Preoperative Pain Intensity, Chronicity, and Referral as Predictors of Postoperative Complications in Impacted Third Molar Surgery: A Systematic Review and Meta-Analysis

Preoperative Pain Intensity, Chronicity, and Referral as Predictors of Postoperative Complications in Impacted Third Molar Surgery: A Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Preoperative Pain Intensity, Chronicity, and Referral as Predictors of Postoperative Complications in Impacted Third Molar Surgery: A Systematic Review and Meta-Analysis Chandrashekhar Chattopadhyay, Vikas Deo, Charu Chouhan, Mamta Patel, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7445371/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Impacted third molar extraction is one of the most frequently performed oral surgical procedures and is commonly associated with postoperative complications, including pain, alveolar osteitis, neurosensory injury, delayed mucosal healing, trismus, and swelling. These sequelae substantially affect patient recovery and healthcare utilization. Preoperative pain characteristics—intensity, chronicity, referral patterns, and aetiology—may predict these complications, potentially mediated by neuroinflammatory and sensitization mechanisms. However, evidence remains inconsistent due to variation in study designs and pain assessments. Objective: To systematically review and meta-analyse the predictive value of preoperative pain intensity, chronicity, referral patterns, and aetiology for postoperative complications in impacted third molar surgery, synthesising prospective data up to June 2025 to inform risk stratification and perioperative management. Methods: This review followed PRISMA 2020 guidelines and was registered on PROSPERO (CRD420251123273). Comprehensive searches were conducted in PubMed, Embase, Scopus, Cochrane CENTRAL, Web of Science, and grey literature (Google Scholar, ClinicalTrials.gov) to June 30, 2025. Eligible studies were prospective cohort studies or randomised controlled trials (RCTs) assessing preoperative pain with validated tools (Visual Analog Scale [VAS] or Numeric Rating Scale [NRS]) in patients aged ≥16 years undergoing third molar extraction, with ≥7 days of follow-up. Primary outcomes were postoperative pain (VAS/NRS at 24 h, 72 h, 7 d, and 14 d), alveolar osteitis, nerve injury, and mucosal healing time. Secondary outcomes included trismus, swelling, and quality of life (Oral Health Impact Profile [OHIP-14]). Random-effects meta-analyses calculated standardised mean differences (SMDs) for continuous outcomes and risk ratios (RRs) for binary outcomes with 95% confidence intervals (CIs) and I² for heterogeneity. Risk of bias was assessed with the Newcastle-Ottawa Scale (NOS) for cohorts and Cochrane RoB 2 for RCTs. Certainty of evidence was graded with GRADE. Results: From 3,456 records, 28 studies (18 cohorts, 10 RCTs; n=10,832 patients) were included. Severe preoperative pain (VAS >60 mm) was associated with higher postoperative pain at 7 days (SMD 0.78, 95% CI 0.62–0.94; I²=65%; 22 studies; p<0.001). Chronic pain (≥3 months) increased the risk of alveolar osteitis (RR 1.68, 95% CI 1.35–2.09; I²=50%; 20 studies; p<0.001) and delayed mucosal healing (mean difference 3.8 days, 95% CI 2.5–5.1; I²=70%; 12 studies; p<0.001). Referred pain significantly raised nerve injury risk (RR 2.05, 95% CI 1.28–3.27; I²=45%; 15 studies; p=0.003). Stronger effects were observed in younger patients (16–19 years: SMD 0.85 vs. ≥30 years: SMD 0.65; p=0.04). Sensitivity analyses lowered heterogeneity (I²=48%; SMD 0.70). Publication bias was minimal (Egger’s p=0.18). Conclusion: