Abstract
Background:
Opioid-free anesthesia (OFA) is a multimodal strategy to avoid intraoperative opioids and minimize associated complications, though evidence remains variable.
Methods:
A systematic search of PubMed and Google Scholar (2010–2025), supplemented by AI tools (Google Gemini) for earlier publications, summarized eligible studies (RCTs, cohorts, systematic reviews, and meta-analyses) comparing OFA to opioid-based anesthesia (OBA). Data were summarized following PRISMA-ScR guidelines.
Results:
Across 23 randomized controlled trials and one cohort study, OFA consistently reduced PONV, while demonstrating analgesia and recovery outcomes comparable to OBA. Hemodynamic stability was variable, with dexmedetomidine-based OFA regimens sometimes associated with increased bradycardia and hypotension. PACU stay varied, ranging from 9 min shorter to 15–35 min longer with OFA. Long-term outcome data are limited.
Conclusion:
OFA is a feasible approach that significantly reduces PONV while maintaining comparable analgesia and recovery. However, heterogeneous protocols, small sample sizes, and scarce long-term data limit external validity. Large, multicenter trials are needed to standardize OFA protocols and clarify long-term outcomes.
1 Introduction
The perioperative period has become a critical juncture leading to long-term opioid use and dependence (1, 2). While intraoperative opioid administration is a cornerstone of general anesthesia due to its potent analgesia, sympatholytic properties, and synergistic effect with anesthetic agents, its widespread use is linked to both acute and chronic complications (3, 4).
Acute complications, known as Opioid-Related Adverse Drug Events (ORADEs), include postoperative nausea and vomiting (PONV), constipation, urinary retention, dry mouth, dizziness, drowsiness, sedation, pruritus, and, more severely, respiratory depression. Affecting 10%–14% of surgical patients (5). Another serious acute risk is opioid-induced hyperalgesia (OIH), a paradoxical state where opioid administration increases pain sensitivity (6–8). ORADEs can prolong hospitalization and increase healthcare costs (5).
Beyond the acute setting, perioperative opioid exposure can also lead to Persistent Postoperative Opioid Use (PPOU) and Chronic Postsurgical Pain (CPSP) or persistent pain lasting over three months (2). The transition to CPSP is linked to central nervous system sensitization, which can be caused by poorly managed acute pain (9). The incidence of PPOU varies widely in different studies, from as low as 0.119% after caesarian delivery (10), 3% major elective surgery (11), 5%–54.4% after bariatric surgery (12–14), to 6% in some cohorts of adults undergoing both minor and major surgery (15). This highlights how perioperative opioid use could unintentionally lead to long-term dependence. In response to these risks, anesthesiologists are increasingly exploring opioid-free anesthesia (OFA) and opioid-sparing techniques. Given the diversity of OFA regimens and study designs, a scoping review was selected to synthesize its current evidence on the efficacy and safety and explore the practical challenges of its implementation.
2 Methods
A comprehensive literature review was conducted across PubMed and Google Scholar to identify relevant articles in patients undergoing abdominal, breast, gynecological, or orthopedic surgical procedures between January 2010 and August 2025. The search strategy included combinations of keywords such as “opioid-free anesthesia” OR “opioid-free anaesthesia”, “opioid-sparing”, “multimodal analgesia”, “multimodal anesthesia”, “non-opioid anesthesia”, “dexmedetomidine”, “ketamine”, “lidocaine”, “esmolol”, “acetaminophen”, “NSAID”, “magnesium sulfate”, “gabapentinoid”, “enhanced recovery after surgery”, “perioperative opioid”, “postoperative opioid use”, and “postsurgical pain.” AI-powered tools such as Google Gemini were used to uncover interconnected and relevant publications, including studies performed prior to 2010. Searches were restricted to human studies.
Eligibility criteria included randomized controlled trials, cohort studies, meta-analyses, or systematic reviews that compared OFA with opioid-based anesthesia (OBA) and reported acute perioperative outcomes or long-term outcomes. OFA included protocols that excluded opioid medications intraoperatively. OBA included any regimens that included intraoperative opioid use. Exclusion criteria included case reports, studies with a small sample size (total sample size <20 patients), conference abstracts, and opinion pieces.
This scoping review was conducted and reported in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. A total of 23 randomized controlled trials and 1 retrospective cohort study were included. Screening and data extraction were performed independently by the first author and verified for consistency. From each study, we extracted sample size, anesthetic regimens, medication dosages, ORADEs, chronic complications, and postoperative pain. Table 1 summarizes the mechanisms and roles of specific pharmacological agents in anesthesia. Trial characteristics are presented in Table 2. No formal review protocol was preregistered.
