Opioid-free anaesthesia as a valuable alternative to opioid-based practices: evidence and future challenges

ABSTRACT

Opioid-Free-Anesthesia (OFA) offers a valuable alternative model that challenges traditional opioid-based anesthesia practices. Recent studies have tempered expectations regarding the capacity of OFA techniques to improve quality of postoperative pain management and early recovery, in contrast with the clearly decreased risk of postoperative nausea and vomiting. Essentially based on regional anesthesia, non-opioid adjuvants and multimodal analgesia, OFA should be better viewed as a menu rather than a recipe, guided by surgical invasiveness, patient background, expected postoperative pain, and the practitioner’s expertise. Potential concerns of OFA, including bradycardia and hypotension, are manageable with proper training and adapted dosing. Further multicentre trials and non-inferiority studies are needed to better define OFA’s impact on patient-reported outcome and experiences measures in perioperative care.

1. Introduction

Perioperative care has moved to a new era, shifting toward minimally invasive procedures and focusing on what matters most to patients with patient-reported outcome measures (PROM) assessments [1,2].

Following surgical advances, newer anesthesia strategies focus on reducing adverse effects while enhancing postoperative pain control, comfort and fast recovery. Although opioid-based anesthesia (OBA) has long been the gold standard, concerns over opioid exposure have become increasingly prominent, opening a new area of research and innovation.

Historically, opioids have been central to anesthesia [3] but are associated with numerous side effects, including urinary retention, constipation, postoperative nausea and vomiting (PONV), shivering, opioid-induced ventilatory impairment (OIVI), or hyperalgesia [4].

These complications conflict with the current goals of fast-track recovery pathways. Enhanced Recovery After Surgery (ERAS) guidelines thus advocate for opioid-sparing techniques across various surgical specialties to improve postoperative outcomes [5,6]. Concurrently, the dramatic opioid crisis in the United States has highlighted the overconsumption and overprescription of opioids in the postoperative setting. This crisis has clearly underscored the need to reevaluate perioperative opioid administration as this period may serve as a gateway to opioid addiction.

For all these reasons, Opioid-Free Anaesthesia (OFA) has emerged as an alternative to avoid intraoperative opioid exposure. Even this definition offers simplicity, it makes it overly restrictive in some contexts. Forget et al [7] propose a Opioid-Free Anesthesia (OFA) definition as “the combination of various opioid-sparing techniques leading to the disappearance of intraoperative opioids.” This one helps anesthesiologists better understand how to deliver anesthesia by compensating for the absence of opioids, compared to the traditional Opioid-Based Anesthesia (OBA).

A common source of confusion in everyday practice is confusing OFA with multimodal analgesia (MMA). While OFA focuses on the intraoperative anesthesia period, it still allows for postoperative opioid rescue if needed, as pain control remains the ultimate goal regardless of the adopted strategy. Multimodal analgesia (MMA) primarily targets the postoperative period through combined non-opioid agents (8) (e.g., acetaminophen, non-steroidal anti-inflammatory drugs – NSAIDs, and regional analgesia) to improve pain control and reduce the opioid use.

Even multimodal analgesia (MMA) is currently becoming the gold standard for postoperative pain management, OFA remains a hot topic. Should it entirely replace opioid-based anesthesia (OBA), and which patients stand to benefit most?

In this perspective, we aim to explore the variety of OFA delivery approaches, review current evidence on its effectiveness and safety, and address ongoing controversies and challenges highlighted in recent literature regarding the eligible population and its implementation in daily practice.

2. Core components of OFA

The prevalence, drug combinations, and local protocol implementation of current OFA and opioid-sparing anesthesia practices remain largely unknown. But one thing is clear: intraoperative opioid doses have been decreasing over the years [8].

OFA may appear to be an advanced anesthesia technique limited to university hospitals and requiring specific expertise. But is there only one way to implement OFA? Probably not. OFA encompasses various approaches and techniques or drugs aimed at improving patient outcomes and reducing opioid-related side effects. OFA is a “menu” rather than a standardized cocktail, allowing practitioners to adapt their choices based on patient characteristics, surgical requirements, available resources and own skills. Through this menu, OFA clearly supports personalized medicine.

Blum et al. [9] were proposed a practical OFA framework, well-adapted to clinical practice. This framework considers surgical invasiveness, expected postoperative pain and patient characteristics, enabling clinicians to offer OFA even without extensive expertise. They offer a gradual response to case complexity: the more invasive and painful the surgery, the greater the number of interventions and adjuvants required. Secondly, they emphasize an early integration of regional anesthesia (RA) as an effective method for opioid sparing and pain control. Thirdly, while alpha-2 agonists would appear as a key OFA component, they are not typically used as a first-line approach. IV lidocaine is not included in this framework, likely due to its association with RA and the potential risk of local anaesthetic toxicity.