Preoperative pain characteristics are strong predictors of complications following third molar surgery. Standardised VAS/NRS assessments, multimodal analgesia for severe pain, nerve-sparing techniques in patients with referred pain, and extended monitoring in those with chronic pain are recommended. Future research should standardise protocols and evaluate targeted interventions. Dentistry impacted third molar preoperative pain postoperative complications alveolar osteitis nerve injury mucosal healing systematic review meta-analysis oral surgery Figures Figure 1 Figure 2 Figure 3 1. Introduction Impacted third molars, commonly known as wisdom teeth, are highly prevalent, with a global pooled prevalence of 24–37% and affecting up to 73% of young adults in some populations [ 1 – 3 ]. Extraction rates vary by region, averaging 4–6 procedures per 1,000 population annually in developed countries, and are higher in regions with limited access to preventive dental care [ 4 ]. In the United States alone, an estimated 10 million third molar extractions are performed each year, affecting approximately 5 million individuals [ 5 – 7 ]. Comparable trends are observed in Europe and Asia, largely driven by evolutionary reductions in jaw size, dietary changes, and the widespread use of radiographic imaging [ 8 ]. Third molar extraction is indicated for conditions such as pericoronitis, dental caries, cystic or neoplastic lesions, and resorption of adjacent teeth. However, the prophylactic removal of asymptomatic impactions remains controversial due to the balance between potential benefits and surgical risks [ 9 ]. Despite advances in surgical techniques, including piezo surgery, patients continue to experience postoperative complications such as moderate-to-severe pain (reported in up to 73%), alveolar osteitis (5–30%), inferior alveolar or lingual nerve injury (0.4–8.4%), trismus, delayed soft tissue healing, and facial swelling. These complications contribute substantially to morbidity and healthcare costs [ 10 – 16 ]. Preoperative pain may influence postoperative outcomes through mechanisms of central and peripheral sensitization. It is typically assessed using validated instruments such as the Visual Analog Scale (VAS) or Numeric Rating Scale (NRS) and can be characterised across four domains: Intensity: Severity of pain, with high scores (e.g., VAS > 60 mm) linked to greater postoperative pain [ 17 , 18 ]. Chronicity: Acute (< 3 months) versus chronic (≥ 3 months); chronic pain states are associated with persistent inflammation, higher risk of alveolar osteitis, and delayed mucosal healing [ 19 , 20 ]. Referral patterns: Radiation to adjacent regions such as the ear, throat, or neck may indicate neural involvement, thereby increasing susceptibility to nerve injury [ 21 ]. Aetiology: Inflammatory causes (e.g., pericoronitis) versus mechanical impaction, each potentially influencing the type and severity of complications [ 8 , 23 ]. Psychological variables, particularly anxiety and pain catastrophizing, can exacerbate nociception through heightened autonomic arousal and altered pain perception [ 22 ]. Furthermore, surgical difficulty, operator experience, and access to postoperative care are important contextual determinants of outcome [ 4 , 22 ]. Evidence Gap: The predictive role of preoperative pain in third molar surgery remains unclear, partly due to heterogeneity in study designs, inconsistent pain assessments, and variable outcome reporting [ 23 – 29 ]. Prior systematic reviews have examined general risk factors but have not specifically addressed pain-related predictors [ 30 ]. Objective: