A central objective of OSA and OFA is to minimize opioid use throughout the perioperative period, and numerous studies have demonstrated their effectiveness in achieving this goal. In a randomized controlled trial (RCT) by Bakan et al. [17], patients undergoing laparoscopic cholecystectomy were assigned to either an OFA group (receiving propofol, dexmedetomidine, and lidocaine) or an OBA group (receiving remifentanil). The OFA group showed significantly lower postoperative morphine consumption at 24 hours and a reduced need for rescue analgesia. Similarly, Shalaby et al. [18] conducted an RCT in patients undergoing laparoscopic cholecystectomy and reported a 33% reduction in postoperative opioid consumption in the OFA group compared with the OBA group.

Meta-analyses have further confirmed these findings. Frauenknecht et al. [19] analyzed 23 studies comparing OFA with OBA (Fig. 1, Ref. [15, 17, 18, 19]) and reported that OFA was associated with a 28% reduction in postoperative opioid use. Olausson et al. [15] conducted a more recent meta-analysis of 26 studies and identified an even greater reduction, with OFA resulting in a 40% decrease in postoperative opioid use. These reductions are clinically significant, as they correspond to a lower risk of opioid-induced adverse events and a reduced likelihood of persistent postoperative opioid use (PPOU).

Fig. 1.

Perioperative opioid-sparing strategies: OBA vs. OFA mechanisms and clinical outcomes [15, 17, 18, 19]. This figure is an original schematic created by the authors for this review. The figure was created using BioRender (Toronto, ON, Canada; https://www.biorender.com). OBA, opioid-based anaesthesia; OFA, opioid-free anaesthesia; GABAA, $\gamma$-aminobutyric acid type A; RCTs, randomized controlled trials.

The reduction in opioid consumption associated with OSA and OFA has a positive impact on multiple postoperative recovery outcomes. One of the most notable benefits is the improvement in gastrointestinal function. Opioid-induced ileus is a major contributor to delayed recovery and prolonged hospital stays, and evidence shows that OSA and OFA can accelerate the return of bowel function. In an RCT by Elsaye et al. [20], patients undergoing laparoscopic surgery who received OFA experienced a significantly shorter time to first flatus and first bowel movement compared with those in the OBA group. Similarly, a systematic review by de Boer et al. [21] reported that OSA techniques reduced the incidence of postoperative ileus by 35% and shortened the time to bowel function resumption by an average of 12 hours.

OSA and OFA also have a favorable impact on the length of hospital stay (LOS). In a retrospective cohort study by Ljungqvist et al. [22], the implementation of an enhanced recovery after surgery (ERAS) protocol incorporating OSA was associated with a 20% reduction in LOS among patients undergoing major abdominal surgery. Similarly, an RCT by Hontoir et al. [23] found that patients undergoing breast cancer surgery who received OFA had a 1.5-day shorter LOS compared with those in the OBA group. These reductions in LOS improve patient satisfaction and carry significant cost implications for healthcare systems.

A key concern regarding the adoption of OSA and OFA is the potential for inadequate pain control. However, current evidence indicates that these techniques provide comparable or even superior analgesia relative to OBA. In a systematic review by Suandika et al. [24], four of seven studies reported that the OFA group had lower mean resting pain scores at the first postoperative assessment and at 24 hours postoperatively compared with the OBA group. Similarly, a meta-analysis by Liu et al. [25] reported no significant difference in postoperative pain scores between the OFA and OBA groups, indicating that OFA does not compromise pain management.

In terms of safety, OSA and OFA are associated with a significantly reduced incidence of opioid-induced adverse events. PONV is among the most consistently observed clinical benefits. For instance, an adaptive randomized controlled trial (aRCT) by Choi et al. [26] demonstrated that patients undergoing thyroidectomy who received OFA had a PONV incidence of 17.5%, compared with 70.0% in the OBA group. Furthermore, a comprehensive meta-analysis by Olausson et al. [15] corroborated these findings, reporting that OFA was associated with a substantial reduction in the risk of both nausea (Odds Ratio [OR] 0.27) and vomiting (OR 0.22), along with a commensurate decrease in the requirement for rescue antiemetic medication.