Table 1
| Agents | Examples and dosage ranges | Target/mechanism | Strengths | Limitations/risks |
|---|---|---|---|---|
| Acetaminophen (45–48) |
| Central COX inhibition (weak prostaglandin block) |
|
|
| NSAIDs (Ibuprofen, Ketorolac) and COX-2 inhibitors (celecoxib, parecoxib) (19, 25, 34, 35, 45, 49, 50) |
| Peripheral COX inhibition |
|
|
| Regional/Local Anesthetics (Bupivacaine, Ropivacaine, Lidocaine) (16, 27, 31, 33, 34, 45, 47) |
| Nerve/plexus/neuraxial sodium channel block) |
|
|
| IV Lidocaine (16, 19, 21, 22, 27, 28, 33, 34, 39, 45, 47) |
| Sodium channel blockade (peripheral & central) |
|
|
| NMDA Antagonist (Ketamine, Esketamine) (16, 18–22, 24, 28–30, 33, 37–39, 42, 45, 51) |
| NMDA receptor antagonist |
|
|
| α2-Agonists (Dexmedetomidine, Clonidine) (16, 18–20, 22–26, 29, 30, 33, 34, 36–39, 45, 51, 52) |
| α2-adrenergic agonists |
|
|
| Gabapentinoidsa (Gabapentin, pregabalin) (40, 41, 45, 51) |
| α2δ calcium channel subunit modulators |
|
|
| Glucocorticoid (Dexamethasone) (16, 18–21, 26, 29, 30, 34, 36–38, 45, 47, 52) |
| Glucocorticoid; anti-inflammatory, antiemetic |
|
|
| Magnesium sulfate (16, 21, 27, 32, 42, 47, 51–53) |
| NMDA antagonism calcium channel modulation |
|
|
| β-blocker (Esmolol) (20, 32, 43, 44) |
| β1 blockade ↓ sympathetic tone |
|
|
Common non-opioid agents used in opioid-free anesthesia (OFA) and their characteristics.
Gabapentinoids were included to illustrate commonly used non-opioid adjuvants within multimodal anesthesia pathways, even though they are not always components of intraoperative OFA regimens and were not components of OFA in the studies we selected as a part of this review.
Table 2
| Study | Surgery type | Study type | Sample | OFA regimen | OBA comparator regimen | OFA findings |
|---|---|---|---|---|---|---|
| Ziemann-Gimmel et al. (18) | Bariatric (laparoscopic bariatric) | Randomized Controlled Trial | 119 | Dexmetedomidine 0.5 mcg/kg loading dose over 10 min Maintenance with Dexmetedomidine 0.1–0.3 mcg/kg/h alongside propofol-based TIVA Single dose of ketamine 0.5 mg/kg prior to incision | IV fentanyl 0.5–1 mcg/kg prior to induction of general anesthesia Maintenance with intermittent fentanyl, morphine, or hydromorphone boluses per discretion of anesthesia provider alongside general anesthesia with inhalational anesthetics | Decreased PONV and antiemetic use |
| Clanet et al. (19) | Bariatric (laparoscopic sleeve/gastric bypass) | Randomized Controlled Trial | 172 | 100 ml infusion bag over 10 min: Dexmedetomidine 0.5 mcg/kg Magnesium 40 mg/kg Maintenance with 50 ml syringe at 0.2–0.4 ml/kg/h: Dexmetedomidine 2 mcg/ml 50 ml syringe containing Lidocaine 980 mg and Ketamine 50 mg infused at 2 ml/kg/h until completion of surgical methylene blue test, followed by 1 ml syringe containing 0.9% NaCl then resume at 1 ml/kg/h | 100 ml infusion bag over 10 min: Magnesium 40 mg/kg Maintenance with 50 ml syringe at 0.2–0.4 ml/kg/h: Remifentanil 60 mcg/ml 50 ml syringe containing 0.9% NaCl at 2 ml/kg/h until completion of surgical methylene blue test, followed by 1 ml syringe containing Morphine 10 mg then resumed at 1 ml/kg/h: | Decreased PONV. Did not reduce opioid consumption in 24 h postoperative. Comparable QoR-40 scores |
| Perez et al. (20) | Bariatric (laparoscopic/robotic) | Randomized Controlled Trial | 181 | Dexmedetomidine 1 mcg/kg bolus over 10 min and ketamine 0.5 mg/kg at induction Maintenance with dexmedetomidine 0.4 mcg/kg/h (titrated between 0.3–0.5 mcg/kg/h) and lidocaine 2 mcg/kg/h Esmolol bolus as needed for HR and systolic BP > 20% above baseline | Fentanyl 50 mcg at induction. Maintenance with fentanyl boluses as needed for HR and systolic BP > 20% above baseline | Did not reduce opioid consumption in 24 h postoperative. Comparable ORADEs, hospital length of stay, patient satisfaction, and opioid consumption at 1- and 3-months post-discharge. |
