioid consumption compared to conventional intravenous patient-controlled analgesia regimens (Bhatia et al., 2019; Gazendam et al., 2022). The incorporation of MMA strategies has also become a cornerstone of Enhanced Recovery After Surgery (ERAS) protocols, which are designed to standardize perioperative care, minimize adverse effects, and promote faster recovery and improved patient outcomes (Kehlet et al., 2021; Gedda et al., 2023). Implementation of MMA requires collaboration among surgeons, anesthesiologists, nursing staff, and patients to ensure effective pain control, minimize opioid-related complications, and enhance patient satisfaction (Bhatia et al., 2019). From a systems perspective, successful use of multimodal analgesia contributes to shorter hospital stays, fewer complications, and better utilization of healthcare resources (Joshi & Ong, 2019; Gedda et al., 2023).

Within this framework, anesthetic techniques such as peripheral nerve blocks, plane blocks, and neuraxial (epidural or spinal) anesthesia play a pivotal role by blocking nociceptive pathways and reducing central sensitization (Guay et al., 2016; Bhatia et al., 2019). The integration of these techniques into multimodal pain management has been shown to improve postoperative comfort, reduce opioid requirements, and facilitate recovery (Hasabo et al., 2022; Hong et al., 2025). Evidence from perioperative studies suggests that when local or regional anesthesia is combined with systemic non-opioid agents—such as acetaminophen, NSAIDs, ketamine, dexamethasone, or gabapentinoids—patients experience lower pain intensity and fewer opioid-related adverse effects (Hussain et al., 2025; Joshi & Ong, 2019). However, the optimal combinations, timing, and duration of these interventions remain variable across different surgical specialties (Myles et al., 2023).

In spine surgery, for example, protocols such as those used at Rush University Medical Center emphasize the use of pre-emptive oral medications including pregabalin, cyclobenzaprine, and extended-release oxycodone; intraoperative agents such as propofol, ketamine, sevoflurane, and bupivacaine infiltration; as well as postoperative use of acetaminophen, dexamethasone, and local cold compression (Bhatia et al., 2019). These protocols have demonstrated reduced pain scores, earlier ambulation, and decreased opioid consumption (Bhatia et al., 2019; Yoo et al., 2019). Thus, anesthetic strategies are fundamental to achieving the goals of MMA by enabling superior pain control, attenuating the surgical stress response, and improving both short- and long-term recovery (Karan et al., 2020; Kehlet et al., 2021).

Objective

The objective of this systematic review is to synthesize and evaluate current evidence on multimodal analgesia strategies that incorporate anesthetic techniques particularly peripheral nerve blocks and neuraxial/epidural anesthesia—for postoperative pain control. The review focuses on their effectiveness in reducing pain intensity, decreasing opioid consumption, and improving functional recovery while highlighting gaps in standardization and future research directions.

This systematic review was conducted to identify and critically evaluate the published evidence on the effectiveness of multimodal analgesia (MMA) approaches that incorporate anesthetic interventions. The review was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure transparency and reproducibility (Page et al., 2021). The inclusion criteria encompassed randomized controlled trials (RCTs), prospective or retrospective comparative studies, and systematic reviews or meta-analyses that investigated MMA protocols integrating regional or neuraxial anesthesia for postoperative pain control. Eligible participants were adult surgical patients undergoing diverse procedures, including orthopedic, abdominal, thoracic, and spinal surgeries, since the pain mechanisms and perioperative requirements differ considerably across these surgical types (Kaye et al., 2020). The interventions of interest were multimodal analgesic regimens incorporating at least one anesthetic component, such as a peripheral nerve block, epidural anesthesia, or local anesthetic infiltration, administered alongside non-opioid adjuncts. These adjuncts included nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, ketamine, gabapentinoids, dexamethasone, or lidocaine, all of which act via distinct mechanisms to achieve synergistic pain relief (Chou et al., 2016; Schug & Palmer, 2020). The comparator arms comprised conventional opioid-based regimens, MMA without anesthetic techniques, or alternative multimodal combinations. The primary outcomes were postoperative pain intensity, quantified by validated measures such as the Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS), and cumulative opioid consumption reported in morphine milligram equivalents (MME). The secondary outcomes included opioid-related adverse events such as nausea, vomiting, ileus, and sedation, as well as indicators of recovery such as time to ambulation, hospital length of stay, and the incidence of chronic postsurgical pain (Gerbershagen et al., 2019). Studies that evaluated only a single nerve block versus opioid therapy, without a full multimodal framework, or those lacking quantifiable opioid-consumption data were excluded to maintain methodological consistency (Kemp et al., 2020). A comprehensive literature search was conducted using PubMed, the Cochrane Library, and ScienceDirect databases to identify relevant studies published between January 2015 and June 2025. The search terms included combinations of “multimodal analgesia,” “nerve block,” “epidural analgesia,” “postoperative pain,” “regional anesthesia,” and “opioid consumption.” Boolean operators and medical subject headings (MeSH) were applied to refine the search strategy (Aldington et al., 2018). Additionally, the reference lists of retrieved papers were manually screened to capture studies not indexed in electronic databases. The process of study selection involved two independent reviewers who screened titles and abstracts, followed by full-text evaluation of potentially eligible studies, with disagreements resolved by consensus. Data extraction was performed using a standardized form that included details such as the author and year of publication, study design, surgical population, anesthetic technique employed, non-opioid adjuncts administered, and postoperative outcomes related to pain intensity, opioid consumption, and complications (Gerbershagen et al., 2019; McIsaac et al., 2022). Due to the heterogeneity of included studies arising from variations in study design, anesthetic technique, timing, and drug combinations a narrative synthesis approach was adopted instead of quantitative meta-analysis (Peden et al., 2020). Where applicable, pooled results from high-quality meta-analyses were summarized to enhance interpretability and provide broader clinical context. Quality assessment focused on key methodological criteria, including randomization procedures, blinding, sample size adequacy, attrition rates, and outcome completeness (Moore et al., 2022). Risk of bias was assessed according to the Cochrane Handbook recommendations, emphasizing internal validity and potential confounding. Consistent with prior multimodal analgesia reviews, it was observed that moderate heterogeneity stemmed from diverse pharmacologic combinations and inconsistent outcome reporting across trials (Kaye et al., 2020; Peden et al., 2020). Nevertheless, the overall quality and consistency of findings across multiple independent studies were considered sufficient to draw meaningful conclusions regarding the analgesic efficacy and opioid-sparing benefits of anesthetic-based multimodal analgesia strategies.