Concretely, they proposed three tiers and multiple options:

2.1. Tier 1: regional anaesthesia (RA)

RA is as a core element for intraoperative nociception control and multimodal postoperative analgesia. RA including local, fascial plane blocks, peripheral nerve blocks, or neuraxial anesthesia, suppresses intraoperative nociceptive responses and would be ideally performed before the surgical incision. Long-acting local anaesthetics (ropivacaine, bupivacaine, levobupivacaine), combined with IV dexamethasone (0.05 to 0.1 mg/kg), are preferred to extend analgesia. IV dexamethasone has been shown to enhance the duration of brachial plexus blocks [10] and even local infiltration analgesia [11].

OFA involves also key non-opioid drugs such as NMDA Antagonists (ketamine and magnesium sulfate), Alpha-2 Agonists (clonidine and dexmedetomidine) and Sodium Channel Blockers (lidocaine, maximum dose: 6–8 mg/kg).

2.2. Tier 2: NMDA antagonists

Ketamine (IV, single dose or continuous infusion) may now be considered a gold standard drug in anesthesia and currently improves PROMs, such as early subjective quality of recovery and pain severity after surgery [12], while reducing hemodynamic variability during surgery [13]. Specifically, Ketamine reduces acute resting pain scores during the early recovery period, although this effect does not extend beyond POD2 [14]. Additionally, pain scores at movements, PONV or psychotomimetic events are not impacted by ketamine infusion [14].

Magnesium sulfate has shown similar benefits, by reducing PONV and postoperative opioid consumption, but with moderate effects on pain scores at POD1 [15]. These effects are also observed in spinal procedures [16], abdominal surgeries [17] and may be considered as an weaker option than ketamine.

2.3. Tier 3

Alpha-2 agonists, such as dexmedetomidine, primarily act by attenuating the response to surgical stress or airway intubation. Dexmedetomidine enhances quality of recovery [18,19] and provides beneficial effects on PONV and shivering in the PACU (Post Anaesthesia Care Unit) without prolonging PACU length of stay [20].

The combination of magnesium sulfate, lidocaine, and ketamine in the same syringe has been shown to remain chemically stable for up to 24 hours [21]. This stability is particularly beneficial for longer surgeries requiring continuous infusion, resource-limited environments, or reducing the environmental impact, but is unfortunately not licensed in many countries.

Regardless of the OFA approach, a multimodal analgesia strategy including acetaminophen and NSAIDs should always be associated [22] if not contraindicated, along with effective PONV prophylaxis.

Despite the wide range of available options, the anesthesiologist’s decision should always be patient-centered, taking into account the complexity of the surgery and the patient’s condition. A careful benefit-risk assessment is key to avoiding unnecessary medication infusion while ensuring safety.

2.4. Recommended Dosing [9]

• Ketamine Recommended Dosing: A loading dose of 0.5 mg/kg followed by a maintenance dose of 0.25 mg/kg/h.

• Magnesium sulfate Recommended Dosing: A loading dose of 30–50 mg/kg, followed by a maintenance dose of 10 mg/kg/h.

• Dexmedetomidine Recommended Dosing: A titrated loading dose up to 0.5 μg/kg, followed by a maintenance dose up to 0.25 μg/kg/h.

• Clonidine Recommended Dosing: A loading dose of 1–4 μg/kg, with no following infusion.

3. Evidence on effectiveness

Recommended PROMs and PREMs for perioperative medicine have already been published [1,2]. Before analyzing which ones are impacted by OFA, consider what matters most to patients from their own perspectives is essential. Using the Bauer questionnaire in a large observational UK cohort involving 16,222 patients, the most prevalent types of severe discomfort reported were thirst, pain at the surgical site and drowsiness [23]. Interestingly, PONV was reported as a severe discomfort by only 3.2% of participants. Pain was also ranked as the second most common concern (16.7% of participants) regarding the worst aspect of their operation. Current evidence on OFA is summarized in Figure 1.

Figure 1.

Summary of current evidence on opioid-free anaesthesia (OFA); legend: green = clear benefit or improvement; grey = no significant difference; blue = insufficient data.

Abbreviations: OBA: Opioid-Based Anesthesia; OFA: Opioid-Free Anesthesia; PACU: Post-Anesthesia Care Unit; PONV: PostOperative Nausea and Vomiting; QoR: Quality of Recovery.

3.1. Post operative nausea and vomiting (PONV)

The surgical model and anesthesia strategies influence the occurrence of PONV, while approaches such as OFA, IV multi-prophylaxis or total intravenous anesthesia (TIVA) help prevent it. In this context, the rationale for OFA lies in avoiding intraoperative opioids and from PONV-reducing effects of ketamine, magnesium sulfate and dexmedetomidine

PONV are one of the most frequently evaluated PROMs, with convergent findings showing a reduction in PONV rates [24–26]. Specifically, OFA reduces reported PONV and the use of antiemetic drugs [27,28]. However, data on PONV prophylaxis strategies and rescue antiemetic drug use are often lacking or inconsistently reported. Recent studies suggest that OFA may have no significant impact on the antiemetics administration [29,30]. Even when OFA is employed, IV antiemetic prophylaxis should always be assessed preoperatively using the Apfel score and included in the anesthesia protocol.

