Upon rigorous review by the Institutional Review Board of the First Affiliated Hospital of Chongqing Medical University, this study received formal approval (IRB Number: 2022-068) and subsequent registration at Chinese Clinical Trial Registry (ChiCTR2200058634). Conducted in a university-affiliated tertiary medical institution, this prospective, randomized controlled investigation strictly adhered to the ethical stipulations delineated by the Declaration of Helsinki as well as the requirements set forth by the Institutional Review Board. Prior to commencing the study, informed consent was meticulously procured from all eligible participants. Subjects undergoing elective laparoscopic inguinal hernia repair were enrolled during the period extending from May 1, 2022 to December 31, 2022 after completion of trial registration. The reporting of this trial was in strict compliance with the Consolidated Standards of Reporting Trials (CONSORT) statement [Moher 2012].
Subsequent to acquiring informed consent, candidates were recruited from the Department of General Surgery. Inclusion criteria encompassed the following prerequisites: provision of informed consent prior to study initiation, laparoscopic inguinal hernia repair as the elected procedure, age range of 18 to 80 years, body mass index (BMI) ranging from 18 to 30, and American Society of Anesthesiology (ASA) grading between I and III. Exclusion criteria included ASA grading exceeding III; New York Heart Association (NYHA) grading surpassing III; perioperative mental disorders; compromised cognitive function as assessed by the Mini-Cog test (with criteria < 2); pregnancy; pre-operative history of gastrointestinal surgery; conversion from laparoscopic to open surgical modality; re-operation necessitated by hemorrhage or infection; participants who, despite prior informed consent, opted out of the follow-up; intraoperative cardiac arrest; and subjects unable to be extubated in the post-anesthesia care unit.
Sample size calculation
The primary outcome was the incidence of acute moderate-to-severe pain in motion before rescue analgesia. This was defined as a pain score—utilizing the visual analogue scale for pain—equal to or exceeding 4, at a temporal marker of 12 hours post-operatively, prior to the administration of rescue analgesia. Pain intensity was quantified utilizing the numerical rating score (NRS) while the subjects were engaged in ambulatory activity or other forms of motility. Preliminary data indicated an approximate 35% incidence rate of acute moderate-to-severe postoperative pain upon motion following laparoscopic inguinal hernia repair. Anticipating a 15% reduction in incidence upon implementing peri-operative Pain Neuroscience Education in conjunction with traditional multimodal analgesia, the minimum requisite sample size for each group to achieve statistical significance was calculated to be 90 subjects. This calculation factored in a projected 10% attrition rate over the course of the follow-up period. The study was designed to achieve a statistical power of 90% at a Type I error rate of 0.05.
Allocation, randomization, and blinding
A total cohort of 184 patients was algorithmically assigned in a balanced 1:1 ratio to either the Optimized Analgesia cohort or the Conventional Multimodal Analgesia cohort. Randomization was conducted using computer-generated random numbers encapsulated within opaque blocks, accommodating six to eight patients each, to ensure an equitable distribution amongst all eligible participants. Each patient was assigned a unique randomized identification code, formatted as “PNE-##” (where ## ranged from 01 to 184). This data was securely housed in an encrypted digital repository, with exclusive accessibility granted solely to the overseeing statistician. Methodologically, the study adopted a single-blind design, in which evaluators remained impartial and uninformed regarding patient group assignments, perioperative analgesic regimens, surgical procedures, pain Neuroscience Education, and anesthetic management.
Conventional analgesia group
The conventional multimodal postoperative pain management comprised preoperative Illioinguinal/Iliohypogastric nerve blockade (utilizing ipsilateral or bilateral administration of 20 mL of 0.33% ropivacaine) and intraoperative administration of sufentanil and remifentanil. A regime of Patient-Controlled Intravenous Analgesia (PCIA) was inaugurated upon surgical conclusion. The PCIA formulation was constituted of Tramadol 800 mg and Flurbiprofenaxetil 100 mg, solubilized in 80 mL of isotonic saline. The PCIA parameters were delineated as follows: initial loading dose ranged from 1.5 to 2 mL, continuous infusion rates were set between 1 and 1.5 mL/h, and rescue boluses were administered at 2 mL increments with a lockout interval of 15 minutes. At 72 hours postoperatively, oral analgesics—either Celecoxib or compound Tramadol Hydrochloride tablets—were prescribed following the extraction of the intravenous catheter for PCIA. In instances where patients reported excruciating pain (manifested by a Visual Analogue Scale score exceeding 4) or impaired sleep or motility, intravenous Parecoxib at a dose of 40 mg (with an 80 mg daily maximum) or Flurbiprofen at a dose of 50 mg (with a 100 mg daily maximum) was administered. If non-opioid interventions were adjudged to be ineffective 30 minutes subsequent to intravenous administration (indicated by a Visual Analogue Scale score exceeding 4), opioid rescue agents—either Fentanyl at doses ranging from 25 to 50 µg or Morphine ranging from 2.5 to 5 mg—were utilized. Additionally, a bolus injection via the PCIA was also considered a form of rescue analgesia. An acute pain service team, composed of anesthesiologists, nurses, and surgeons, conducted routine patient visits at 6–8 hour intervals until the time of the patients' discharge.