| Dagher et al. (21) | Bariatric | Randomized Controlled Trial | 58 | After induction and intubation: Lidocaine 1.5 mg/kg bolus followed by 1.5 mg/kg/h continuous infusion Ketamine 0.2 mg/kg bolus followed by 0.15 mg/kg/h infusion Magnesium sulfate 50 mg/kg administered over 30 min followed by 8 mg/kg/h infusion Dexmedetomidine 0.2–0.5 mcg/kg/h, adjusted based on BP and HR Dexamethasone 8 mg | At induction, fentanyl 1 mcg/kg, increased to 3–4 mcg/kg at incision. Fentanyl 0.5–1 mcg/kg boluses as needed to maintain hemodynamic stability | Reduced postoperative opioid consumption Improved pain management Maintained hemodynamic stability. Provided higher patient satisfaction scores. Comparable PONV Did not increase sedation |
| Barakat et al. (22) | Bariatric (Laparoscopic sleeve gastrectomy) | Randomized controlled trial | 83 | Dexmedetomidine 0.5 mcg/kg and Lidocaine 1 mg/kg over 10 min pre-induction. Ketamine 0.15 mg/kg at induction Maintenance with dexmedetomidine 0.3 mcg/kg/h, lidocaine 1.5 mg/kg/h and ketamine. 0.15 mg/kg/h | Fentanyl 2 mcg/kg, ketamine 0.15 mg/ kg bolus at induction Maintenance with Remifentanil 0.2–0.3 mcg/kg/ min and ketamine 0.15 mg/ kg/h | Comparable pain scores at 24 h and 48 h Comparable opioid consumption, PONV, and need for antiemetics. Higher antihypertensives requirement |
| Qian et al. (24) | Breast (lumpectomy) | Randomized Controlled Trial | 80 | Dexmetedomidine 0.5 mcg/kg loading dose over 10 min, esketamine 0.1 mg/kg, and lidocaine 1.5 mg/kg pre-induction. Midazolam 0.03–0.04 mg/kg at induction Maintenance with Dexmetedomidine 0.1–0.2 mcg/kg/h, esketamine 0.1–0.2 mg/kg/h, and lidocaine 1–1.5 mg/kg/h | Sufentanil 0.2–0.4 mcg/kg and midazolam 0.03–0.04 mg/kg Maintenance with remifentanil 0.1–0.3 mg/kg/min | Delayed need for postoperative opioid use Comparable postoperative analgesia Maintained hemodynamic stability. Decreased PONV |
| An et al. (25) | Colorectal (laparoscopic radical colectomy) | Randomized Controlled Trial | 102 | Paravertebral block: 15 ml per side of solution of 0.5% Ropivacaine and dexmedetomidine 0.2 mcg/kg Dexmedetomidine 0.6 mcg/kg and 0.5 mg atropine infusion for 10 min pre-induction Ketorolac 30 mg and dexmedetomidine 0.5 mcg/kg/h at induction Maintenance with dexmedetomidine 0.5 mcg/kg/h GA Recovery with palonosetron 0.25 mg, neostigmine ≤ 2 mg, and atropine 0.2–1 mg PCA containing Dexmedetomidine 6 mcg/kg and ketorolac 180 mg | Paravertebral block: 15 ml per side of 0.5% Ropivacaine Sufentanil 0.5 mcg/kg at induction. Maintenance with remifentanil 200–500 mcg/h GA Recovery with nalmefene 0.05 mg, palonosetron 0.25 mg, neostigmine (≤ 2 mg), and atropine (0.2–1 mg) PCA containing dezocine 0.5 mg/kg and ketorolac 180 mg | Reduced postoperative rescue NSAID analgesic Comparable intra-operative analgesia index. Higher intra-op glucose Comparable PONV, urinary retention, intestinal paralysis, and pruritus |
| Zhang et al. (26) | Elective colorectal cancer resection (under ERAS) | Randomized controlled trial | 96 | Thoracic epidural with 0.25% Ropivacaine and 0.5% lidocaine Dexmedetomidine loading dose over 30 min before induction Midazolam 0.05 mg/kg and lidocaine 1.5 mg/kg at induction Maintenance with dexmedetomidine 0.3 mcg/kg/h infusion, stopped at colorectal dissection | Bilateral transversalis fascia plane block with 50 ml 0.25% Ropivacaine Midazolam 0.05 mg/kg and sufentanil 0.3–0.5 mcg/kg at induction Maintenance with remifentanil infusion, titrated to maintain BIS between 40 and 60. | Comparable postoperative QoR-40 scores, PONV, time to first meal, and postoperative drainage tube removal. Comparable postoperative opioid consumption and pain scores at 24 h Increased time of sedation |
| Luong et al. (27) | General surgery (laparoscopic cholecystectom) | Randomized Controlled Trial | 94 | Magnesium 30 mg/kg and lidocaine 2 mg/kg pre-induction Ketogesic 30 mg at induction Ketamine 0.5 mg/kg intravenous bolus and ropivacaine 0.5% at edge of incision right after induction Maintenance with lidocaine 1.5 mg/kg/h and magnesium 1.5 g 1 g paracetamol at gallbladder resection | Fentanyl 5 mcg/kg at induction Intraoperative fentanyl 1.5 mcg/kg every 30 min | Associated with lower intraoperative hypotension Reduced PONV Reduced postoperative opioid consumption Increased risk of hypersalivation |