A total of eight major studies were identified and reviewed, including randomized controlled trials, cohort studies, and systematic reviews published between 2016 and 2025. Collectively, these studies demonstrated consistent benefits of multimodal analgesia protocols that incorporated anesthetic techniques such as nerve blocks and neuraxial analgesia. The integration of anesthetic methods within MMA regimens produced clinically meaningful reductions in both postoperative pain scores and opioid consumption, along with improved functional recovery and decreased incidence of opioid-related side effects. The study by Guay et al. (2016) provided strong evidence that epidural local anesthetics, with or without supplemental opioids, offered superior pain relief compared to systemic opioid regimens following abdominal surgery and were associated with faster recovery of gastrointestinal function. Similarly, Gazendam et al. (2022) reported that patients undergoing arthroscopic surgery who received an opioid-sparing multimodal protocol which included local anesthetic infiltration and non-opioid agents—used significantly fewer opioids, with median 6-week consumption of 0 mg compared to 40 mg in the standard opioid-based group, while maintaining equal or improved pain scores.

In a large cohort analysis of 842 colorectal surgery patients, Gedda et al. (2023) observed that the implementation of a structured ERAS bundle integrating anesthetic interventions, individualized opioid regimens, and adjuvants such as gabapentinoids and clonidine reduced median in-hospital opioid consumption from 75 morphine milligram equivalents in 2016 to 22 morphine milligram equivalents in 2019, with the proportion of patients receiving fewer than 45 MME rising from 35% to 66%. Studies focusing on orthopedic surgery further reinforced the value of specific regional techniques: Hasabo et al. (2022) and Gong et al. (2024) demonstrated that adductor canal block provided equivalent analgesia and opioid-sparing effects compared to femoral nerve block while better preserving quadriceps strength and early ambulation following total knee arthroplasty.

Evidence from abdominal and thoracic procedures also supported the opioid-sparing potential of fascial-plane blocks. Hong et al. (2025) found that both transversus abdominis plane (TAP) and quadratus lumborum (QL) blocks significantly decreased postoperative opioid consumption compared with systemic analgesia alone, while Hussain et al. (2025) highlighted that erector spinae plane (ESP) and QL blocks provided similar degrees of pain control, supporting their inclusion in MMA bundles for abdominal surgery. In the context of spine surgery, Bhatia et al. (2019) demonstrated that a pre-emptive and intraoperative multimodal protocol consisting of pregabalin, cyclobenzaprine, controlled-release oxycodone, ketamine, propofol, and local bupivacaine infiltration effectively reduced postoperative opioid use and improved patient mobilization. These findings collectively underscore that combining anesthetic techniques with non-opioid agents such as acetaminophen, NSAIDs, ketamine, dexamethasone, and gabapentinoids enhances analgesic efficacy while minimizing opioid-related side effects.

In addition to reductions in pain and opioid use, several studies reported favorable secondary outcomes including shorter hospital stays, reduced postoperative nausea and vomiting, faster mobilization, and better patient satisfaction scores. Epidural analgesia, in particular, was associated with earlier return of bowel function, fewer pulmonary complications, and smoother recovery trajectories. However, across studies, the degree of benefit varied depending on surgical type, technique selection, and timing of administration. While most trials confirmed a positive impact, a few reported modest or nonsignificant differences, emphasizing that outcomes are influenced by multimodal combinations, surgical invasiveness, and patient variability.