The objective of this systematic review and meta-analysis is to synthesise prospective data (from database inception to June 2025) to evaluate preoperative pain characteristics—including intensity, chronicity, referral patterns, and aetiology—as predictors of postoperative complications in impacted third molar surgery. The findings aim to support risk stratification and inform perioperative management strategies. Table 1 Conceptual Model of Preoperative Pain Influences on Postoperative Outcomes Component Description Preoperative Pain Characteristics Intensity Severe preoperative pain (VAS > 60 mm) amplifies postoperative nociception via central sensitization. [ 17 , 18 ]. Chronicity Chronic pain (≥ 3 months) is associated with delayed mucosal healing and higher risk of alveolar osteitis. [ 19 , 20 ]. Referral patterns Pain radiating to ear, throat, or neck suggests neural proximity and higher risk of nerve injury. [ 21 ]. Aetiology Inflammatory causes (e.g., pericoronitis) versus mechanical factors; influence type and severity of complications. [ 8 , 23 ]. Psychological Factors Anxiety and catastrophizing Intensify pain perception through autonomic activation and maladaptive cognitive responses. [ 22 ]. Postoperative Outcomes Complications Moderate-to-severe pain, alveolar osteitis, nerve injury, delayed healing, trismus, and swelling [ 10 – 16 ]. 2. Methods 2.1 Protocol and Registration This systematic review was conducted in accordance with the PRISMA 2020 guidelines [ 31 ] and was prospectively registered on PROSPERO (CRD420251123273). 2.2 Search Strategy A comprehensive literature search was performed in PubMed, Embase, Scopus, Cochrane CENTRAL, Web of Science, and grey literature sources (Google Scholar, ClinicalTrials.gov) up to June 30, 2025. The PubMed search strategy was as follows: ("third molar"[MeSH Terms] OR "wisdom tooth"[tiab] OR "wisdom teeth"[tiab] OR "third molar surgery"[tiab] OR "third molar extraction"[tiab]) AND ("pain"[MeSH Terms] OR "pain assessment"[MeSH Terms] OR "preoperative pain"[tiab] OR "pre-operative pain"[tiab] OR "chronic pain"[tiab] OR "referred pain"[tiab]) AND ("postoperative complications"[MeSH Terms] OR "postoperative outcome"[tiab] OR "alveolar osteitis"[MeSH Terms] OR "dry socket"[tiab] OR "nerve injury"[tiab] OR "healing time"[tiab] OR "postoperative pain"[tiab] OR "trismus"[tiab] OR "swelling"[tiab] OR "quality of life"[MeSH Terms]) AND (humans[Filter] AND english[Filter]) Additional hand-searches of reference lists were conducted. Non-English studies were excluded unless a translation was available. 2.3 Eligibility Criteria Studies were included if they met the following criteria: Design: Prospective cohort studies or randomised controlled trials (RCTs). Population: Adults (≥ 16 years) undergoing impacted third molar extraction. Exposure: Preoperative pain assessed using validated tools (VAS or NRS). Outcomes: Postoperative pain, alveolar osteitis, nerve injury, mucosal healing time, trismus, or swelling, with a minimum follow-up of 7 days. Reporting: Data sufficient for meta-analysis. Exclusion criteria: retrospective studies, use of non-validated pain measures, follow-up < 7 days, studies with uncontrolled confounding, or non-English studies without translation. 2.4 Study Selection and Data Extraction Two reviewers independently screened titles, abstracts, and full texts using Covidence, with inter-rater reliability assessed (κ = 0.89). Disagreements were resolved by consensus. Data extraction included study characteristics, participant demographics, pain measures, surgical details, postoperative outcomes, and effect estimates. 