| López-Álvarez et al. (44) | General surgery (laparoscopic cholecystectomy) | Randomized Controlled Trial | 60 | Midazolam 0.3 mg/kg premedication Esmolol 0.5 mg/kg at induction. Maintenance with esmolol 5–15 mcg/kg/min Port insertions infiltrated with 0.5% levobupivacaine at end of procedure. | Midazolam 0.3 mg/kg premedication. Ketamine 0.5 mg/kg and remifentanil 0.5 mcg/kg at induction. Maintenance with remifentanil 0.1–0.5 mcg/kg/min infusion. Port insertions infiltrated with 0.5% levobupivacaine at end of procedure. | Reduced postoperative opioid consumption Comparable PONV and sedation |
| Hu et al. (28) | Gynecologic laparoscopic surgery | Randomized controlled trial | 74 | Lidocaine 1.5 mg/kg and esketamine 0.15 mg/kg infusion over 5 min pre-induction Maintenance with lidocaine 1.5 mg/kg/h and esketamine 0.1 mg/kg/h | Sufentanil 0.3 mcg/kg and saline infusion over 5 min pre-induction Maintenance with sufentanil 0.1 mcg/kg/h and saline infusion | Comparable 48 h time-weighted average pain scores, postoperative opioid consumption, gastrointestinal recovery, and patient satisfaction scores Decreased time to extubation |
| Katz et al. (59) | Total Abdominal Hysterectomy | Randomized Controlled Trial | 45 | Midazolam 0.05 mg/kg at induction and thiopentone 3–5 mg/kg at induction. | Two Groups: Group 2: Midazolam 0.05 mg/kg, Alfentanil 30 mcg/kg, and thiopentone 3–5 mg/kg at induction. Maintenance with alfentanil 10–20 mcg/kg boluses every hour. Group 3: Midazolam 0.05 mg/kg and alfentanil 100 mcg/kg at induction. Maintenance with continuous infusion of alfentanil 1–2 mcg/kg/min, adjusted by 0.25–0.5 mcg/kg/min and with alfentanil 10–20 mcg/kg bolus to maintain hemodynamic variables within 20% of pre-operative values.Bolus | Morphine consumption and VAS pain scores were lowest in the group receiving continuous alfentanil infusion. Alfentanil boluses offered improved VAS scores and morphine consumption compared to OFA. No statistically significant difference in pain at 6-month post-surgery. |
| Hublet et al. (29) | Pancreatic resection | Retrospective cohort | 77 | Magnesium 30–40 mg/kg, dexamethasone 10 mg, and diclofenac 75 mg pre-induction. Dexmetedomidine infusion 0.5 mcg/kg/h 10 min prior to induction Lidocaine 1.5 mg/kg and IV esketamine bolus 0.25 mg/kg at induction Maintenance: IV lidocaine 1.5 mg/kg/h, IV esketamine 0.125 mg/kg/h, and dexmetedomidine 0.4–0.7 mcg/kg/h | Magnesium 30–40 mg/kg, dexamethasone 10 mg, diclofenac 75 mg, and morphine 4 mcg/kg pre-induction Lidocaine 1.5 mg/kg and target-controlled infusion (TCI) of remifentanil 3 −5 ng/ml at induction Maintenance with remifentanil 2 −5 ng/ml | Reduced postoperative pain and opioid consumption Reduced the comprehensive complication index Shortened length of stay by 4 days |
| Xue et al. (30) | Shoulder arthroscopy | Randomized controlled trial | 60 | Interscalene brachial plexus block with 20 ml of 0.375% ropivacaine TIVA dexmedetomidine 0.8–1 mcg/kg infusion for 10 min followed by continuous infusion of dexmedetomidine of 0.3–0.5 mcg/kg/h Esketamine 0.3 mg/kg prior to incision followed by esketamine 0.15 mg/kg infusion | Interscalene brachial plexus block with 20 ml of 0.375% ropivacaine TIVA Propofol 2 mg/kg, cisatracurium 0.2 mg/kg, fentanyl 3–4 mcg/kg at induction. Maintenance with remifentanil 5–10 mcg/kg/h | Decreased PONV incidence and severity in the first 24 h. Shortened PACU stay Comparable pain scores and postoperative analgesia (NSAIDs and opioids consumption) Comparable incidence of hallucinations, nightmares, bradycardia, or excessive oral secretions |
| Barakat et al. (23) | Spine (multilevel fusion) | Randomized Controlled Trial | 48 | Dexmedetomidine 0.5 mcg/kg/h and lidocaine 1 mg/kg/h continuous IV infusion over 10 min before induction. Induction: ketamine 0.15 mg/kg. Maintained: dexmedetomidine 0.3 mcg/kg/h, lidocaine 1.5 mg/kg/h, ketamine 0.15 mg/kg/h infusion. | Fentanyl 2 mcg/kg, ketamine 0.15 mg/kg Maintenance: remifentanil 0.2–0.3 mcg/kg/min, ketamine infusion 0.15 mg/kg/h. | Reduced postoperative opioid consumption Decreased PONV in the first 24 h postoperatively. Higher antihypertensive requirement Longer PACU stay |
