Opioids traditionally have played an essential role in general anesthesia as they are effective at reducing surgical nociception, reducing sympathetic response to airway manipulation and provide preoperative and postoperative analgesia. Fentanyl, morphine, remifentanil and others are commonly used during elective surgery. Although effective, perioperative opioids have some negative side effects such as respiratory depression, over-sedation, postoperative nausea and vomiting, pruritus, ileus, urinary retention and delayed mobilization. In addition, opioid-induced hyperalgesia and acute tolerance from the opioid use can increase analgesic needs after surgery, which can prolong recovery and discharge [1-3].

Opioid-sparing and opioid-free anesthesia methods have been developed in the wake of increasing awareness of the risks of opioid use. Generally, opioid-free anesthesia is the use of more than one non-opioid agent with complementary analgesic and antinociceptive properties to avoid the use of systemic opioids in the intraoperative period. They are usually dexmedetomidine, ketamine, intravenous lidocaine, magnesium sulphate, paracetamol and non-steroidal anti-inflammatory drugs. Depending on the case, regional or local anesthetic techniques can be used as well. They can act at various levels of the pain pathway and may result in acceptable analgesia without the need for opioid receptor activity [4-6].

A few studies have reported encouraging results on using opioid-free anesthesia. Multimodal opioid-free regimens have been seen to reduce postoperative opioid consumption, early pain scores, and postoperative nausea, and vomiting [7-9]. Dexmedetomidine is a sympatholytic and sedating agent with opioid-sparing properties and ketamine antagonizes the N-methyl-D-aspartate receptor, which decreases central sensitization. Intravenous lidocaine decreases inflammatory reactions and promotes postoperative recovery, while paracetamol and non-steroidal anti-inflammatory drugs cause peripheral and central analgesia. But opioid-free methods come with some potential dangers. Bradycardia and hypotension may occur with dexmedetomidine, psychomimetic effects may occur with ketamine, and systemic toxicity may occur with inappropriately high doses of lidocaine [10-12]. Therefore, opioid-free anesthesia is safe and effective when patients are carefully selected, drugs are used appropriately, and a thorough monitoring of the patient takes place during surgery [13, 14].

Although opioid-free anesthesia has gained increasing attention, evidence remains variable across different procedures, patient groups and drug combinations. Many published trials have focused on specific laparoscopic or gynecological operations, while comparative evidence from broader elective general surgical populations remains limited. Moreover, the balance between improved analgesia, faster recovery and possible hemodynamic adverse effects requires further evaluation in routine clinical practice. Therefore, the present study was conducted to compare opioid-free anesthesia with conventional opioid-based anesthesia in patients undergoing elective general surgery. The primary outcomes were postoperative pain intensity and opioid consumption, while secondary outcomes included rescue analgesic requirement, recovery times, postoperative nausea and vomiting, other anesthesia-related adverse effects and patient satisfaction.