Respiratory depression, a potentially life-threatening opioid-related complication, is also less common among patients receiving OSA or OFA. Nagappa et al. [27] conducted a systematic review of opioid-related respiratory adverse events and reported that OSA techniques reduced the risk of respiratory depression by 30% compared with OBA. This finding is especially relevant in high-risk populations, such as obese individuals and patients with obstructive sleep apnea, who face substantially increased vulnerability to OIRD.

CPSP and PPOU are long-term consequences of perioperative opioid use that carry significant implications for patient quality of life and healthcare resource utilization. Emerging evidence suggests that OSA and OFA may reduce the risk of these outcomes. Van Gulik et al. [28] conducted a prospective cohort study in patients undergoing cardiac surgery and found that the use of high-dose remifentanil was associated with a 2.5-fold increased risk of CPSP at one year postoperatively. In contrast, a study by Lavand’homme et al. [29] reported that patients undergoing major digestive surgery who received an OFA technique incorporating epidural analgesia and ketamine had a 40% lower incidence of CPSP at six months postoperatively compared with those in the OBA group.

Regarding PPOU, few studies have directly evaluated the impact of OSA and OFA, yet indirect evidence suggests a beneficial effect. Crucially, a study by Travaglini et al. [30] identified preoperative opioid use as a major risk factor for PPOU; by reducing intraoperative and postoperative opioid exposure, OSA and OFA may help interrupt the progression toward opioid dependence.

In terms of PPOU, few studies have directly evaluated the impact of OSA and OFA, but indirect evidence suggests a beneficial effect. Verla and Iqbal [31] conducted a narrative review and noted that strategies to minimize perioperative opioid use, including OSA and OFA, are associated with a reduced risk of PPOU. A study by Travaglini et al. [30] identified preoperative opioid use as a major risk factor for PPOU, and by reducing intraoperative and postoperative opioid exposure, OSA and OFA may help interrupt the progression toward opioid dependence. Future studies with long-term follow-up are warranted to clarify the relationship between OSA/OFA and PPOU.

Multimodal analgesia, defined as the use of multiple analgesic agents or techniques that act through different mechanisms to achieve effective pain control, is the foundation of OSA and OFA [32]. By targeting various pathways within the pain signaling cascade, multimodal analgesia enables the use of lower doses of individual drugs, thereby reducing the risk of adverse events while maintaining or enhancing analgesic efficacy. Key components of multimodal analgesia for OSA and OFA include non-opioid analgesics, regional anaesthesia, and adjuvant medications [33].

The successful implementation of OSA and OFA requires careful patient selection and comprehensive assessment. Although these techniques can be applied across a broad range of patients, several factors must be considered to optimize clinical outcomes. Patient-specific factors must be considered to optimize clinical outcomes. Patient-specific variables, such as age, comorbidities, and prior opioid exposure, play a key role in determining the suitability of OSA and OFA [46].

The selection of drugs for OSA and OFA depends on patient characteristics, the type of surgical procedure, and the desired clinical outcomes. The overarching goal is to choose a combination of agents that provides effective pain control with minimal adverse events [53]. Below is a summary of the principal drugs used in OSA and OFA, along with their recommended dosing strategies and monitoring parameters.

Clonidine and dexmedetomidine are the most frequently used alpha-2 adrenergic agonists in OSA and OFA. Clonidine is typically administered as a preoperative oral dose of 0.2 mg, followed by a continuous intravenous infusion of 1–2 mcg/kg/h during surgery [54]. Dexmedetomidine is administered as a loading dose of 0.5–1 mcg/kg over 10–15 minutes, followed by a continuous infusion of 0.2–0.7 mcg/kg/h [55]. The infusion rate should be titrated according to hemodynamic responses, with a target heart rate of 50–70 beats per minute and a mean arterial pressure of 60–80 mmHg. Vigilant monitoring for bradycardia and hypotension is essential, particularly in elderly individuals and those with pre-existing cardiac conditions [56].