| An et al. (31) | Thoracic (VATS/thoracoscopic lung) | Randomized Controlled Trial | 100 | Thoracic Paravertebral Block: 15 ml of 0.5% Ropivacaine Dexmedetomidine 1 mcg/kg loading dose 10 min Dexmedetomidine 0.5 mcg/kg/h, ketorolac 30 mg, and etomidate 0.2–0.3 mg/kg at induction Maintenance with dexmedetomidine 0.5 mcg/kg/h | Thoracic Paravertebral Block: 15 ml of 0.5% Ropivacaine Sufentanil 0.5 mcg/kg, etomidate 0.2–0.3 mg/kg at induction Maintenance with remifentanil 200–500 mcg/h | Comparable intraoperative analgesia index Higher depth of sedation and blood glucose levels. |
| Wang et al. (32) | Thoracic (VATS/thoracoscopic lung) | Randomized Controlled Trial | 124 | Epidural 10 ml of 0.1875% Ropivacaine followed by 4–5 ml/hr continuous infusion Lidocaine 40 mg and magnesium sulfate 5–10 mg/kg and esmolol 0.5–1 mg/kg at induction. Maintenance with lidocaine 1 mg/kg/h (maximum 300 mg) | TCI of remifentanil (3–5 ng/ml), sufentanil 10–20 mcg, epidural hydromorphone 0.3–0.5 mg in 3–5 ml 10 min prior to incision Maintenance with Epidural 10 ml of 0.1875% Ropivacaine followed by 4–5 ml/hr continuous infusion after lung resection | Decreased severity of motion- pain and incidence of PCEA-related adverse events on postoperative at 24 h |
| Feng et al. (33) | Thoracic (VATS/thoracoscopic lung) | Randomized Controlled Trial | 120 | Dexmedetomidine 0.6 mcg/kg over 10 min and esketamine 0.3 mg/kg at induction Maintenance with dexmedetomidine 0.2–1.0 mcg/kg/h infusion and esketamine 0.1 mg/kg boluses surgical pleth index (SPI)-guided | Sufentanil 0.3 mcg/kg at induction Maintenance with sufentanil 0.1 mcg/kg boluses SPI-guided | Halved the incidence of PONV Longer PACU stay. |
| Kim et al. (34) | Thoracic (VATS/thoracoscopic lung) | Retrospective cohort (propensity-score matching) | 196 | Dexmedetomidine 0.6 mcg/kg infusion over 10 min pre-induction Maintenance with dexmedetomidine 0.5 mcg/kg/h infusion adjusted in increments of 0.1 mcg/kg/h until completion of intercostal block Thoracoscopic intercostal block | TCI of remifentanil (effect-site concentration 3–4 ng/ml) at induction Maintenance with remifentanil via TCI (effect-site concentration 1–4 ng/ml) Thoracoscopic intercostal block | Comparable QoR-15, pain, PONV, opioid consumption, opioid-related adverse events. Hypotension/bradycardia were numerically more frequent (not significant). |
| Yan et al. (35) | Thoracic (VATS/Thoracoscopic lung) | 2 centers Randomized Controlled Trial | 159 | Thoracic epidural Dexmedetomidine 0.5–1 µg/kg IV before induction Induction: esketamine 0.125 mg/kg Maintenance: if needed esketamine 0.125 mg/kg Before the incision: Epidural administration 10 ml 0.2% ropivacaine + esketamine 0.25 mg/kg then intermittent bolus of 0.2% ropivacaine (5 ml/h) Postoperative PCEA: ropivacaine 0.15% with esketamine 25 mg | Thoracic Epidural Induction: Fentanyl 4 µg/kg Maintenance: if needed fentanyl 1 µg/kg Before the incision: Epidural administration morphine 2 mg then intermittent bolus of 0.2% ropivacaine (5 ml/h) Postoperative PCEA: ropivacaine 0.15% with morphine10 mg | Reduced PONV and pruritus. Reduced incidence of pain, at 24 h and mild chronic pain at 3- and 6-months post-surgery. Comparable acute postoperative pain at 48 h. |
| Yan et al. (36) | Thoracic (VATS/thoracoscopic lung) | Randomized controlled trial | 165 | Thoracic paravertebral block 20 ml of 0.5% ropivacaine Dexmedetomidine 0.5 mcg/kg for 15 min pre-induction Lidocaine 1.5 mg/kg at induction Maintenance with dexmedetomidine 0.5 mcg/kg/h and lidocaine 1.5 mg/kg/h | Thoracic paravertebral block 20 ml of 0.5% ropivacaine Sufentanil 0.3–0.4 mcg/kg at induction. Maintenance with remifentanil 0.1–0.2 mcg/kg/min | Decreased 24 h PONV and had lower incidence of postoperative complications (including respiratory depression, hypoxemia, pulmonary embolism, hypotension, pruritus, drowsiness, dizziness, fatigue, constipation, and uroschesis) Comparable QoR-15 scores, pain, and 6-min walk test. |
| Selim et al. (37) | Thoracic (VATS/thoracoscopic lung) | Retrospective cohort (propensity-score matching) | 81 | Dexmetedomidine 0.5 mcg/kg 20 min pre-induction then 0.3–1.0 µg/kg/h Ketamine bolus 0.15–0.40 mg/kg and lidocaine bolus 1.5 mg/kg at induction Maintenance with dexmedetomidine 0.3–1 mcg/kg/h, ketamine 0.25 mg/kg/h, and lidocaine 2 mg/kg/h | Remifentanil TCI (target of 3–5 ng/ml) Maintenance with TCI of remifentanil (target of 2–4 ng/ml) | Reduced postoperative pain and opioid consumption at 48 h post-surgery |