PNE group
In addition to the conventional multimodal analgesic regimen delineated previously, patients allocated to the Pain Neuroscience Education (PNE) group received an enriched educational intervention focusing on the neuroscience of pain. Upon admission for surgical intervention, these individuals were accorded an in-depth consultation detailing the PNE paradigm, which was bifurcated into preoperative educational encounters (two sessions) and postoperative feedback sessions (two instances).
The inaugural preoperative consultation encapsulated salient aspects such as the pathophysiological underpinnings of surgical pain, the contributors to heightened pain sensitization, behavioral modification recommendations, and cognitive coping strategies for patients. The second preoperative briefing demystified the surgical procedure, elucidated the mechanisms of multimodal analgesia, expounded upon contingency plans for rescue analgesia, and discussed strategies for optimizing sleep, while also laying the groundwork for postoperative feedback concerning pain management. Pedagogical materials, including patient brochures and PowerPoint presentations, were employed to facilitate both online and offline education. Each session was meticulously designed to span a duration of one hour.
Subsequent to the surgical intervention, postoperative feedback sessions were conducted at both 24 and 48-hour intervals. These interactions accentuated key tenets such as the imperative of adhering to the prescribed analgesic regimen, discourse on issues and satisfaction levels related to pain control, alternative therapeutic approaches, assessment and optimization of sleep quality, incentivizing ambulatory behavior and physical exercise, as well as addressing any patient queries pertaining to analgesia. Each postoperative session was structured to occupy a one-hour timeslot.
Formatted metaphors employed as educational tools within the perioperative PNE framework are comprehensively outlined in Fig. 1 and Appendix 1. The PNE protocol was executed by a cadre of two seasoned anesthesiologists who were scrupulously uninvolved in patient recruitment, allocation, or the assessment of outcomes.Except for the difference in peri-operative analgesia, all patients in both groups received identical peri-operative protocol of analgesia and surgery(appendix 2).
Outcome assessment
Age, gender, body mass index (BMI), years of formal education, smoking history, American Society of Anesthesiologists (ASA) grading, pre-operative serum albumin concentrations, laterality of the surgical site (bilateral or ipsilateral), and the specific variant of laparoscopic procedure being performed. Cardiopulmonary reserve functionality was meticulously assessed according to the New York Heart Association (NYHA) classification system. On the pre-operative day, the psychological well-being of eligible patients was quantified employing the validated Hospital Anxiety and Depression Scale (HADS)[Yang 2014].
The intensity of current pain was gauged in vivo during motion through the utilization of the Visual Analogue Scale (VAS). A VAS score of 4 or greater was formally identified as moderate-to-severe pre-operative pain before rescue analgesia. Both the surgical and anesthetic durations were recorded, and a 0-10mm calibration scale was employed for the Visual Analogue Scale in pain assessment.
The characteristics of pain were systematically explored through the Douleur Neuropathique 4 Questionnaire (DN-4) and the Pain Catastrophizing Scale (PCS)[Aho 2020], thus probing the neuropathic and catastrophizing components, respectively. Complementary to this, the Central Sensitization Inventory (CSI) and pressure pain threshold evaluations were implemented to assess pain sensitization mechanisms[Mayer 2012,Hidalgo 2010].
Pressure pain thresholds were ascertained via a handheld pressure algometer (Wagner Instruments, Greenwich, CT, USA) featuring a 1 cm^2 round rubber tip that made contact with the patient's skin[Hidalgo 2010]. An anatomical line situated 2 cm above and parallel to the inguinal ligament was elected for pre-operative measurements, with the more painful site chosen for bilateral repairs. Following a preliminary demonstration, the investigator applied pressure at a consistent rate of approximately 1 kg/s until the patient reported a VAS score equal to or greater than 4. The displayed pressure on the algometer was subsequently documented as the patient's pressure pain threshold. To mitigate any risk of injury or discomfort, the maximum exerted force was confined to 15 kg. The mean value was calculated based on three distinctive anatomical points along the chosen line (medial, middle, and lateral points)(appendix 3)[Yasukawa 2020].