Ketamine is administered as a bolus dose of 0.2–0.5 mg/kg at induction, followed by a continuous infusion of 0.1–0.5 mg/kg/h during surgery [57]. Higher doses may be required in patients with a history of opioid use or those undergoing major surgery [58]. Ketamine use may be associated with hallucinations, nightmares, and hypertension, and premedication with a benzodiazepine can help mitigate these effects [59]. Monitoring for the emergence of delirium is important, particularly among pediatric patients and young adults.

Intravenous lidocaine is administered as a bolus dose of 1–2 mg/kg at induction, followed by a continuous infusion of 1–3 mg/kg/h during surgery [60]. The infusion should be discontinued 30–60 minutes before the conclusion of surgery to prevent prolonged local anesthetic toxicity. Monitoring for signs of lidocaine toxicity, including tinnitus, perioral numbness, and seizures, is essential [61]. Patients with renal or hepatic dysfunction may require dose adjustments to avoid drug accumulation [62, 63].

Acetaminophen is administered as a preoperative oral dose of 1000 mg, followed by intravenous doses of 1000 mg every 6 hours during the postoperative period [64]. The maximum daily dose should not exceed 4000 mg to prevent hepatotoxicity. In patients with hepatic dysfunction, the total daily dose should be reduced to 3000 mg/day or less [65].

Ketorolac is the most commonly used NSAID in the perioperative period, administered as an intravenous dose of 15–30 mg every 6 hours [66]. The maximum duration of administration should not exceed 5 days to reduce the risk of gastrointestinal bleeding and renal dysfunction. Ibuprofen is also used, given as an oral dose of 400–600 mg every 6 hours [67]. NSAIDs should be avoided in patients with a history of gastrointestinal ulcers, renal dysfunction, or bleeding disorders [68].

The implementation of OSA and OFA requires the development of standardized protocols that clearly outline patient selection, drug choice and dosing, monitoring parameters, and the management of adverse events [69]. These protocols should be evidence-based, adapted to the specific needs of the institution, and regularly reviewed and updated based on emerging evidence and clinical experience [70]. To facilitate this process, the following template (Table 1, Ref. [15, 22, 31, 37, 42, 48, 49, 59, 61, 71]) incorporates the essential components, with practical examples grounded in the clinical evidence presented earlier. This template aims to ensure that each protocol element is not only evidence-informed but also actionable and directly applicable to daily clinical practice.

The development of OSA and OFA protocols should involve a multidisciplinary team including anesthesiologists, surgeons, nurses, pharmacists, and pain management specialists. The team should begin by conducting a formal needs assessment to identify the target patient population, common surgical procedures, and current challenges in opioid management. This assessment may include a review of hospital data on opioid consumption, postoperative adverse events, and LOS [71]. To ensure that every phase of care, from preoperative preparation to postoperative discharge, is comprehensively addressed, a clear delineation of role-specific responsibilities is crucial. The following framework (Table 2) outlines the core responsibilities for key members of the perioperative team in the context of OSA/OFA implementation.

The team should review the current evidence on OSA and OFA to identify the most effective drugs and techniques for the target population [72]. This review should include RCTs, systematic reviews, and meta-analyses, as well as clinical practice guidelines from professional bodies such as the American Society of Anesthesiologists (ASA) and the European Society of Anesthesiology and Intensive Care (ESAIC).

Based on the needs assessment and evidence review, the team should develop draft protocols outlining patient selection criteria, drug selection and dosing for OSA and OFA, monitoring parameters, management of adverse events, and postoperative pain management plans. The draft protocols should then be pilot-tested in a small group of patients to evaluate feasibility and effectiveness [73]. Feedback from healthcare providers and patients should be collected and used to refine the protocols before full implementation.