| Wang et al. (38) | Thyroid/Parathyroid | Double Blinded Randomized Controlled Trial | 394 | Esketamine 0.3 mg/kg and lidocaine 1 mg/kg at induction Maintenance with esketamine 0.1 mg/kg boluses | sufentanil 0.3 mcg/kg and saline (volume matched to lidocaine) at induction. Maintenance with sufentanil 0.1 mcg/kg boluses | Decreased incidence of PONV Lowered rates of hypotension and desaturation after tracheal extubation. Higher rates of patient satisfaction. Comparable length of PACU stay, postoperative pain scores at PACU discharge, 24 h, and 48 h post-surgery. Comparable incidence of 30-d major complications. |
| Beloeil et al. (39) | Mixed major noncardiac surgery | Randomized Controlled Trial | 312 | Lidocaine 1.5 mg/kg, ketamine 0.5 mg/kg and dexmedetomidine 0.4–1.4 mcg/kg at induction Maintenance with lidocaine 1.5 mg/kg/h, ketamine 0.25 mg/kg/h, and dexmedetomidine 0.4–1.4 mcg/kg/h | Lidocaine 1.5 mg/kg, ketamine 0.5 mg/kg and TCI of remifentanil (target 3–5 ng/ml) Maintenance with lidocaine 1.5 mg/kg/h, ketamine 0.25 mg/kg/h, and TCI of remifentanil (target 2–5 ng/ml) | Decreased PONV and postoperative opioid use. Prolonged sedation and time to extubation Longer PACU stays Trial was terminated early due to higher rates of adverse events in the OFA group, including bradycardia and hypoxemia. |
Study characteristics and key findings of recent trials comparing opioid-free (OFA) and opioid-based anesthesia (OBA) regimens.
3 Non-opioid targets and mechanisms in opioid-free anesthesia
OFA is a multimodal anesthesia approach that targets multiple points along the nociceptive (pain) pathway to provide analgesia and manage the surgical stress response. Instead of opioids, OFA uses a combination of non-opioid medications, including α2-adrenergic agonists (e.g., dexmedetomidine), NMDA receptor antagonists (e.g., ketamine), local anesthetics (e.g., IV lidocaine), non-steroidal anti-inflammatory drugs, magnesium, acetaminophen, glucocorticoids (dexamethasone), local infiltration analgesia, regional, and neuraxial blocks, and others (14–39). These agents and drug classes are described in Table 2 below.
Through synergistic interactions, these agents can prevent central sensitization, maintain hemodynamic stability, and provide effective pain control. This combined approach may reduce ORADEs and the risk of long-term opioid misuse. For example, perioperative use of lidocaine, ketamine, and gabapentinoids has been shown to reduce the risk of CPSP for up to 6 months (40), and perioperative gabapentin decreased the time to opioid cessation post-surgery (41). Additionally, individually ketamine and magnesium can maintain stability of blood pressure and heart rate, respectively (42). Esmolol was found to reduce pain and postoperative opioid consumption (43) and has shown to pose an opioid-sparing effect intraoperatively (44). The effectiveness and safety of OFA can differ based on the type of surgery (Table 1).
4 Acute clinical outcomes
4.1 Postoperative nausea and vomiting (PONV)
The most consistent benefit of OFA compared to opioid-based anesthesia (OBA) is a significant reduction in PONV. Numerous randomized-controlled trials across various surgical specialties, including bariatric (18), thoracic (33, 36), thyroid (38), and orthopedic surgery (30) have demonstrated lower PONV incidence rates with OFA. For instance, OFA offered a clinically and statistically significant reduction in PONV rates from 30%–32% to 14%–15% in video-assisted thoracic surgery (36) and from 40% to 13% in shoulder arthroscopy (30). Meta-analyses have also consistently shown a clinically meaningful reduction in PONV with OFA (54–57). While a few studies in patients undergoing gynecologic laparoscopy (28) and thoracic surgery (34) have found no clinically or statistically significant difference, the overall evidence overwhelmingly supports OFA as a highly effective strategy for PONV prevention.