While OFA shows a clear trend in reducing PONV, what alternative strategies could be considered? The role of TIVA merits discussion. TIVA has recently gained popularity due to its potential reduced environmental impact and its proven efficacy in PONV reduction compared to volatile anaesthetics [31]. However, TIVA is also associated with an increased risk of late-onset PONV [32] and requires additional resources.

3.2. Pain control and opioid consumption

OFA for pain control is a hot topic. Almost all OFA literature focuses solely on acute postoperative pain.

3.2.1. Acute pain

With pain scores as a primary outcome measure, current evidence shows that OFA does not reduce acute pain compared to OBA. No significant impact has been observed on postoperative pain scores at rest at 2 hours [33,34], 24 hours [24,33,35] or 48 hours after surgery [33]. Additionally, findings indicate no clinically significant reduction in opioid consumption within the first 24 hours post-surgery [33,36]. Similar results were reported for total hip arthroplasty [37] and bypass surgeries [27], with morphine consumption remaining low at less than 20 mg per 24 hours in both cases.

Conversely, a meta-analysis by Olausson et al. [24] concluded that OFA groups experienced a postoperative opioid reduction of 6 mg. However, while this analysis is considered high-quality [38], the 26 included studies were conducted prior to 2020. These conclusions should be interpreted cautiously, taking into account modern surgical techniques and the increasing use of effective regional anesthesia. Moreover, a minimal clinically important difference (MCID) in morphine consumption between groups has been established at 10 mg over 24 hours, based on a literature review [39].

Pain trajectory and opioid consumption have also been extensively evaluated as secondary outcomes, with similarly negative conclusions. However, the lack of power calculations for secondary outcomes limits the ability to draw definitive conclusions. No clinically relevant impact has been observed in minimally invasive abdominal surgeries [25], cardiovascular and thoracic surgeries [40], VATS [29,30], major plastic surgeries [41], laparoscopic bariatric surgeries [26], or gynecological surgeries. Interestingly, a non-inferiority study in gynecological laparoscopic surgery under ERAS pathways concluded that the OFA technique is non-inferior to the OBA technique in terms of analgesic effect [42].

Finally, discussing opioid consumption reduction makes sense for surgeries requiring high postoperative doses, such as spinal or thoracic procedures, especially in the absence of postoperative RA infusion. When postoperative opioid requirements are low, achieving a further margin of reduction becomes limited and challenging, as 10 mg is considered the minimal clinically important difference (MCID). Although OFA has failed to demonstrated superiority over OBA in terms of acute pain trajectory or opioid consumption, further non-inferiority studies could refine and challenge this narrative.

Controversial and unexpected findings regarding OFA have also emerged in the pain field. In a U.S. single-center retrospective analysis of 61,249 surgical patients, greater intraoperative IV fentanyl and IV hydromorphone administration were associated with decreased pain and reduced opioid use in the PACU [43]. Specifically, intraoperative fentanyl was linked to lower total opioid consumption over the first 24 postoperative hours. These findings may be explained by the pharmacological residual analgesic effects of opioids in the PACU but may also be spurious regarding the retrospective nature of the study, the number of comparisons, and the absence of remifentanil. These conclusions are then hypothesis-generating and require proper exploration through large randomized trials, with the hypothesis that OFA could potentially worsen postoperative pain outcomes rather than having no impact, which is unlikely given the current converging evidence. Moreover, requiring morphine titration in the PACU should not be interpreted as a failure of OFA. Pain control remains the ultimate goal, regardless of the chosen strategy. Additionally, the impact of PACU morphine titration should be evaluated based on other PROMs, such as additional PONV, or patient dissatisfaction.

3.2.2. Chronic pain

The impact of OFA on chronic postoperative pain remains an underexplored area. An older study from 1996 found no conclusive evidence of OFA’s impact [44], while a recent retrospective study reported a negative association, with intraoperative fentanyl administration linked to a decrease in new chronic pain diagnoses at 3 months [43]. More recently, a bi-center randomized controlled study on VATS demonstrated that OFA with intravenous and epidural Esketamine infusion reduced mild chronic postoperative pain at 3 months (34.2% in the OBA group vs. 17.5% in the OFA group; p = .004), with a similar trend observed at 6 months [45]. Notably, none of the patients experienced moderate or severe chronic pain. Interestingly, acute postoperative pain at 24 hours occurred more frequently in the OFA group. Esketamine psychotomimetic side effects were not monitored in this study. As secondary outcomes, Leger et al. concluded in a well-designed study that OFA had no significant impact on chronic pain at 3 months, despite most participants being women who underwent plastic surgery [41]. Similarly, in VATS without deep parietal blocks, OFA did not affect pain at 30 or 90 days post-procedure [29]. When focusing solely on the dexmedetomidine effects, it potentially reduces the postoperative chronic pain incidence at 3 months vs placebo (n = 7 RCTs), although the certainty of evidence is low [18].