To evaluate the effectiveness of OSA and OFA implementation, hospitals should track both clinical and operational KPIs, comparing baseline data with post-implementation outcomes to identify areas for improvement and validate the added value of these techniques. These metrics provide objective indicators of success, supporting ongoing adoption and institutional commitment.

Clinical KPIs include postoperative opioid consumption (reported in oral morphine equivalents [OME] at 24 and 48 hours post-operation, targeting at least a 30% reduction from baseline [19]); incidence of PONV (aiming for 20% in the OSA/OFA group, compared with the 65% typically observed with opioid-based anaesthesia [OBA] [26]); pain scores at rest and during movement (targeting $\le$3/10 at rest and $\le$4/10 with movement at 24 and 48 hours post-operation [15]); and incidence of OIRD (goal 5% vs. approximately 15% in OBA [27]).

Operational KPIs include length of hospital stay (LOS), with a target of $\ge$20% reduction [22]; PACU discharge time (aiming for $\le$60 minutes, compared with approximately 90 minutes in OBA [23]); and 7- and 30-day readmission rates (target 3%, vs. around 5% with OBA [31]). Additionally, patient-reported outcomes such as satisfaction with pain management (goal $\ge$4/5 on Press Ganey scores) and time to first ambulation (target $\le$24 hours post-operation, compared with 48 hours in OBA [20]) should be monitored to capture the patient experience.

Data for these KPIs can be extracted from electronic health records (EHRs) for opioid consumption and LOS, nursing documentation for pain scores and PONV, and post-discharge surveys for patient satisfaction, ensuring a comprehensive evaluation of implementation success.

One of the main barriers to the implementation of OSA and OFA is the concern among healthcare providers that these techniques may not provide adequate pain control. This concern is often rooted in limited experience with non-opioid analgesics and regional anaesthesia, as well as misconceptions about the effectiveness of these approaches [74]. To address this barrier, healthcare providers should be educated on the latest evidence supporting the efficacy of OSA and OFA and given opportunities to gain hands-on experience with these techniques [75].

Healthcare providers should receive structured education on the current evidence supporting the analgesic efficacy of OSA and OFA. This education may include reviews of meta-analyses and RCTs that demonstrate that OSA and OFA provide comparable or superior pain control relative to OBA [76]. Olausson et al. [15] reported no significant difference in postoperative pain scores between OFA and OBA groups, while Frauenknecht et al. [19] showed that OFA was associated with a reduction in PONV without compromising analgesia.

Hands-on training is essential for building confidence in the use of OSA and OFA. This may include shadowing experienced anesthesiologists who routinely apply these techniques, participating in workshops on regional anaesthesia, and practicing drug dosing and monitoring in simulation settings. Simulation training is particularly useful for rehearsing the management of adverse events, such as lidocaine toxicity and bradycardia, that may occur infrequently in routine clinical practice [77].

Pilot projects can also be employed to demonstrate the effectiveness of OSA and OFA in a controlled cohort, thereby increasing provider confidence before full-scale implementation. For example, a pilot project could be conducted in patients undergoing laparoscopic cholecystectomy, comparing outcomes between a small OFA group and a control group receiving OBA [78]. The results of such pilots should be shared with the interdisciplinary team as evidence of the clinical benefits of OSA and OFA.

Resource constraints, including limited access to regional anaesthesia equipment and personnel, can also pose significant barriers to OSA and OFA implementation. To address these limitations, hospitals should prioritize resource allocation to support these techniques and explore innovative strategies to overcome operational constraints.

Hospitals should allocate adequate resources to support the adoption of OSA and OFA, including the procurement of regional anaesthesia equipment and the recruitment of additional personnel such as nurse anesthetists and pain management specialists. Additionally, institutions should consider investing in EHR systems that can be used to collect and analyze OSA/OFA outcome data, thereby supporting quality improvement efforts.

Innovative solutions can further help mitigate resource constraints. Telemedicine can provide remote support to anesthesiologists in rural or underserved areas who may have limited experience with regional anaesthesia. Additionally, nurse-led pain management teams can be established to support postoperative management for patients receiving OSA and OFA, thereby reducing the workload placed on anesthesiologists.

