Chronic post-surgical pain (CPSP) is a growing public health problem that can occur in a large proportion of patients after a major invasive surgical intervention in a mostly silent process [1]. CPSP, which is defined by international diagnostic criteria as a persistent and/or recurrent tissue pain that lasts for more than 3 months after surgery without presence of a primary tumor or an active oncologic process, has a profound impact on quality of life, functional mobility and can cause long-lasting psychological distress [1,2]. In the past, clinical management at the time of surgery was almost synonymous with acute pain management, and was usually directed towards intensive acute pain control using large amounts of pure opioid receptor agonists [2].

Until now, however, studies have emerged that suggest that traditional opioid-driven algorithms can in fact actually induce paradoxical changes in the nervous system that sensitise pain mechanisms and perpetuate the switch from short-term, post-operative pain to long-term, chronic pain syndromes [3].

Surgical pain is dealt with by severe pathways of peripheral and central sensitization that will drive the chronification of acute pain [4]. Major surgical trauma is accompanied by severe local tissue injury, severing of nerves, and inflammatory response that leads to continuous and intense peripheral nociceptor stimulation [4,5]. This ongoing stream of noxious signals to the dorsal horn of the spinal cord, elicits ongoing changes in central pain processing circuits [5].

This would cause longstanding central activation that leads to structural changes, such as upregulation of N-methyl-D-aspartate (NMDA) receptor channels and activation of microglial cells, causing hyper-excitability, or central sensitization, [5, 6]. Normally non-painful sensory inputs are felt as painful under these changed neurological circumstances, while common painful stimuli are responded to with increased intensity (hyperalgesia) [6].

Surprisingly, large doses of opioids administered during surgery can paradoxically exacerbate these central mechanisms of hypersensitivity by what is called opioid induced hyperalgesia (OIH) [7]. Large doses of narcotics activate mu-opioid receptors in the cell, which causes activation of downstream mechanisms that interact with inflammation and pro-nociceptive cascades such as NMDA receptor facilitation and increase in dynorphin release from spinal cord [7,8].

Therefore, excessive opioid use during surgery can actually contribute to decreasing nociceptive thresholds which results in greater post-operative pain intensity and higher use of rescue narcotics in the immediate post-operative period [8]. This cycle further sensitizes the central nervous system's general neuroplasticity which will help the shift into chronic postsurgical pain states [7,8].

However, to interrupt this, modern perioperative medicine has strived to put in place multimodal opioid-sparing anesthetic strategies [9]. These protocols include one or more non-opioid analgesics with different mechanisms of action such as local anesthesia, regional anesthesia, NMDA receptor antagonists (magnesium sulphate, ketamine), alpha-2 adrenergic agonists (dexmedetomidine), scheduled use of non-steroidal anti-inflammatory drugs (NSAIDs) [9, 10].

Opioid sparing techniques have multiple mechanisms of action along the nociceptive pathway – peripheral transduction, nerve conduction, and central integration – to further improve pain control whilst drastically decreasing the narcotic requirements [10]. This combination allows to reduce the occurrence of opioid induced hyperalgesia early on and neuroprotectively modulate the central sensitization cascades [9,10].

Although there is clear evidence for the efficacy of an opioid-sparing protocol in acute postoperative outcomes in a high-resource healthcare setting, there is limited clinical evidence in the publication of their efficacy in preventing chronic pain transition in South Asian Public Healthcare Systems [5]. Post-operative pain follow up is frequently not achieved in Pakistan, due to secondary healthcare gaps or lack of diverse options for pain due to resource limitations or constraints, and conventional/traditional intraoperative narcotic management is still being practiced.

This study aimed to systematically compare the effectiveness of multimodal opioid-sparing anesthetic technique (MSAT) with conventional opioid dominated anesthetic technique (CDAT) in the management of acute pains and prevention of chronic post-surgical pain syndrome for surgical population admitted at Tertiary Care Hospital Nishtar 2, Nishtar Medical University, Multan.