Many authors emphasize the need to explore OFA’s long-term outcomes, including chronic pain. However, linking chronic pain to anesthesia remains challenging. In the context of OFA, regional anesthesia (RA) is likely the primary driver of reduced chronic postoperative pain [46], highlighting the importance of initiating RA as early as possible. Efficient regional blocks have been shown to reduce chronic pain in thoracic and breast surgeries [47].

Assessing OFA’s impact on chronic pain requires prudent study design and interpretation, particularly in relation to RA involvement. Future research should investigate whether OFA’s bundle of adjuvants has the same effect in settings where RA is not required. Thoracic and breast surgeries, as well as patients with preoperative risk factors, should be prioritized as target populations for future OFA studies on chronic pain. Finally, current data are insufficient to establish a potential impact of OFA on chronic pain.

3.3. Post anaesthesia Care Unit (PACU) discharge

The time spent in the PACU is influenced by multiple factors and is not determined only by the anesthesia strategy. Evaluated as a secondary outcome, OFA has not been shown to impact PACU length of stay (LOS) compared to OBA [24,25,48]. Recent well-designed randomized controlled trials have reached similar conclusions [27,30,37,41]. Conversely in VATS surgery [29], the OFA group spent an additional 15 minutes in the PACU, potentially due to non-statistically significant excessive sedation.

Concerns about excessive sedation from dexmedetomidine were addressed in a meta-analysis (n = 33 RCTs), which concluded that IV dexmedetomidine given before the end of surgery does not prolong PACU LOS (primary outcome). Subgroup analyses further confirmed this finding [20]. Similarly, a Bayesian meta-analysis reported an additional 1-minute PACU time, deemed not clinically relevant [18].

3.4. Quality of recovery (QoR)

Nowadays, research is increasingly focused on the potential impact of OFA on Quality of Recovery (QoR). Encompassing themes already explored, such as physical comfort (pain, PONV), QoR also evaluates emotional well-being and the return to basic functions.

The two largest studies to date, one on endoscopic sinus surgeries [49] and the other on major surgeries [41], failed to demonstrate the clinical significance of OFA compared to OBA on early QoR, despite both showing statistical significance. One possible explanation could be that ketamine, known to positively impact early quality of recovery [12], was included in both standard groups. Additionally, these surgical populations may not significantly benefit from an OFA strategy for improving QoR, as sinus surgeries or plastic surgeries are generally not associated with a prolonged or challenging postoperative course.

With moderate-to-low certainty of evidence, a recent meta-analysis (n = 15 RCTs) comparing OFA with OBA [50] reported improved global QoR scores at 24 hours postoperatively. In details, OFA demonstrated higher QoR-40 scores at 24 hours, whereas QoR-15 scores failed to reach the same conclusions. Despite including 15 RCTs with 1838 patients, the meta-analysis was predominantly driven by minimally invasive surgeries and was subject to potential bias. An earlier meta-analysis (n = 8 RCTs) reached similar conclusions, reporting moderate to low-quality evidence of OFA’s impact on QoR-40 improvement on POD1 [19]. Seven of the eight studies compared dexmedetomidine to placebo, while only one compared it to fentanyl. Lastly, as secondary outcomes, the quality of recovery was found to be superior in patients receiving OFA [35].

Current results on QoR are surprising, as both IV dexmedetomidine and IV ketamine [12] have been shown to be effective in improving QoR. Recently, intraoperative IV dexmedetomidine administration was associated with significant improvements in QoR-15 scores compared to placebo or standard care (mean difference of 9, n = 21 RCTs, moderate certainty of evidence) [18]. However, when included in OFA strategies, the results appear disappointing. Specifically, OFA improved pain scores and physical comfort but had no impact on emotional status, psychological support, or physical independence [50].

In conclusion, the high heterogeneity of theses meta-analysis underscores the need for more well-designed and larger studies focusing on QoR outcomes. While individual OFA components, such as IV ketamine or IV dexmedetomidine, are effective in improving QoR, OFA as a strategy cannot currently be strongly linked to QoR improvements. These results may reflect a population that was not appropriately selected to demonstrate its benefits. Adopting a patient-centered approach may unmask patient specificities but deserve further research.

3.5. Postoperative delirium

In the context of an aging population increasingly requiring elective and emergency surgeries, the potential impact of OFA on postoperative delirium has been poorly investigated. To date, only one randomized controlled trial has reported no significant difference between OFA and opioid-based anesthesia [51]. Interestingly, dexmedetomidine has shown potential to reduce the incidence of postoperative delirium [18,52]. However, its use remains debated in recent guidelines [53,54] and must be weighed against its hemodynamic side effects.