Changing organizational culture is another significant barrier to the implementation of OSA and OFA. This requires shifting from a culture that relies heavily on opioids for pain control to one that prioritizes opioid minimization and multimodal analgesia [79]. To achieve this shift, hospital leadership should be actively involved in supporting the implementation of OSA and OFA and should communicate the importance of these techniques to all healthcare providers. Hospital leadership should provide visible support for implementation of OSA and OFA, including allocating resources, approving changes to policies and procedures, and recognizing the efforts of healthcare providers who adopt these techniques [80]. Leadership should also communicate the goals of OSA and OFA across the institution, emphasizing the benefits for patients, healthcare providers, and the hospital as a whole.

Interdisciplinary teams should be established to guide the implementation of OSA and OFA and to promote collaboration and communication among healthcare providers [81]. These teams should meet regularly to review outcome data, address challenges, and share best practices. By working together, healthcare providers can develop a shared vision for opioid minimization and collectively work toward achieving common goals. Recognition and incentives may also be used to encourage healthcare providers to adopt OSA and OFA practices.

Sharing real-world success stories can help overcome skepticism and offer a practical roadmap for implementation. For example, a tertiary academic center in Belgium [29] successfully implemented an opioid-sparing protocol combining ketamine and epidural analgesia for patients undergoing major digestive surgery. This institutional approach not only optimized acute pain control but also resulted in a 40% lower incidence of CPSP at six months post-operation. Furthermore, comprehensive evidence from recent meta-analyses [15] reinforces that the systematic institutional integration of multimodal agents, such as dexmedetomidine, can reliably reduce postoperative opioid consumption and decrease the incidence of acute adverse events like PONV, facilitating a shorter LOS.

A U.S. community hospital focused on OSA for total knee arthroplasty, incorporating acetaminophen, lidocaine, and femoral nerve blocks. This approach reduced PONV by 60%, shortened PACU stay by 20%, and achieved 90% patient satisfaction, supported by nurse-led pain teams and targeted equipment investment.

A Canadian rural hospital [78] simplified OFA protocols for laparoscopic surgery (using propofol and dexmedetomidine) and leveraged telemedicine for regional anaesthesia support, resulting in 33% lower opioid use, no increase in pain scores, and zero cases of OIRD, demonstrating that OSA/OFA can be successfully implemented even in resource-limited settings. These cases collectively demonstrate that with appropriate strategies, barriers to OSA and OFA adoption can be effectively overcome, leading to improved patient outcomes and reduced opioid-related harm.

A critical premise for the clinical application of opioid-free anaesthesia (OFA) is to clarify that its primary goal is opioid minimization rather than rigid adherence to absolute opioid avoidance. This distinction reflects the need to balance the benefits of opioid reduction with the fundamental requirement for adequate perioperative pain control. In clinical practice, certain scenarios, such as major complex surgeries (e.g., extensive thoracic or abdominal resections) involving intense nociceptive stimulation, or patients with pre-existing severe chronic pain and opioid tolerance, may render non-opioid analgesic regimens insufficient to control acute pain. In such cases, short-term, low-dose opioid administration (e.g., a small bolus of remifentanil during peak surgical stimulation) is not only clinically justifiable but necessary to prevent the adverse consequences of uncontrolled pain, including excessive sympathetic activation, intraoperative hemodynamic instability, and an increased risk of chronic postsurgical pain (CPSP) mediated through central sensitization. This goal-oriented approach ensures that OFA does not become a dogmatic protocol but remains a flexible strategy tailored to individual patient needs.