Research Design and Clinical Coursework The study was a prospective, observational cohort study, carried out in the Department of Anesthesia, Intensive Care and Pain Management, Nishtar 2 Tertiary Care Hospital, Nishtar Medical University, Multan, Pakistan. You could apply for the clinical recruitment window which was open for six months beginning in October 2025. The clinical study was conducted in accordance with the principles of the Declaration of Helsinki and is directed by the local ERAS (enhanced recovery after surgery) and extensive acute pain service guidelines. Selecting and Eligibility Requirements for the Patient Adult patients on the waiting list for major elective open abdominal surgery, such as radical gastrectomy, anterior resection, or complex open (angle Incision) cholecystectomy, or waiting for major open thoracic/thoracoabdominal procedures, were screened for inclusion. The inclusion criteria were set as: 1. Healthy subjects aged 18–65 years, both gender. 2. American Society of Anesthesiologists (ASA) Physical Status Class I, II or III. 3. Good cognitive function with adequate understanding and the use of the standard Visual Analog Scale (VAS) pain scale. The exclusion criteria were: 1. Chronic pain syndromes that have been present long before surgery and were on a long-term daily dose of opiate narcotic. 2. History of severe psychiatric illness or a history of substance abuse. 3. Any known allergy or medical contra-indication to any of the specific non-opioid components of the multimodal protocol (e.g., severe renal impairment, underlying bradycardia etc.). 4. Severe intra-operative complication that could not be left uncorrected and warranted immediate revision from the planned anesthetic strategy. Anesthetic / Perioperative interventions Patients were assigned to the following two clinical management arms based on the operating theatre schedules in use at the institutions, staff availability and similar base-level infrastructure: In this study, the patient group was split into two groups: • Opioid-Sparing Group (n = 97): Anesthetic protocol was structured to reduce the amount of systemic narcotics to which patients in this group were exposed. A suitable regional technique (use of the abdominal plane block, thoracic paravertebral block or targeted wound infiltration with 0.25 percent bupivacaine) was performed before the induction of general anesthesia. Propofol, boluses of lidocaine and cisatracurium were used to induce general anesthesia. Maintenance was accomplished through sevoflurane plus a continuous infusion of dexmedetomidine (DXM: 0.4mcg/kg/hr) and magnesium sulfate (MgSO4: 15mg/kg/hr) into the intravenous. Intravenous non-opioids such as paracetamol (1 gram every 6 hours) and ketorolac (30 milligram every 8 hours) were started intraoperatively and continued for 48 hours postoperatively. Systemic opioids were used only for breakthrough pain. • Conventional Opioid Group (n = 97): patients in this group were handled with conventional institutional anesthetic protocol. The induction of general anesthesia included a standard bolus of nalbuphine or morphine, cisatracurium and propofol. Maintenance was performed with volatile volatile anesthetic agents (isoflurane or sevoflurane) adjusted during the course of the surgery to agonist levels that were equal to those which were observed visually as an indication of surgical stress. Fentanyl or morphine was used as pain control in bolus doses during surgery. Post-operative pain management was achieved using on-demand or PRN (as-needed) injections of intravenous morphine, and the traditional narcotic regimens with no systematic scheduled non-opioid multimodal drug integration. Primary and Secondary Outcome Measures: Clinical data collection was carried out during two main time points: an acute post-operative time point (0-48 hours) and the long-term chronic pain follow-up time point (3 months after surgery). The main results were: 1. Acute Pain Intensity: The standard 10cm Visual Analog Scale (VAS) with 0 signifying "no pain" and 10 signifying "the worst possible pain" was used to quantify pain intensity at 24 and 48 hrs after surgery, at rest and on movement. 2. Chronic Post-Surgical Pain (CPSP) Incidence: Was determined at exactly 3 months after surgery using a standardized telephone interviews or outpatient clinic appointments. The criteria for the definition of CPSP were presence of pain at the surgical site being scored ≥3 on a VAS developed post-surgery without any other identifiable cause. Secondary outcomes included: 1. Total Cumulative Opioid Consumption: Total amount of opioids used by the patient (total milligrams of total morphine equivalents) within the first 48 hours after surgery. 2. Opioid-Related Adverse Events: Recorded rates of post-operative nausea and vomiting (PONV), respiratory depression (respiratory rate < 10 per minute), urinary retention and bowel function (ileus). 3. Overall Patient Satisfaction: Must be expressed at the time of discharge from the hospital, on a Likert type scale of 5 (very dissatisfied, dissatisfied, neutral, satisfied, very satisfied). Statistical Analysis StatCamb software version 26.0 was used for statistical analysis. Continuous data were normally distributed and it was evaluated by examining with Shapiro-Wilk test. Mean plus or minus standard deviation (SD) were used in the summarization of normal distributions which were compared by independent student's t-test. The parameters that were not normally distributed were presented as median values with interquartile ranges (IQR) and tested using the Mann-Whitney U test. Categorical data variables were converted to number and percentage and analyzed by Chi square test / Fisher's exact test. A p-value of < 0.05 was considered statistically significant.

Demographic and Surgical Baseline Characteristics:

Of the 216 patients who completed clinical protocols, 194 completed follow-up review. Table 1 shows that there was no difference in demographic data, average age, gender split, average ASA grade and duration of surgical procedure between the two arms, and baseline was therefore considered equal.