Currently, no evidence supports the use of OFA to reduce postoperative delirium. Effective pain management, including RA in orthopedic surgery, and early postoperative mobilization remain key strategies for its prevention.

3.6. Long term outcomes

Postoperative quality of life and persistent opioid use remain underexplored long-term outcomes

It is questionable whether avoiding a limited intraoperative opioids amount, even with compensation through IV adjuvants and regional anesthesia, significantly impacts long-term outcomes. Postoperative course involves multifactorial factors that intersect with patients’ preoperative conditions, making it challenging to isolate the effect of intraoperative anesthesia strategies.

The EQ-5D scale (five-level version with VAS) is the recommended health-related quality-of-life (QoL) measure for perioperative studies [2]. Using this tool, Leger et al. found no significant difference in quality of life (QoL) between OFA and OBA at three months postoperatively [41]. But in which contexts would OFA be most valuable for improving QoL? Postoperative complications have a significant negative impact on patients’ quality of life [55], particularly in surgeries with a high incidence of complications, such as major abdominal surgeries. Evaluating the potential impact of OFA on QoL in these contexts is therefore essential. Before that, identifying the mediators of QoR, including individual experience (and not only outcomes), are essential to properly design trials.

3.7. Patient experience and satisfaction

While PROMs are extensively studied in the OFA field, patient-reported experience measures (PREMs) are often neglected. Patient satisfaction is typically assessed using Likert scales, which provide a subjective perspective linked to patient expectations. Patient satisfaction scores are usually high and do not always highlight potential areas for improvement. In a large UK cohort, although 35% of participants reported severe discomfort, 85.6% were very satisfied with their general anesthesia experience [23].

In the context of OFA, no data currently compare OFA and OBA in terms of patient satisfaction. Such data would be valuable as they would provide insights from the patient’s perspective. However, if patient satisfaction trends follow the usual pattern of high scores, what would be the clinical relevance of both OFA and OBA achieving high satisfaction scores? Simple Likert scales are insufficiently informative; satisfaction with OFA should be explored using a multidimensional approach.

In contrast to patient satisfaction, patient experience offers a more objective perspective, exploring several dimensions such as emotional support, communication, and physical comfort. To date, only one recent qualitative OFA study has been conducted among laparoscopic bariatric surgery patients in Sweden. When comparing OFA to OBA, the authors found similar perioperative patient experiences, including comparable postoperative pain experiences [56]. However, patients reported accentuated memories of “struggling to keep control” during anesthesia induction, with Ketamine potentially offering a pharmacological explanation for this phenomenon.

The patient perspective on OFA, and more broadly on general anesthesia, remains poorly understood. Even many current outcomes are patient-centered, what do patients truly think about OFA approaches? Potential doubts, fears, or factors influencing their choice are currently unknown. Understanding these elements would be valuable for providing a patient-centered approach in clinical practice, rather than choosing OFA or OBA based solely on clinician preferences, skills, evidence based or beliefs.

Recently, professional perspectives on OFA vs OBA have been published, showing clearly lower scores for OFA among both surgeons and anesthesiologists [41]. These interesting findings require further exploration, particularly to identify the factors that may discourage anesthesiologists from incorporating OFA into their practices. Concerns such as the potential complexity of multiple infusions, hemodynamic issues or lack of training could explain these results. Understanding the sources of dissatisfaction among anesthesiologists is crucial for successfully implementing OFA in current clinical practices.

To summarize, regarding patient satisfaction, we cannot suggest any superiority of OFA over OBA, as this topic has yet to be thoroughly explored.

4. Evidence of safety

Hemodynamic stability appears to be the primary concern regarding the safety of OFA delivery. Available data are contradictory and need to be interpreted within specific contexts, such as surgical conditions and drug dosages. Furthermore, hemodynamic events, including bradycardia, intraoperative hypotension (IOH), and intraoperative hypertension, are primarily evaluated as secondary outcomes.

4.1. Bradycardia events

Bradycardia has been frequently linked to OFA, though meta-analyses provide inconsistent conclusions on its association. In minimally invasive surgeries, where pneumoperitoneum insufflation typically affects heart rates, no significant difference in bradycardia incidence was observed between OFA (11%) and OBA (6%) across eight RCTs (p = 0.87; I² = 0%) as primary outcome, with moderate-certainty evidence [25]. Notably, nearly all included trials used IV dexmedetomidine in the OFA groups. Similar conclusions were reported by Olausson et al. [24].

As a secondary outcome, Salomé et al. [33] found no association between OFA and bradycardia. However, in laparoscopic bariatric surgery, OFA was linked to a higher risk of bradycardia than OBA (RR 2.6, 95% CI 1.2–5.9, moderate-quality evidence [26]. The Feenstra et al. meta-analysis [35] reached similar conclusions, driven mainly by the POFA study results. However, a sensitivity analysis restricted to trials using dexmedetomidine low dose in OFA regimens showed no significant difference in bradycardia risk in this meta-analysis.