The selection of OFA requires a rigorous assessment of patient-specific factors and the pharmacological characteristics of non-opioid alternatives, as several conditions represent clear contraindications to the implementation of OFA. First, contraindications related to key non-opioid analgesics are essential to consider. For $\alpha$₂-adrenergic agonists (e.g., dexmedetomidine), absolute contraindications include severe bradyarrhythmias (e.g., sinus node dysfunction with a baseline heart rate 50 bpm) or symptomatic hypotension (baseline mean arterial pressure 60 mmHg), as dexmedetomidine’s central suppression may exacerbate these conditions and lead to inadequate organ perfusion (e.g., cerebral or myocardial hypoperfusion).

For ketamine, relative contraindications include a history of schizophrenia, bipolar disorder, or severe anxiety disorders, as its dissociative effects may trigger acute exacerbation of psychotic symptoms or emergence of delirium. Patients with active substance use disorders involving dissociative agents (e.g., phencyclidine) are also at heightened risk of adverse psychological reactions to ketamine, warranting heightened caution. For intravenous lidocaine, severe hepatic dysfunction (e.g., Child-Pugh Class C cirrhosis) or a history of lidocaine-induced seizures constitutes an absolute contraindication, due to impaired hepatic metabolism that may lead to drug accumulation and increased risk of central nervous system (CNS) toxicity (e.g., tinnitus, perioral numbness, or generalized seizures). Second, patient-specific physiological states further limit the applicability of OFA. Pregnant patients in the third trimester are generally excluded from ketamine-based OFA, as ketamine crosses the placental barrier and may transiently influence fetal CNS development. Patients with severe chronic obstructive pulmonary disease (COPD) in acute exacerbation may also be unsuitable for high-dose dexmedetomidine, as even mild sedation can reduce respiratory drive and worsen hypercapnia.

The non-opioid analgesics central to OFA regimens are associated with distinct safety risks, which may be amplified in high-risk patient populations and therefore require targeted monitoring and management. Dexmedetomidine-associated bradycardia and hypotension are particularly concerning in elderly patients ($\ge$65 years) and in individuals with pre-existing cardiovascular disease (e.g., coronary artery disease, heart failure). Age-related declines in autonomic nervous system reserve reduce the ability of elderly patients to compensate for dexmedetomidine-induced sympathetic inhibition, which can result in prolonged bradycardia (heart rate 40 bpm) requiring atropine or hypotension that is unresponsive to fluid resuscitation and necessitates vasopressor support (e.g., phenylephrine). In patients with heart failure with reduced ejection fraction (HFrEF), dexmedetomidine’s negative chronotropic effect may decrease cardiac output by lowering heart rate without a corresponding increase in stroke volume, potentially worsening heart failure symptoms.

Ketamine’s psychotomimetic effects, including hallucinations, vivid dreams, and disorientation, are more common in young adults (18–30 years) and in patients with a history of anxiety disorders. These manifestations typically occur during emergence from anaesthesia. Although premedication with a low-dose benzodiazepine (e.g., midazolam 0.5–1 mg) can attenuate these effects, high-risk patients may require extended post-anaesthesia care unit (PACU) observation to ensure resolution of psychological symptoms. Additionally, ketamine’s sympathomimetic activity (e.g., increased blood pressure and heart rate) may present risks in patients with uncontrolled hypertension or coronary artery disease, as transient elevations in myocardial oxygen demand could precipitate myocardial ischemia.

Lidocaine toxicity remains a significant safety concern, especially in patients with renal dysfunction or those receiving medications that impair lidocaine metabolism (e.g., propranolol, a cytochrome P450 inhibitor). Even within recommended infusion ranges (1–3 mg/kg/h), patients with end-stage renal disease (ESRD) may experience delayed clearance and progressive accumulation, manifesting initially as mild CNS symptoms (e.g., dizziness) and potentially advancing to severe toxicity such as tonic-clonic seizures. Intraoperative monitoring of lidocaine plasma concentrations (target 5 µg/mL) is therefore advisable in high-risk individuals, alongside close observation for indicators of toxicity. Collectively, these risks highlight the need for individualized OFA protocols, enhanced intraoperative monitoring, and the availability of rapid rescue strategies to ensure patient safety, particularly among vulnerable populations.