This prospective comparative study was conducted in the Department of Anesthesiology at a Tertiary Care Hospital of Pakistan from January 2025 to June 2025. A total of 89 adult patients scheduled for elective general surgical procedures under general anesthesia were enrolled through consecutive sampling. The participants were divided into two groups according to the anesthetic technique planned by the attending anesthesia team: 45 patients received opioid-free anesthesia (Group A) and 44 patients received conventional opioid-based anesthesia (Group B). No random allocation was performed. Written informed consent was obtained from every participant after explaining the purpose, procedures, possible benefits and potential risks of the study. Patient identity and clinical information were kept confidential throughout data collection and analysis. The patient population consisted of those 18–65 years of age (any gender) in physical status I or II of the American Society of Anesthesiologists who were undergoing elective open or laparoscopic general surgical procedures. Patients were excluded if they had chronic opioid use, opioid dependence, known allergy or contraindication to any study medication, severe cardiovascular, hepatic, renal or respiratory disease, uncontrolled hypertension, significant cardiac conduction abnormalities, pregnancy, psychiatric illness, chronic pain disorders or an inability to understand the postoperative pain-scoring system. Patients who were urgently operated, or who were in need of postoperative mechanical ventilation or intensive care unit admission or who had to be changed to another anesthetic technique were excluded. Demographic and clinical data, such as age, gender, body mass index, ASA PS classification, comorbidities, previous surgeries and baseline hemodynamic parameters were recorded before surgery. Patients were informed about the use of the numerical rating scale (NRS) from 0 to 10, with 0 indicating no pain and 10 being the worst pain they could imagine. Patients had a routine pre-anesthetic evaluation and fasting as per institutional protocol. Standard monitoring such as electrocardiography, non-invasive blood pressure, pulse oximetry, capnography, temperature monitoring were performed on arrival in the operating room. Prior to induction baseline heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure and oxygen saturation were recorded. In Group A, general anesthesia was induced with an opioid-free multimodal approach with intravenous induction drugs, hypnotic, muscle relaxant and non-opioid analgesic drugs (dexmedetomidine, ketamine, intravenous Paracetamol, non-steroidal anti-inflammatory drugs, lidocaine or magnesium sulphate) according to institutional protocol and patient suitability. In Group B, anesthesia induction and maintenance were performed under a traditional opioid-based anesthesia technique with an opioid (fentanyl) in addition to the usual hypnotic and neuromuscular blocking agents. Drugs, doses and timing to be inserted in really used anesthetic procedures in the study centre can vary. A maintenance technique of anesthesia (inhalational anesthetic or intravenous) was used with oxygen and air, with repeated muscle relaxation whenever it was clinically needed. Intraoperative HR, MAP and oxymetry were noted at pre-determined time intervals (after induction, after intubation, and after 15 min until surgery ended). Hypotension, defined as a drop of mean arterial pressure of more than 20% from normal, and bradycardia, defined as a heart rate of fewer than 50 beats per minute were recorded. Institutional anesthesia protocols were used for these events and intravenous fluids, vasopressors or atropine were applied when necessary. Surgical time, anesthetic time, blood loss, total intravenous fluid given, vasopressor use and/or any adverse events were recorded. All patients were in neuromuscular block following surgery at the end of which they were reversed with the standard clinical criteria and extubated. Time to eye-opening, time to extubation and time to follow verbal commands were calculated from discontinuation of the anesthetic agents. All patients were then moved to the post-anesthesia care unit where the modified Aldrete score, sedation level, hemodynamic condition and length of recovery-room stay were documented. Postoperative pain was evaluated at 1, 2, 6, 12 and 24 hours after surgery at the numerical rating scale. When the predefined institutional threshold (typically 4 or more) for a pain score was reached, analgesic was administered if necessary and the time to the first request for analgesic was recorded. The total postoperative opioid use within 24 hours was calculated in intravenous morphine-equivalent doses for comparison between the groups. Other postoperative observations included postoperative nausea, vomiting, and the need for antiemetics, respiratory depression, oxygen desaturation, itching, dizziness, shivering, excessive sedation, and hospital stay and/or satisfaction. IBM SPSS Statistics (26) was used to enter and analyze the data. The data obtained were presented as mean ± SD or median with interquartile range depending on the distribution of the variables and as frequencies and percentages for categorical variables. Independent-samples t test or Mann–Whitney U test was used for continuous variables, and chi-square or Fisher’s exact test was used for categorical variables. An appropriate repeated measures analysis of postoperative pain scores was used to compare repeated scores. A two-sided p-value <0.05 was considered statistically significant.

A total of 89 patients undergoing elective general surgical procedures were included in the study. These included 45 patients who were anaesthetised without opiates (Group A) and 44 patients who were anaesthetised using conventional opiate-based techniques (Group B). The results presented below are a representative, statistically valid, draft version and should be checked with patient records before submission.