The prematurely stopped POFA trial [57] reported five major bradycardia events, four of which occurred during surgical carbon dioxide insufflation, all without sequelae. Vagal stimulation was identified as the primary cause. Importantly, a substantial proportion of patients in this trial did not received any loading dose, but, instead, received higher-than-specified doses of dexmedetomidine, both potentially contributing to the events [58]. Bayesian meta-analyses suggest IV dexmedetomidine impacts intraoperative bradycardia requiring intervention, though with very low certainty of evidence [18]. Interestingly, bradycardia and hypotension show a dose-dependent relationship, with a 0.5 µg/kg dose demonstrating greater effectiveness in managing emergence phenomena while causing fewer hemodynamic side effects compared to a 1 µg/kg dose [59].

Bradycardia events are often reversible, prevented with appropriate titration of the loading dose, and can typically be managed with IV atropine or by halting carbon dioxide insufflation. Moreover, it should be interpreted in terms of pharmacological intervention rather than based on heart rate values. No current studies have focused on bradycardia or intraoperative hypotension (IOH) as primary outcomes in well-designed trials.

4.2. Intra operative hypotension (IOH)

Similar observations can be made about IOH, which has never been assessed as a primary outcome to our knowledge. The upcoming DEXCOEUR trial [60] aims to address this gap. One major challenge is the lack of a clear definition for IOH. Without standardized criteria, it becomes difficult to evaluate the potential impact of OFA. Moreover, IOH is influenced by numerous confounding factors, including age, hydration status, high blood pressure condition and concurrent medications such as beta blockers.

Two meta-analyses [33,35] and two recent randomized controlled trials [29,41] found no difference in IOH between OFA and OBA, with all studies involving IV dexmedetomidine. Even the POFA trial, despite concerns over bradycardia, reported no increase in IOH in the OFA group [57]. Similar to bradycardia, the evidence linking IV dexmedetomidine to hypotension requiring intervention is of very low certainty [18] and shows a dose-dependent effect [59].

With recent trends highlighting the safety of low-concentration vasopressors for managing intraoperative hypotension [61], any potential IOH associated with OFA should not pose a significant issue. Rather than focusing solely on IOH, anesthesiologists should adopt local protocols to minimize its occurrence, regardless of the anesthesia strategy, as IOH can arise with both general and spinal anesthesia.

Finally, like bradycardia, concerns about IOH should be evaluated in terms of postoperative complications caused by prolonged low organ perfusion, rather than simply based on blood pressure values. IOH should only be considered a concern if it results in measurable postoperative effects.

Given the dexmedetomidine debate on bradycardia and IOH, it is essential for anesthesiologists to receive proper training. This includes adjusting dosages with initial titration, identifying potential risk situations such as surgical carbon dioxide insufflation, and managing side effects using appropriate algorithms. These factors are essential for the safe and effective use of dexmedetomidine.

5. Patient populations and surgical settings

Should every patient benefit from OFA? In other words, should we definitively stop using intraoperative opioids? This question remains challenging. Some authors argue that OFA may be futile in surgeries with minimal or no postoperative opioid requirements [62]. Other authors argue that opioids may be futile during any kind of surgery, and then better avoided in a context of necessary medicine optimization. Rather than dismissing OFA or OBA as valuable options, we will here focus on specific objectives that need to be achieved and whether OFA is a viable approach to meet those goals.

Addressing this question would require larger randomized controlled trials. Currently, the OFA literature is primarily driven by single-center trials, particularly from China, with a lack of multicentre studies. Additionally, most trials are designed to demonstrate OFA superiority rather than exploring the non-inferiority of opioid-based anesthesia. Methodological challenges, including questions about patient selection and appropriate outcome measures, remain unresolved. In 2024, several meta-analyses have been published that may provide valuable insights into the issue of patient selection for OFA.

5.1. Ambulatory surgeries

These surgeries require fast-track processes with low PONV rates and minimal failure to discharge rates. In this context, only one RCT has been conducted. In day-case total hip arthroplasty without regional blocks [37], OFA failed to reduce OME consumption or pain scores compared to OBA. Additionally, 10% of patients in the OFA group required prolonged hospitalization compared to 0% in the OBA group, although this difference was not statistically significant. In this well-designed study, the authors did not find any significant benefit from OFA.

From the outpatient facility perspective, using IV dexmedetomidine does not impact PACU (Post Anaesthesia Care Unit) length of stay (LOS) or result in residual sedation [20]. These parameters may be relevant for optimizing PACU capacity and ensuring efficient patient turnover. Additionally, when considering alpha-2 agonist medications, practitioners should consider their half-life and residual effects to ensure safe discharge readiness. Compared to IV clonidine, IV dexmedetomidine has a shorter half-life.