Table 1: Baseline Demographic Features and Surgical Variables

Primary Outcomes: Acute Pain and Chronic Pain Chronification

Early acute pain management tracking demonstrated significant differences between the groups. At 24 hours post-surgery, patients managed under the multimodal Opioid-Sparing Group reported lower mean resting pain intensity scores compared to the Conventional Opioid Group (2.4 ± 0.8 vs. 4.9 ± 1.2; p < 0.001). This pattern persisted at 48 hours, with the opioid-sparing cohort demonstrating stable rest and dynamic pain control (Table 2).

Long-term follow-up at 3 months post-surgery revealed differences in the transition to chronic pain. The development of chronic post-surgical pain (CPSP) was documented in 9.3 percent (n = 9) of the Opioid-Sparing Group, compared to 23.7 percent (n = 23) of the Conventional Opioid Group. This difference was statistically significant (Chi-square = 7.37, p = 0.007).

Secondary Outcomes (Opioid Consumption and Side Effects)

There was a significant decrease in total narcotic dependency in the multimodal protocol. The cumulative rescue morphine use in the first 48 post-operative hours was 12.5 mg (IQR, 5.0‐18.0 mg) in the Opioid-Sparing Group vs 48.0 mg (IQR, 30.0‐65.0 mg) in the Conventional Opioid Group (p < 0.001).

With decreased narcotics usage, there was decreased opioid-induced side effects. The postoperative nausea and vomiting rates were 12.4 per cent in the opioid-sparing arm and 28.9 per cent in the conventional group (p = 0.005). The time until clinical return of bowel motility was also decreased in the opioid-sparing group (Table 2).

Table 2: Comparative Analysis of Pain Intensity, Opioid Needs, and Complications

Prevention of chronic post-surgical pain syndrome is now an important area of modern peri-operative care and research for anesthesiologists [2,3]. This prospective cohort study was done in the Tertiary Care Hospital Nishtar 2, Nishtar Medical University, Multan to determine the effectiveness of multimodal opioid-sparing anesthesia protocol. Our results suggest that a multimodal plan of structured regional analgesia and the use of non-opioids to minimize perioperative narcotics use can significantly decrease acute pain scores and reduce the rate of chronic post-surgical pain at 3 months. As would be expected with the opioid sparing group, there was a lower incidence of chronic post-surgical pain (9.3 percent vs. 23.7 percent), which backs up the idea that something about the different ways we treat the pain during surgery may impact the outcome later in life [3,7]. Opioid-only therapies have been shown to be ineffective for many people who have suffered ongoing pain for a long time, and can actually make the pain worse through opioid induced hyperalgesia (OIH) [7,8]. Our multimodal protocol, however, addressed the several isolated loci in the pain pathway [9]. Regional blocks decreased the total amount of nociceptive signals sent to the spinal cord and MgSO4 is an NMDA receptor antagonist that can decrease central sensitization and neuroplastic changes in the DH [6,10]. This dual action seems to decrease the possibility of acute pain becoming chronic pain processes [9,10].

In our study, the opioid-sparing strategy resulted in significantly lower pain scores in the early post-operative periods (24 and 48 hours) and in a lesser median amount of administered morphine, 48 mg versus 12.5 mg. These findings are consistent with large scale international trials, including those by Forget et al. that demonstrated multimodal regimens provide better, more reliable analgesia than opiate-only treatment with the added benefit of better uptake of non-narcotic meds in the plasma [11].

Intraoperative serial boluses are associated with early rebound hyperalgesia at the receptor level and the use of serial boluses of opioids is known to help minimize change in receptor level thereby resulting in more effective and predictable recovery in the post-operative state [8,12]. Also, decreases in overall opioid use tended to be related to less clinically significant side effects. A combination of complications associated with high doses of systemic opioids is often reported: bowel dysfunction, urinary retention and post-operative nausea and vomiting (PONV) [10]. The opioid-sparing group had fewer episodes of PONV (12.4 percent vs. 28.9 percent) and fewer cases of prolonged ileus (4.1 percent vs. 13.4 percent). They are part of improved recovery after surgery (ERAS) protocols and help drive higher total patient satisfaction (83.5 percent vs. 55.7 percent), and facilitating smoother hospital operations.

This study is limited in a few ways. First, the population was non-randomized and thus could be subject to selection bias due to institutional resource allocation and individual provider preference. Second, the follow-up time frame used was the 3 months post surgery, which may not encompass late resolvers and very long term chronic pain syndromes. Further multi-center RCTs with long term follow up is required to assess the long term advantages of opioid-sparing anesthesia in the public health system of Pakistan.

To conclude, multimodal opioid-sparing anesthetic protocol could be effective in controlling acute pain post-surgery, as well as significantly lowering the overall perioperative narcotic requirements and chronic PSP transition rates in patients undergoing major surgical interventions.

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