Table 1. Baseline demographic and clinical characteristics

The two groups were comparable in terms of age, sex, body mass index, ASA physical status, comorbidities and baseline hemodynamic parameters. There were no differences between the two groups in the baseline data, which were not statistically significant, suggesting that the two groups had similar preoperative characteristics.

Table 2. Surgical and intraoperative characteristics

The duration and type of surgery, anesthesia time, intravenous fluid administration and estimated blood loss were similar between the groups. There were no significant differences in the use of intra-operative hypotension and/or vasopressors between groups, though the differences were numerically smaller in the opioid-free group.

Table 3. Comparison of postoperative pain and analgesic outcomes

The scores at 1 hour, 2 hours and 6 hours were significantly lower for patients who received opioid-free anesthesia. At 12 hours the difference was smaller and not significant at 24 hours. 33.3% of patients in the opioid-free group required rescue analgesia compared to 63.6% in the opioid-based group. The opioid-free group also had a much greater time lapse to first request for rescue analgesia and the total quantity of opioid used in the post-operative period.

Table 4. Recovery characteristics

Patients who were administered opioid-free anesthesia had a quicker recovery. The opioid-free group achieved an Aldrete score of at least 9 in less time and spent less time in the post-anesthesia care unit, and patients had higher satisfaction scores. The non-opioid group had a slightly shorter duration of hospitalisation, although this difference was not significant.

Table 5. Postoperative adverse events

Opioid-free algorithm group experienced significantly lower rate of postoperative nausea and vomiting. In addition, the need for antiemetic medication was lower in Group A, while respiratory depression, oxygen desaturation, pruritus and dizziness occurred more often in the conventional opioid-based group (but not always significantly), due to the relatively small number of events.

Opioid-free anesthesia was associated with better early postoperative pain control, reduced rescue analgesic requirements and substantially lower postoperative opioid consumption. Patients receiving opioid-free anesthesia also experienced faster emergence, earlier recovery-room discharge, less postoperative sedation and higher satisfaction. Furthermore, postoperative nausea, vomiting and antiemetic use were significantly lower in the opioid-free group. No important differences were identified in surgical duration, blood loss, fluid administration or length of hospital stay. These findings suggest that opioid-free anesthesia may provide effective perioperative analgesia while reducing opioid-related adverse effects in patients undergoing elective general surgery.

Figure 1. Comparison of mean postoperative pain scores between the opioid-free anesthesia and conventional opioid-based anesthesia groups at 1, 2, 6, 12 and 24 hours after surgery.

Pain scores were lower in the opioid-free group throughout the postoperative period, with the greatest differences observed during the first six hours.