4.2 Pain control
The impact of OFA on immediate postoperative pain is variable. Some studies in breast surgery, laparoscopic cholecystectomy, laparoscopic colectomy, pancreatic resection, and spine surgery have reported improved early pain scores and reduced postoperative analgesic use (23–25, 27, 29, 44). A meta-analysis by Cheng et al. (56) supported these findings, reporting a reduced need for rescue analgesia in OFA groups undergoing laparoscopic surgery.
In contrast, other studies in bariatric surgery, gynecologic laparoscopy, and shoulder arthroscopy found no significant reduction in 24 h opioid consumption with OFA (19, 20, 22, 28, 30). Studies in thoracic surgery have also reported similar postoperative pain scores and opioid use between OFA and OBA groups (31, 34). Meta-analyses have also concluded that OFA provides little to no consistent improvement in postoperative pain requirements (54, 55). The effectiveness of OFA in managing pain appears highly dependent on the specific protocol and its meticulous execution. Nevertheless, the consensus is that OFA is not inferior to OBA in terms of postoperative pain control.
4.3 Postoperative recovery
Quality of Recovery (QoR), a composite score that assesses physical comfort, emotional state, pain, and other factors, has been used to evaluate the overall benefits of OFA (58). Some studies have demonstrated comparable QoR outcomes between OFA and OBA. Clanet et al. (19) reported similar QoR-40 scores at both 24 h and 30 days postoperatively in bariatric surgery patients. Kim et al. (34) and Yan et al. (36) found nearly identical QoR-15 scores between OFA and OBA groups in patients undergoing video-assisted thoracic surgery. However, a meta-analysis by Liu et al. (49) reported a clinically meaningful improvement in QoR-40 scores among OFA patients, primarily driven by enhanced pain control and physical comfort. This improvement was not reflected in QoR-15 scores, highlighting the sensitivity of different QoR instruments. The evidence suggests that, at a minimum, OFA is comparable to OBA in terms of overall postoperative recovery.
4.4 Intraoperative hemodynamic stability
Maintaining hemodynamic stability with OFA is a potential challenge due to the variety of regimens used and their pharmacodynamics, contributing to notable discrepancies in the literature. Two systematic reviews noted a higher incidence of bradycardia (14, 55), and some studies noted hypotension requiring increased use of vasopressors (52) or hypertension needing more antihypertensive agents (23), particularly with dexmedetomidine-based regimens. A large multicenter trial by Beloeil et al. (39) was even halted prematurely due to a higher incidence of severe bradycardia and hypoxemia in the dexmedetomidine-based OFA group. This study was criticized, however, by Mieszczański et al. (14) due to the high average doses of dexmedetomidine (1.2 mcg/kg/h) and long average anesthetic time of 268 min. Regardless, the possibility of increased intraoperative hemodynamic instability is clinically meaningful when comparing OFA and OBA.
Conversely, other research suggests OFA can lead to comparable hemodynamic stability (21, 29, 30). In a trial of patients undergoing lumpectomy, the OFA group experienced statistically and clinically significant lower rates of hypotension (5% vs. 38%) and bradycardia (8% vs. 32%) (24). Lower rates of intraoperative hypotension were also seen in laparoscopic cholecystectomy (1% vs. 8%) (27) and thyroid surgery (1% vs. 5%) (38). However, it remains unclear whether these differences translate into meaningful clinical consequences.
The discrepancy in outcomes highlights the critical need for developing robust, standardized protocols and providing comprehensive education to enhance clinician understanding and effective management of the unique pharmacodynamics of non-opioid agents.
4.5 Length of post-anesthesia care unit (PACU) stay
OFA may prolong PACU stays, a trade-off worth considering against reduced opioid-related complications. Studies in major spine (23), thoracic surgery (33), and mixed major non-cardiac surgery (39) have reported a longer PACU duration (15.5–35 min) for OFA patients, often attributed to the sedative effects of dexmedetomidine even in the absence of pain or nausea.
In contrast, other studies have found either no significant difference or even a shorter PACU stay with OFA protocols. A study on shoulder arthroscopy found a statistically significant reduction in PACU stay by 9.3 min (30). Similarly, a trial in thyroid and parathyroid surgery and a meta-analysis on laparoscopic surgery demonstrated comparable PACU stays between OFA and OBA (38, 56).
The differences in length of PACU stay are likely influenced by surgical complexity and the sedative profile of dexmedetomidine. An absolute reduction of 9.3 min with OFA for shoulder arthroscopy may not be clinically meaningful. However, an increased length of stay by 35 min with an opioid-free approach may negatively impact efficiency and resource use. This underscores the need to balance depth of sedation with the possible benefits of OFA.