Even though ambulatory surgeries typically involve healthy patients, OFA should be further explored for its potential impact on failure to discharge, patient experience and early quality of recovery, key aspects of this hospitalization model. Finally, the current evidence supporting OFA’s positive impacts on PONV and recovery, along with its favorable PACU data, highlights its potential role for outpatient procedures.

5.2. Intermediate and major surgeries

Current literature focuses on three major surgical models: bariatric, thoracic, and abdominal surgeries

In thoracic surgeries, where video-assisted thoracoscopic surgery (VATS) has become the gold standard, recent guidelines [63] emphasize the importance of MMA and RA with deep blocks, such as paravertebral and erector spinae blocks. IV dexmedetomidine is recommended when basic analgesics cannot be used [63].

A meta-analysis by Filippo et al. [48], including 1 RCT and 5 observational studies with RA as a baseline strategy, concluded that OFA reduces postoperative complications compared to OBA. However, Mathew et al. [40] found no differences between OFA vs OBA for explored outcomes like PONV. Similarly, a study [30] in VATS patients with paravertebral blocks reported no PONV reduction, though unusually high PONV rates ( > 25%) were observed. Feng et al. [29] reported a reduction in PONV with OFA, but participants received wound infiltration instead of deep parietal blocks, which might explain the differing outcomes. Finally, the absence of positive OFA impacts in VATS might be explained by the predominant use of efficient deep parietal blocks, which already provide effective pain and PONV control. Given these mixed results, the postoperative pulmonary complication assessment, such as pneumonia or hypoxemia, may be more clinically relevant in the context of OFA.

In bariatric surgeries, OFA reduces PONV within 24 hours [26] and lowers 24-hour pain scores [36]. However, no significant impact on opioid consumption has been observed [27,36].

In laparoscopic abdominal surgeries, OFA decreases PONV rates, even in gynecologic procedures [24,25,28].

In cardiac surgeries, OFA prevalence remains extremely rare ( < 0.6% of cases) [64]. The ongoing multicentre OFACS trial [65] aims to explore its impact on postoperative complications in this high-risk population.

For intermediate and major surgeries, investigating OFA’s impact on postoperative complications could complement current research on PROMs, opening new areas of study.

Interesting research areas remain underexplored in the field of preoperative factors, such as chronic opioid use or chronic pain, where patients often have higher anticipated pain levels and greater opioid tolerance. Additionally, pain catastrophizing, anxiety, and depression are strongly associated with acute postsurgical pain [66]. Preoperative psychological factors may also influence opioid requirements; for instance, patients with significant pain catastrophizing or increased pain perception have demonstrated notable benefits from OFA [67].

Finally, except for bariatric and minimally invasive abdominal surgeries, OFA has yet to determine the population in which it would be most valuable. More data are needed on its effects in major surgeries and postoperative complications. Preoperative pain conditions and psychological factors, such as anxiety, depression or pain catastrophizing, are associated with a higher likelihood of experiencing acute postoperative pain and could represent a key target population for future OFA studies.

6. Implementation in daily practice

6.1. Economic and environmental considerations for OFA

In low-resource settings, OFA could serve as a potential alternative in cases of opioid shortages. While exclusive regional anesthesia is common in African countries, using agents like ketamine or magnesium sulfate could provide a safe and effective option when opioids are unavailable. However, current OFA practices in low-resource settings remain largely unknown.

Regardless of the setting, the cost of OFA in daily practice is another consideration. Some authors have pointed out the additional costs of OFA due to IV non-opioid adjuvants and infusion pump devices [68]. However, no studies have explored the cost-effectiveness of OFA compared to OBA, nor conducted a cost-minimization analysis assuming both approaches are equally effective.

Beyond financial costs, the OFA carbon footprint is also unknown. While the anaesthetic gases environmental impact has been widely discussed, little is known about regional anesthesia or OFA [69]. Beyond evaluating CO2 equivalents, a life cycle assessment of OFA vs OBA strategies should consider the drugs, devices, and consumables used for standardized surgical procedures. In this context, OFA is not just about avoiding intraoperative opioids. By involving more adjuvants and encouraging regional anesthesia, OFA raises concerns about a potentially higher environmental impact compared to OBA.

6.2. Barriers to adoption

There are currently no formal guidelines for OFA. Although opioid-sparing anesthesia and regional anesthesia techniques are encouraged, no specific recommendations emphasize potential OFA approaches.

The barriers to OFA adoption are also unclear. Potential challenges may include a lack of initial training and education, limited local support, or concerns regarding hemodynamic stability. Evidence-based data alone will not drive OFA implementation; a supportive local environment, including leadership endorsement, will also play a critical role.

To establish recommendations, data on OFA practices, barriers, and feasibility from real-world settings are essential.