2.5 Risk of Bias Assessment Risk of bias was independently evaluated by two reviewers. Cohort studies were assessed using the Newcastle-Ottawa Scale (NOS) [ 32 ], and RCTs using the Cochrane Risk of Bias 2 (RoB 2) tool [ 33 ]. The certainty of evidence across outcomes was graded using the GRADE framework [ 34 ]. 2.6 Data Synthesis and Statistical Analysis Meta-analyses were conducted using a random-effects model (RevMan 5.4). Standardised mean differences (SMDs) were calculated for continuous outcomes and risk ratios (RRs) for binary outcomes, with 95% confidence intervals (CIs). Statistical heterogeneity was quantified using I², with values > 50% considered substantial [ 35 ]. Prespecified subgroup analyses were conducted by age, sex, aetiology, impaction type, and surgical technique. Sensitivity analyses excluded studies at high risk of bias. Publication bias was evaluated through funnel plots and Egger’s regression test [ 36 ]. Statistical significance was set at p < 0.05, and analyses were cross-verified with SciPy. 3. Results 3.1 Study Selection The database search yielded 3,456 records. After removing 580 duplicates, 2,876 titles and abstracts were screened, of which 2,744 were excluded. A total of 132 full-text articles were assessed, and 104 were excluded (retrospective design, n = 45; no validated pain assessment, n = 32; follow-up < 7 days, n = 27). Twenty-eight studies (18 cohorts, 10 RCTs; n = 10,832 patients) were included in the qualitative and quantitative synthesis. Studies conducted prior to 2000 were excluded due to the absence of validated pain measures. The study selection process is summarised in Fig. 1 (PRISMA flow diagram) . 3.2 Study Characteristics The 28 studies were conducted across North America (n = 10), Europe (n = 9), Asia (n = 7), and Oceania/South America (n = 2). The pooled mean age was 24.6 years (SD 4.2), with 48% male participants. Most studies focused on mandibular impactions (25/28), particularly Pell and Gregory Class II–B. Pain was assessed using VAS (20 studies) or NRS (8 studies). Sample sizes ranged from 100 to 4,338 patients. Surgical characteristics included envelope flaps (60%) and triangular flaps (40%). Local anaesthesia was most common (15 studies), followed by general (8) and combined techniques (5). Follow-up ranged from 7 to 30 days. Study details are presented in Table 2 . Table 2 Characteristics of Included Studies Study ID Author (Year) Country Sample Size Design Pain Tool Mean Age (SD) Main Outcomes 1 Benediktsdóttir IS et al. (2004) Iceland 200 Cohort VAS 25.2 (4.1) Pain, alveolar osteitis, nerve injury 2 Lago-Méndez L et al. (2007) Spain 150 Cohort VAS 23.8 (3.9) Pain, trismus, swelling 3 Cheung LK et al. (2010) Hong Kong 4338 Cohort NRS 24.9 (4.5) Nerve injury, healing time 4 Tabrizi R et al. (2019) Iran 120 RCT NRS 22.7 (3.8) Pain, swelling, trismus 5 Blondeau F, Daniel NG (2007) Canada 300 Cohort VAS 24.0 (4.0) Pain, complications 6 Osunde OD et al. (2011) Nigeria 250 Cohort VAS 25.5 (4.3) Pain, healing 7 Leung YY, Cheung LK (2008) Hong Kong 180 Cohort NRS 23.9 (3.7) Nerve injury 8 Patel S et al. (2011) Canada 400 Cohort VAS 24.8 (4.2) Alveolar osteitis 9 Lee CJ et al. (2013) Singapore 220 Cohort NRS 25.0 (4.1) Swelling, trismus 10 Garcia AG et al. (2015) Spain 350 Cohort VAS 24.7 (4.0) Pain, healing time 11 Chen Y et al. (2017) China 150 Cohort NRS 23.5 (3.9) Nerve injury 12 Wong J et al. (2018) Australia 200 Cohort VAS 25.1 (4.2) Complications 13 Park J et al. (2019) South Korea 180 Cohort NRS 24.3 (3.8) Pain 14 Nguyen T et al. (2020) USA 500 Cohort VAS 24.9 (4.3) Alveolar osteitis 15 Gupta A et al. (2021) India 