The collective evidence indicates that multimodal analgesia incorporating anesthetic techniques—such as peripheral nerve blocks, plane blocks, and neuraxial analgesia—significantly enhances postoperative pain management while reducing opioid consumption. This finding aligns with the underlying pharmacologic rationale that blocking peripheral nociceptive transmission and reducing central sensitization through regional or neuraxial anesthesia provides a synergistic benefit when combined with non-opioid pharmacologic agents. Bhatia et al. (2019) highlighted that MMA regimens tailored to spine and other surgeries achieve more stable hemodynamics, lower opioid requirements, and faster return to function compared to opioid-centric methods. Furthermore, regional anesthetic interventions, when combined with systemic agents such as acetaminophen, NSAIDs, gabapentinoids, and low-dose ketamine, appear to produce a cumulative analgesic effect while attenuating side effects such as nausea, ileus, and pruritus commonly associated with opioids.

From a mechanistic perspective, regional anesthesia limits the influx of nociceptive signals to the central nervous system, thereby mitigating the amplification of pain pathways that often contributes to hyperalgesia and chronic pain syndromes. The addition of anti-inflammatory and neuromodulatory agents further enhances this effect by dampening peripheral sensitization. For instance, the inclusion of dexamethasone in MMA protocols not only reduces postoperative nausea and vomiting but also prolongs the duration of analgesia and delays the need for rescue opioids. Similarly, gabapentinoids such as gabapentin and pregabalin modulate voltage-gated calcium channels in dorsal root ganglia, reducing neurotransmitter release and consequently diminishing pain perception and opioid consumption. These pharmacologic and physiologic mechanisms collectively underpin the success of multimodal approaches.

Clinically, the benefits of MMA are reflected in multiple outcome domains beyond pain and opioid use. Patients managed with regional-anesthetic-based MMA demonstrate shorter hospital stays, earlier mobilization, and improved participation in physiotherapy, which are central to ERAS objectives. The orthopedic literature demonstrates this particularly well, with adductor canal blocks enabling rapid ambulation without motor impairment, whereas epidural analgesia remains beneficial for thoracoabdominal and major open procedures due to its capacity to blunt the surgical stress response. The broader system-level advantages of MMA include reduced rates of readmission and fewer opioid-related adverse events, translating into both improved patient satisfaction and healthcare efficiency.

Despite these encouraging findings, some limitations persist. Heterogeneity across studies in analgesic combinations, dosing regimens, and timing complicates direct comparison and the development of universal MMA guidelines. Additionally, many trials are single-center with relatively small sample sizes, potentially limiting external validity. While the majority of evidence demonstrates short-term benefits, the long-term implications—such as prevention of chronic postsurgical pain and sustained opioid abstinence—remain underexplored. Another key limitation involves variability in anesthetic technique; for example, single-shot nerve blocks, while effective initially, may lead to rebound pain once the block wears off if not supported by continuous infusions or supplemental agents. Moreover, safety concerns, such as local anesthetic systemic toxicity or the risk of epidural hematoma in anticoagulated patients, warrant careful patient selection and adherence to safety protocols. These challenges underscore the need for ongoing research to refine MMA strategies for different surgical populations.

Future investigations should aim to standardize multimodal analgesia protocols by surgical type and patient risk profile, employing well-designed randomized controlled trials with uniform outcome measures. There is also a need to evaluate optimal combinations of anesthetic and pharmacologic modalities for example, comparing NSAID plus nerve block plus dexamethasone versus NSAID plus block alone to identify the most efficient and safe regimens. Moreover, studies should focus on long-term outcomes such as quality of life, chronic pain incidence, and cost-effectiveness to fully quantify the benefits of these protocols. Integration of predictive analytics and personalized medicine could further enhance decision-making, allowing analgesic regimens to be tailored to individual pain phenotypes, opioid tolerance, and comorbidities.

In conclusion, the current body of evidence strongly supports that multimodal analgesia strategies incorporating anesthetic techniques whether peripheral nerve blocks, fascial plane blocks, or neuraxial analgesia provide superior postoperative pain control, significantly reduce opioid consumption, and improve overall recovery outcomes. These multimodal approaches align with the goals of modern perioperative care, particularly within Enhanced Recovery After Surgery programs, by optimizing pain management while minimizing opioid-related complications. The synergy between anesthetic techniques and systemic non-opioid pharmacologic agents enables effective analgesia through multiple mechanisms, including peripheral blockade of nociceptive input, attenuation of central sensitization, and reduction of inflammatory responses. The adoption of these approaches has been shown to improve not only patient comfort but also healthcare efficiency by reducing length of stay, complications, and costs. However, despite the growing evidence base, variability in study designs, patient populations, and protocol details continues to pose challenges to standardization. Future research should focus on large, multicenter randomized trials to define the optimal multimodal combinations and to establish robust, procedure-specific guidelines. Additionally, long-term follow-up studies are needed to determine whether these strategies prevent chronic postsurgical pain and persistent opioid use. Until then, clinicians are encouraged to integrate anesthetic-based multimodal analgesia into perioperative care tailored to individual patient needs and surgical contexts. This holistic and evidence-based approach represents a pivotal advancement toward safer, more effective, and sustainable postoperative pain management.

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