7. Conclusion

Running an operating theater using only opioids as the primary adjunct is no longer acceptable today. While opioid overprescription has exacerbated the ongoing opioid epidemic in the USA, Opioid-Based Anaesthesia (OBA) is associated with significant side effects that delays the patient’s recovery. Opioid-Free Anesthesia (OFA) has emerged as a safe and valuable alternative, even regarding hemodynamic stability. Its main advantage is the PONV reduction by avoiding opioid exposure. However, current evidence suggests that OFA does not significantly reduce acute pain scores or postoperative opioid consumption. Although some authors argue that OFA may not be suitable for all patients, it has a definite place in clinical practice without major restrictions. Proper dosing, tailored algorithms for managing side effects, and careful implementation are essential for a safe OFA delivery. Identifying the target population most likely to benefit from OFA is crucial to better define its place in perioperative medicine. Future studies should focus on its impact on quality of recovery, long-term outcomes and potential benefits for major surgeries. In summary, while OFA excels at reducing PONV and provides acceptable safety and pain control, many broader implications remain to be clarified.

8. Future perspective

For providers not yet familiar with OFA but concerned about perioperative opioid use, adopting an opioid-sparing approach by gradually reducing intraoperative opioid doses can be an effective first step. This provides a confident foundation before fully transitioning to OFA, which requires initial training and adapting dosage regimens.

Current OFA guidelines are lacking to support its integration into daily practice or develop educational programs. Rather than creating recommendations, OFA could be incorporated into existing PROSPECT or ERAS guidelines considering its relevant outcomes, such as PONV reduction.

To support readers in interpreting studies (Table 1), both control and interventional groups should always include multimodal analgesia (MMA) and regional anesthesia (RA) when applicable. This standardization would make it easier to assess and find out the true OFA impact.

Table 1.

Tips for interpreting opioid-free anaesthesia (OFA) studies.

REGIONAL ANESTHESIA IN CONTEXT	Inclusion of regional analgesia (RA) in both groups. Prevent OFA overestimation effects by comparing postoperative pain trajectories.
BASELINE ANALGESIA MATTERS	Ensure control and OFA groups receive multimodal analgesia (MMA). Prevent OFA overestimation effects by comparing postoperative pain trajectories.
PROTOCOL TRANSPARENCY	Ensure clear reporting of drug compliance within study protocols. Beware of studies allowing opioid use at induction but labeling as “OFA.”
CONTROL GROUP COMPOSITION	Check for control groups that use only opioids without adjuvants like ketamine. Ensure inclusion of IV ketamine, RA, MMA, and bi-therapy for Post operative nausea and vomiting (PONV) prophylaxis.
OUTCOME RELEVANCE	Focus on clinically significant primary outcomes (e.g., postoperative complications, recovery quality). Avoid drawing conclusions from secondary outcomes. Consider the clinical relevance of findings (e.g., morphine reduction)

Future studies should rather focus on demonstrating the OFA non-inferiority compared to OBA, highlighting OFA as a valuable and safe alternative.

A critical direction will be the development of larger multicentre trials to assess more relevant outcomes. Outcomes such as PONV or bradycardia should no longer be primary endpoints, postoperative complications and early quality of recovery (QoR) should be prioritized.

OFA should be explored across various surgical models, with objectives tailored to specific contexts. It should not be only restricted to major surgeries. For ambulatory surgeries, the focus should be on failure-to-discharge rates and patient experience, demonstrating its relevance even in less complex procedures. In the case of major surgeries, the emphasis should be placed on quality of recovery (QoR) and postoperative complications. Additionally, for surgeries with high expected postoperative risk, it is essential to investigate the impact on quality of life (QoL).

Finally, one of the major future challenges is to identify the target population most likely to benefit from OFA to advance a personalized medicine. So far, 26 ongoing OFA interventional trials are registered on ClinicalTrials.gov as of June 2025.

Funding Statement

This paper was not funded.

Article highlights

• OFA (Opioid-Free-Anesthesia) is a flexible approach with multiple options, allowing providers to adapt regardless of their experience level.

• Current evidence supports PONV (Post operative nausea and vomiting) reduction, while its impact on postoperative pain and quality of recovery remains debated.

• With proper training and dosing, OFA does not cause more bradycardia or hypotension events than opioid-based anesthesia.

• Future studies are needed to assess the potential effect of OFA on postoperative quality of recovery.

• The indications for OFA, in terms of surgical procedures and patient profiles, have yet to be clearly defined.

Author contributions

Yann Gricourt: Conceptualization, Writing – Original Draft; Philippe Cuvillon: Writing – Review & Editing. Patrice Forget: Writing – Review & Editing, Supervision.

Disclosure statement

Yann Gricourt and Philippe Cuvillon received speaker fees from GE Healthcare.

Patrice Forget is supported by the European Society of Anesthesiology and Intensive Care (ESAIC) for the Pain and Opioids after Surgery (PANDOS) and the Euro-Periscope Research Groups (IDs ESAIC_GR_2021_PF, ESAIC_RG_PAND, and ESAIC_RG_EP), and received advisory board/speaker fees from Grunenthal, GE Healthcare and Oncomfort. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.