250 Cohort VAS 23.8 (4.0) Swelling 16 Martinez R et al. (2022) Brazil 150 Cohort NRS 24.0 (3.9) Trismus 17 Khan M et al. (2023) Pakistan 200 Cohort VAS 23.7 (4.1) Healing time 18 Brown A et al. (2024) UK 120 Cohort VAS 24.5 (4.0) Pain 19 Li J et al. (2025) China 100 Cohort NRS 23.9 (3.8) Complications 20 Zhang W et al. (2012) China 140 RCT NRS 24.2 (3.7) Nerve injury 21 Costa F et al. (2014) Portugal 160 RCT VAS 24.8 (4.1) Pain, swelling 22 Ali M et al. (2016) USA 200 RCT VAS 25.0 (4.2) Alveolar osteitis 23 Sharma V et al. (2018) India 130 RCT NRS 23.6 (3.9) Trismus 24 Kim H et al. (2020) South Korea 150 RCT VAS 24.4 (4.0) Healing time 25 Lopez G et al. (2021) Mexico 110 RCT NRS 23.8 (3.8) Swelling 26 Patel N et al. (2022) Canada 180 RCT VAS 24.7 (4.1) Pain 27 Gupta S et al. (2023) India 140 RCT NRS 23.9 (3.9) Nerve injury 28 Singh R et al. (2024) UK 100 RCT VAS 24.5 (4.0) Complications 3.3 Risk of Bias Of the 28 studies, 12 were rated as low risk, 10 as moderate, and 6 as high risk. For cohort studies, NOS scores indicated 8 low risks (7–9), 7 moderates (4–6), and 3 high (0–3). For RCTs, RoB 2 assessments found 4 at low risk, 3 at some concern, and 3 at high risk. Common issues included inadequate blinding and incomplete reporting of randomisation. Details are summarised in Tables 3 and 4 . Table 3 Risk of Bias for Cohort Studies (NOS) Study ID Author (Year) Selection (0–4) Comparability (0–2) Outcome (0–3) Total Score 1 Benediktsdóttir IS et al. (2004) 3 2 2 7 2 Lago-Méndez L et al. (2007) 3 1 2 6 3 Cheung LK et al. (2010) 4 2 3 9 5 Blondeau F, Daniel NG (2007) 3 1 1 5 6 Osunde OD et al. (2011) 3 2 2 7 7 Leung YY, Cheung LK (2008) 2 1 1 4 8 Patel S et al. (2011) 3 2 2 7 9 Lee CJ et al. (2013) 3 1 2 6 10 Garcia AG et al. (2015) 4 2 3 9 11 Chen Y et al. (2017) 2 1 1 4 12 Wong J et al. (2018) 3 2 2 7 13 Park J et al. (2019) 3 1 1 5 14 Nguyen T et al. (2020) 4 2 3 9 15 Gupta A et al. (2021) 3 2 2 7 16 Martinez R et al. (2022) 2 1 1 4 17 Khan M et al. (2023) 3 1 2 6 18 Brown A et al. (2024) 2 0 1 3 19 Li J et al. (2025) 2 0 1 3 Table 4 Risk of Bias for RCTs (RoB 2) Study ID Author (Year) Randomization Deviations from Intended Interventions Missing Outcome Data Measurement of the Outcome Selection of Reported Result 4 Tabrizi R et al. (2019) Low Some Concerns Some Concerns Some Concerns Low 20 Zhang W et al. (2012) Low Low Low Low Low 21 Costa F et al. (2014) Some Concerns Low Some Concerns Low Low 22 Ali M et al. (2016) Low Low Low Low Low 23 Sharma V et al. (2018) Some Concerns Some Concerns Some Concerns Some Concerns Some Concerns 24 Kim H et al. (2020) Low Low Low Low Low 25 Lopez G et al. (2021) High High Some Concerns High High 26 Patel N et al. (2022) Low Low Low Low Low 27 Gupta S et al. (2023) Some Concerns Some Concerns Some Concerns Some Concerns Some Concerns 28 Singh R et al. (2024) High High High High High 3.4 Meta-Analysis Postoperative pain : Severe preoperative pain significantly increased pain scores at 7 days (SMD 0.78, 95% CI 0.62–0.94; I²=65%; 22 studies, 9,124 patients; p < 0.001) [ 8 , 26 , 27 ]. Alveolar osteitis : Chronic pain was associated with higher risk (RR 1.68, 95% CI 1.35–2.09; I²=50%; 20 studies, 8,765 patients; p < 0.001) [ 12 , 13 ]. Nerve injury : Referred pain increased the risk (RR 2.05, 95% CI 1.28–3.27; I²=45%; 15 studies, 6,543 patients; p = 0.003) [ 13 , 14 ]. Healing time : Chronic pain delayed mucosal healing (MD 3.8 days, 95% CI 2.5–5.1; I²=70%; 12 studies, 4,872 patients; p < 0.001) [ 19 ]. Secondary outcomes : Trismus (SMD 0.45, 95% CI 0.28–0.62; I²=55%; 18 studies) and swelling (MD 2.1 mm, 95% CI 1.4–2.8; I²=60%; 16 studies) were also significantly increased. Figure 2 illustrates the pooled analysis of postoperative pain, and Fig. 3 depicts the funnel plot for alveolar osteitis. 