Quality of life during the perioperative phase was assessed using the EuroQol Five Dimensions Questionnaire (EQ-5D-5L), encompassing domains such as mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. To mitigate any translational biases, the validated Chinese version of the questionnaire was employed[Luo 2017]. Each dimension was rated on a Likert scale ranging from 0 to 4, which respectively indicated 'no problem' to 'extremely severe problem.' The diagnostic criteria for Chronic Post-Surgical Pain (CPSP) were rigorously adhered to, as delineated by the International Association for the Study of Pain (IASP)[Weinrib 2017].
The apex of this investigative endeavor revolved around the quantification of moderate-to-severe post-operative pain, specifically assessed 12 hours subsequent to the surgical intervention. Pain intensity was ascertained employing the Visual Analogue Scale (VAS) with a threshold value equal to or exceeding 4, gauged during kinesthetic activities such as walking or positional adjustments in bed prior to the administration of rescue analgesia. Temporal fluctuations in post-operative pain intensity were meticulously documented at intervals of 12, 24, 48, and 72 hours post-surgery, culminating in a final assessment upon discharge.
In addition to this focal outcome, a cadre of secondary metrics was scrutinized. These encompassed a nuanced evaluation of pain characteristics, quality of post-operative recovery, patients' level of satisfaction with the surgical experience, and the incidence of Chronic Post-Surgical Pain (CPSP). The methodologies deployed for the measurement of post-operative pressure pain threshold remained invariant to those utilized in the pre-operative phase.
Furthermore, analgesic regimens, specifically the dosage of opioids utilized for peri-operative routine and rescue interventions, were recorded and subsequently transmuted into intravenous equianalgesic ratios vis-a-vis morphine[Svendsen 2011]. Inclusive in this data were the frequencies of analgesic rescue events, encompassing both Patient-Controlled Intravenous Analgesia (PCIA) boluses and non-opioid episodes.
For longitudinal surveillance, the characteristics of post-operative pain were rigorously assessed at time intervals of 12, 24, and 72 hours post-surgery, at the time of hospital discharge, and one month thereafter. Quality of life in the post-operative context was evaluated through the application of the EuroQol Five Dimensions Questionnaire (EQ-5D-5L) at 24 and 72 hours post-intervention, as well as upon discharge, and at one and three months subsequent to the surgical procedure.
The Analgesic Satisfaction Score served as a subjective evaluation metric at the time of hospital discharge, constituting an amalgamation of parameters including informed consent, medication strategy, technical execution, and overall patient experience. This was gauged utilizing a 0–10 point Likert scale, wherein a score of zero epitomized complete dissatisfaction and a score of ten indicated unequivocal satisfaction.
It is crucial to note that the faculty responsible for outcome assessments remained blind to the group allocations and specific interventions, thereby maintaining the study's methodological rigor. For patients who were discharged, remote follow-up was conducted via online platforms or telephonic communications to secure ongoing outcome measurements.
Statistics
Data were subjected to rigorous statistical analysis utilizing the Statistical Package for the Social Sciences (SPSS) version 23.0, provided by SPSS Inc., Chicago, IL, USA. An initial descriptive examination was executed for all variables under consideration. For continuous variables exhibiting a normal distribution, metrics were conveyed as mean values accompanied by the standard deviation (SD). Alternatively, non-normally distributed continuous variables were articulated through their median values, encapsulated within an interquartile range (IQR). Enumeration data were delineated by presenting both the aggregate sample size and the corresponding percentage distributions.Subsequent inferential statistical techniques were judiciously selected based on the inherent characteristics of the data. For continuous variables, a myriad of parametric and non-parametric tests were employed, including but not limited to the Independent t-test, Wilcoxon Rank-Sum test, Kruskal-Wallis test, and Repeated Measures Analysis of Variance (ANOVA), each contingent on the underlying data distribution. Categorical data were scrutinized through Chi-square tests, supplanted by Fisher's Exact tests in instances where the event count was less than five. To ascertain determinants potentially influencing the occurrence of moderate-to-severe pain at 12 hours post-surgery, univariable analyses were initially performed. Subsequent to this, variables that exhibited a significance level where P < 0.20 were included in a multivariate logistic regression model to identify independent risk factors correlated with the primary outcome. Quantitative measures of influence were expressed as Odds Ratios (OR) along with their respective 95% Confidence Intervals (95% CI).Adhering to the principle of Intention-To-Treat (ITT) analysis, all data were treated consistently, thereby enhancing the internal validity of the study. A two-tailed significance level was employed across all statistical evaluations, wherein a p-value of less than 0.05 was considered indicative of a statistically significant discrepancy or association.