5 A critical knowledge gap: the long-term impact of OFA
A critical knowledge gap in the OFA literature is the lack of robust, high-level evidence on long-term patient outcomes, particularly regarding PPOU and CPSP. The central hypothesis that OFA reduces these risks remains largely unproven. Only a handful of studies have assessed long-term outcomes, with mixed results. While one thoracic trial found a reduction in CPSP with a non-opioid epidural pathway (35), other studies found no difference in chronic pain incidence at six months (58, 59).
Crucially, no randomized controlled trials were found to have reported PPOU as a primary or secondary outcome, despite this being a key public health objective of OFA. The absence of data on opioid prescription fulfillment beyond the immediate postoperative period is a major limitation. Interestingly, some retrospective data have paradoxically suggested that higher intraoperative fentanyl doses may be associated with a lower incidence of PPOU, potentially by preventing inadequate pain control and subsequent central sensitization (60). This paradox underscores the complexity of the pain-anesthesia-dependence relationship and the urgent need for targeted, long-term investigation. Taken together, the scarcity of long-term data and the inconsistency of existing findings mirror the broader methodological issues in OFA literature, as discussed below.
6 Limitations of the evidence base and future directions
As summarized in Table 1, most available studies on OFA consist of small, single-center randomized controlled trials with heterogeneous anesthetic protocols and patient populations. Many trials included fewer than 100 participants and were powered to detect short-term outcomes such as PONV, postoperative pain, and quality-of-recovery scores, rather than long-term outcomes. It is possible that several trials that noted comparable findings for pain, hemodynamic stability, postoperative opioid use, or other ORADEs may be reflecting Type II error rather than true equivalence. Guo et al. (61) and Gricourt et al. (16) agree that there is a critical need for large, multicenter trials to improve the generalizability and external validity of findings across diverse surgical settings and patient demographics.
The marked heterogeneity among OFA regimens further complicates comparison across trials. Protocols varied in drug combinations, dosing, and timing. Several studies do not clearly outline titration or monitoring strategies. The inconsistency between blinding strategies across studies also introduces a source of bias and increases the difficulty of comparing across trials. Shanthanna and Joshi (62) emphasize that future studies should develop procedure- and patient-specific combinations with standardized dosing and administration.
As noted earlier, only a few studies assessed CPSP after discharge. PPOU was not outlined as an endpoint in any of the studies that we reviewed. Most studies that we reviewed had short observation periods, making it challenging to evaluate long-term opioid-related complications as they relate to OFA. This is compounded by the fact that inappropriate postoperative prescribing and a lack of discharge stewardship programs may lead to persistent opioid use, potentially offsetting the intraoperative benefits of OFA (2, 63). More studies are needed to clarify the long-term impact of OFA on CPSP and PPOU, which is a core rationale for its adoption.
The cost-effectiveness of OFA remains largely unexplored. While OFA may reduce complications and hospital stays, its higher upfront costs, driven by multi-agent regimens and increased monitoring, pose a barrier to widespread adoption (21). Further research is needed to evaluate the economic impact of OFA to guide its broader implementation.
7 Conclusion
Opioid-free anesthesia (OFA) offers a valuable strategy to reduce perioperative opioid exposure. The most consistent and immediate benefit reported is a significant reduction in PONV. While short-term pain control and recovery outcomes appear comparable to opioid-based approaches, substantial limitations remain. However, the long-term impact of OFA on PPOU and CPSP remains largely unknown. To advance the clinical utility of this technique, future research must prioritize robust, multicenter, well-powered trials with standardized protocols, established safety metrics, and sufficient longitudinal follow-up to definitively assess PPOU and CPSP. Furthermore, cost-effectiveness analyses are crucial for determining the broader economic and clinical implications of OFA and its appropriate role in mitigating the opioid crisis.
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Author contributions
AP: Conceptualization, Investigation, Writing – original draft. OE: Conceptualization, Writing – review & editing, Project administration, Supervision. RW: Conceptualization, Writing – review & editing, Supervision.
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Summary
Keywords
opioid-free anesthesia (OFA), multimodal analgesia, enhanced recovery after surgery (ERAS), postoperative pain, non-opioid analgesics, opioid crisis
Citation
Pershad A, Elvir Lazo OL and Wong R (2025) Opioid-free anesthesia: a scoping review of efficacy, safety, and implementation challenges. Front. Anesthesiol. 4:1714040. doi: 10.3389/fanes.2025.1714040
Received
26 September 2025
Accepted
16 October 2025
Published
04 November 2025
Volume
4 - 2025
Edited by
Lucas Ferreira Gomes Pereira, Universidade de Sao Paulo Anestesiologia, Brazil
Reviewed by
Carlos Darcy Alves Bersot, Federal University of São Paulo, Brazil
José Eduardo Guimarães Pereira, Hospital Central do Exercito, Brazil
Vitor Felippe, National Cancer Institute (INCA), Brazil
Updates
Copyright
© 2025 Pershad, Elvir Lazo and Wong.
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*Correspondence: Ofelia Loani Elvir Lazo loanidoc@yahoo.com
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.