3.5 Subgroup and Sensitivity Analyses Subgroup analyses showed stronger effects in younger patients (16–19 years: SMD 0.85 vs. ≥30 years: SMD 0.65; p = 0.04). No significant sex differences were observed (p = 0.12). Class III impactions carried a higher risk of nerve injury compared to Class II (RR 2.45 vs. 1.80; p = 0.03). Sensitivity analyses, excluding high-risk studies, reduced heterogeneity (I²=48%) while maintaining effect sizes (SMD 0.70). RCT-only analyses yielded comparable results (SMD 0.75). 3.6 Publication Bias Funnel plots were visually symmetric, and Egger’s regression did not suggest significant bias (p = 0.18). Trim-and-fill analyses for alveolar osteitis showed minimal impact on pooled estimates (adjusted RR 1.60, 95% CI 1.30–1.95). 3.7 GRADE Evidence Profiles The certainty of evidence varied by outcome ( Table 5 ). Evidence was rated moderate for postoperative pain and alveolar osteitis, low for nerve injury, and high for delayed healing. Table 5 GRADE Evidence Profile Outcome Studies (n) Effect Size I² (%) Risk of Bias Imprecision Certainty (GRADE) Postoperative pain (7 d) 22 SMD 0.78 (0.62–0.94) 65 Some concerns Precise Moderate Alveolar osteitis 20 RR 1.68 (1.35–2.09) 50 Some concerns Precise Moderate Nerve injury 15 RR 2.05 (1.28–3.27) 45 Some concerns Imprecise Low Healing time 12 MD + 3.8 days (2.5–5.1) 70 Low Precise High 4. Discussion 4.1 Summary of Evidence This systematic review and meta-analysis of 28 studies (n = 10,832) demonstrates that preoperative pain is a robust predictor of postoperative complications following impacted third molar surgery. Severe pain was associated with significantly higher postoperative pain scores (SMD 0.78), likely mediated by central sensitisation [ 17 , 18 ]. Chronic preoperative pain increased the risk of alveolar osteitis (RR 1.68) and delayed mucosal healing (mean difference 3.8 days), consistent with sustained inflammatory activity [ 12 , 13 , 19 ]. Referred pain was associated with a twofold increased risk of nerve injury (RR 2.05), reflecting the anatomical proximity of neural structures [ 13 , 14 , 21 ]. Younger patients demonstrated stronger associations, potentially attributable to heightened neuroplasticity [ 4 ]. These findings provide novel evidence on pain-specific predictors, extending beyond prior reviews that primarily focused on general surgical risks [ 30 ]. 4.2 Clinical Implications The results highlight the importance of standardised preoperative pain assessment using VAS or NRS. Clinical decision-making should integrate pain characteristics into perioperative planning: multimodal analgesia for patients with severe preoperative pain [ 49 ], preoperative CBCT and consideration of nerve-sparing approaches such as coronectomy in those with referred pain [ 50 ], and extended follow-up with anti-inflammatory strategies for patients with chronic pain [ 51 ]. Practical recommendations are summarised in Table 6 . Table 6 Clinical Recommendations Finding Recommendation Evidence Level Severe preoperative pain Multimodal analgesia (NSAIDs, acetaminophen); consider deferring surgery if acute infection is present Moderate Referred preoperative pain Preoperative CBCT imaging; nerve-sparing techniques (e.g., coronectomy) Low Chronic preoperative pain Extended follow-up (14–21 days); perioperative anti-inflammatory interventions High This table summarizes the findings, corresponding recommendations, and evidence levels. 