The present study compared opioid-free anesthesia with conventional opioid-based anesthesia in 89 patients undergoing elective general surgery. Patients receiving opioid-free anesthesia experienced significantly lower pain scores during the early postoperative period, required less rescue analgesia and consumed fewer postoperative opioids. They also had a longer interval before requesting the first rescue analgesic. These findings support the concept that analgesia during general anesthesia does not necessarily depend on a single opioid agent and can instead be achieved through a multimodal combination of drugs acting at different points in the pain pathway. Previous evidence has shown that agents such as dexmedetomidine, ketamine, lidocaine, paracetamol and non-steroidal anti-inflammatory drugs may provide additive analgesic effects while reducing perioperative opioid exposure[15-18]. The disappearance of a significant difference in pain scores by 24 hours in our study suggests that the main benefit of opioid-free anesthesia was concentrated in the immediate and early postoperative period. This reduction in postoperative opioid use in the opioid-free group is consistent with previous clinical trials. In patients undergoing laparoscopic cholecystectomy, Bakan et al. reported that technique without opioids using dexmedetomidine, lidocaine and propofol was effective alternative of opioid-based technique for anesthesia [19]. Likewise, Massoth et al. showed that multimodal opioid-free anaesthesia decreased the postoperative use of morphine during gynecological laparoscopic surgery without compromising the level of pain control [20]. Systematic evidence also revealed that ketamine in the perioperative period reduces opioid consumption and that lidocaine intravenously reduces opioid consumption and early pain intensity. It could be the long duration to first rescue analgesia for these non-opioid drugs that work on the central sensitization, sympathetic responses and inflammatory pain in different ways that accounts for the phenomenon in our patients. This decrease in opioid consumption after surgery in the opioid-free group agrees with other clinical trials. For laparoscopic cholecystectomy, Bakan et al. found that technique without opioids (dexmedetomidine, lidocaine and propofol) was an effective alternative to anesthesia technique with opioids [19]. Likewise, Massoth et al. showed that multimodal opioid-free anaesthesia decreased the postoperative use of morphine during gynecological laparoscopic surgery without compromising the level of pain control [20]. Systematic evidence also showed that ketamine in the peri-operative period decreases opioid use and lidocaine intravenously decreases opioid use and early pain intensity [17, 19]. Perhaps the time to first rescue analgesia for these non-opioid drugs (which are different in their effects on the central sensitization, sympathetic responses and inflammatory pain) is to blame in our patients. In addition, patients who received opioid-free anesthesia had shorter times for eye opening, extubation, and moving to an Aldrete score of ≥ 9 and post-anesthesia care unit discharge. This group had fewer incidences of excessive sedation and higher satisfaction. The outcomes may be associated with less residual effects of opioids, such as sedation, respiratory depression, dizziness, delayed psychomotor recovery. But the safety of each opioid-free agent should also be taken into account. Keep in mind that dexmedetomidine has sympatholytic properties and may lead to hypotension and bradycardia, and that lidocaine may be psychomimetic in high doses, so care must be taken when using it in high doses to avoid systemic toxicity, and ketamine must be given carefully since it can cause systemic toxicity [21]. The study by Beloeil et al. [21] reported increased serious bradycardia in the dexmedetomidine-based opioid-free anesthesia group, prompting early termination of the POFA trial. Thus, the term "opioid-free" should not be read as "automatically safer" for all patients: drug selection, dose, and hemodynamic monitoring and patient factors are all important. There are a number of limitations in the present findings. It was a prospective comparative study in a single centre with a relatively small number of patients (89) and there was no randomisation of patients into the different anaesthetic groups. Although baseline characteristics were similar, there was a risk of selection bias and differences in clinical decision-making. Variation in the type of surgical pain and recovery may have also been a result of the different open and laparoscopic procedures included. Only the first 24 postoperative hours were assessed for pain, and long-term outcomes including chronic postsurgical pain, subsequent opioid use and readmission were not considered. Moreover, there are several combinations of drugs that can be used during opioid-free anesthesia and it is important to note that the results may not be applicable to all opioid-free anesthesia. Standardised multicentre randomized trials with larger patient cohorts and the consideration of procedure-specific analysis are needed to clarify which patients benefit most and which suffers from the least adverse hemodynamic side effects.The present study compared opioid-free anesthesia with conventional opioid-based anesthesia in 89 patients undergoing elective general surgery. Patients receiving opioid-free anesthesia experienced significantly lower pain scores during the early postoperative period, required less rescue analgesia and consumed fewer postoperative opioids. They also had a longer interval before requesting the first rescue analgesic. These findings support the concept that analgesia during general anesthesia does not necessarily depend on a single opioid agent and can instead be achieved through a multimodal combination of drugs acting at different points in the pain pathway. Previous evidence has shown that agents such as dexmedetomidine, ketamine, lidocaine, paracetamol and non-steroidal anti-inflammatory drugs may provide additive analgesic effects while reducing perioperative opioid exposure[15-18]. The disappearance of a significant difference in pain scores by 24 hours in our study suggests that the main benefit of opioid-free anesthesia was concentrated in the immediate and early postoperative period. This reduction in postoperative opioid use in the opioid-free group is consistent with previous clinical trials. In patients undergoing laparoscopic cholecystectomy, Bakan et al. reported that technique without opioids using dexmedetomidine, lidocaine and propofol was effective alternative of opioid-based technique for anesthesia [19]. Likewise, Massoth et al. showed that multimodal opioid-free anaesthesia decreased the postoperative use of morphine during gynecological laparoscopic surgery without compromising the level of pain control [20]. Systematic evidence also revealed that ketamine in the perioperative period reduces opioid consumption and that lidocaine intravenously reduces opioid consumption and early pain intensity. It could be the long duration to first rescue analgesia for these non-opioid drugs that work on the central sensitization, sympathetic responses and inflammatory pain in different ways that accounts for the phenomenon in our patients. This decrease in opioid consumption after surgery in the opioid-free group agrees with other clinical trials. For laparoscopic cholecystectomy, Bakan et al. found that technique without opioids (dexmedetomidine, lidocaine and propofol) was an effective alternative to anesthesia technique with opioids [19]. Likewise, Massoth et al. showed that multimodal opioid-free anaesthesia decreased the postoperative use of morphine during gynecological laparoscopic surgery without compromising the level of pain control [20]. Systematic evidence also showed that ketamine in the peri-operative period decreases opioid use and lidocaine intravenously decreases opioid use and early pain intensity [17, 19]. Perhaps the time to first rescue analgesia for these non-opioid drugs (which are different in their effects on the central sensitization, sympathetic responses and inflammatory pain) is to blame in our patients. In addition, patients who received opioid-free anesthesia had shorter times for eye opening, extubation, and moving to an Aldrete score of ≥ 9 and post-anesthesia care unit discharge. This group had fewer incidences of excessive sedation and higher satisfaction. The outcomes may be associated with less residual effects of opioids, such as sedation, respiratory depression, dizziness, delayed psychomotor recovery. But the safety of each opioid-free agent should also be taken into account. Keep in mind that dexmedetomidine has sympatholytic properties and may lead to hypotension and bradycardia, and that lidocaine may be psychomimetic in high doses, so care must be taken when using it in high doses to avoid systemic toxicity, and ketamine must be given carefully since it can cause systemic toxicity [21]. The study by Beloeil et al. [21] reported increased serious bradycardia in the dexmedetomidine-based opioid-free anesthesia group, prompting early termination of the POFA trial. Thus, the term "opioid-free" should not be read as "automatically safer" for all patients: drug selection, dose, and hemodynamic monitoring and patient factors are all important. There are a number of limitations in the present findings. It was a prospective comparative study in a single centre with a relatively small number of patients (89) and there was no randomisation of patients into the different anaesthetic groups. Although baseline characteristics were similar, there was a risk of selection bias and differences in clinical decision-making. Variation in the type of surgical pain and recovery may have also been a result of the different open and laparoscopic procedures included. Only the first 24 postoperative hours were assessed for pain, and long-term outcomes including chronic postsurgical pain, subsequent opioid use and readmission were not considered. Moreover, there are several combinations of drugs that can be used during opioid-free anesthesia and it is important to note that the results may not be applicable to all opioid-free anesthesia. Standardised multicentre randomized trials with larger patient cohorts and the consideration of procedure-specific analysis are needed to clarify which patients benefit most and which suffers from the least adverse hemodynamic side effects.

Opioid-free anesthesia was associated with improved early postoperative pain control, reduced rescue analgesic and opioid requirements, a lower incidence of postoperative nausea and vomiting and faster postoperative recovery compared with conventional opioid-based anesthesia in patients undergoing elective general surgery. It was also associated with less excessive sedation and greater patient satisfaction. Nevertheless, opioid-free anesthesia should be implemented through carefully selected multimodal regimens with close hemodynamic monitoring, particularly when dexmedetomidine is used. These findings suggest that opioid-free anesthesia is a useful alternative for appropriately selected patients, although larger randomized studies are needed before it can be recommended as a universal replacement for conventional opioid-based anesthesia.

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