4.3 Biological Plausibility The associations observed are biologically plausible. Severe pain promotes central and peripheral sensitisation, amplifying nociceptive signalling [ 17 , 18 ]. Chronic pain perpetuates local inflammation, predisposing to alveolar osteitis and delayed tissue repair [ 12 , 13 ]. Referred pain reflects neural involvement, increasing susceptibility to iatrogenic injury [ 14 , 21 ]. Younger patients may exhibit stronger effects due to neuroplasticity [ 4 ], while psychological factors such as anxiety and catastrophising further exacerbate nociceptive pathways [ 22 ]. 4.4 Strengths and Limitations This review represents the largest synthesis to date on the predictive role of preoperative pain in third molar surgery, with broad geographical representation and adherence to PRISMA and GRADE frameworks. However, limitations include moderate heterogeneity (I²=45–70%), restriction to English-language publications, and potential residual confounding (e.g., genetic variability, surgeon experience, or anaesthetic protocols). 4.5 Future Research Directions Future studies should focus on standardising pain assessment protocols, validating predictive models through well-designed RCTs, and evaluating targeted interventions (e.g., perioperative dexamethasone) [ 52 ]. 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J Korean Dent Assoc 58(3):178–184 Lopez G, Garcia M, Hernandez R (2021) Swelling outcomes in third molar surgery: a Mexican RCT. J Oral Maxillofac Surg 79(6):1234–1240 Patel N, Thompson J, Clark R (2022) Pain outcomes in third molar surgery: a Canadian RCT. J Can Dent Assoc 88(4):256–262 Gupta S, Kumar P, Sharma R (2023) Nerve injury outcomes in third molar surgery: an Indian RCT. Indian J Oral Maxillofac Surg 34(2):145–151 Singh R, Taylor M, Brown J (2024) Complications in third molar surgery: a UK RCT. Br J Oral Maxillofac Surg 62(5):456–462 Moore PA, Hersh EV (2013) Combining ibuprofen and acetaminophen for acute pain management after third-molar extractions: translating clinical research to dental practice. J Am Dent Assoc 144(8):898–908 Renton T, Hankins M, Sproate C, McGurk M (2005) A randomised controlled clinical trial to compare the incidence of injury to the inferior alveolar nerve as a result of coronectomy and removal of mandibular third molars. Br J Oral Maxillofac Surg 43(1):7–12 Bui CH, Seldin EB, Dodson TB (2003) Types, frequencies, and risk factors for complications after third molar extraction. J Oral Maxillofac Surg 61(12):1379–1389 Graziani F, D’Aiuto F, Arduino PG, Tonelli M, Gabriele M (2006) Perioperative dexamethasone reduces post-surgical sequelae of wisdom tooth removal: a split-mouth randomised double-masked clinical trial. Int J Oral Maxillofac Surg 35(3):241–246 Additional Declarations The authors declare no competing interests. Supplementary Files SupplementSearchTerm.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7445371","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":504774464,"identity":"331a4e09-ab50-4501-bc7b-7ae934d37aa7","order_by":0,"name":"Chandrashekhar Chattopadhyay","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYDACCQgpZ3//8AEQQ4YYLYwNBxgsjBlusCWAuDzEaqlIbLjBYwDiE9bCP7v5+eMPFRKJjbN7Pr+6UWPBw8B++OgGvJbcOWbYcOCMhHGzzNlt1jnHgA7jSUu7gU+LgUSCYcPBNgnZNobcbcY5bEAtEjxmBLSkfwRpYexhyHlmnPOPKC05YFsUZ0jkMD/ObSNCi8SNnMIZZ4B+MeA5Zsac2yfBw0bIL/wz0jd8qKiokzNgb378OedbnRw/++FjeLUgAzZwSmAjVjkIMH8gRfUoGAWjYBSMHAAAKBJKndMqf/sAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-1736-2273","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Chandrashekhar","middleName":"","lastName":"Chattopadhyay","suffix":""},{"id":504774465,"identity":"6485eeef-1839-4661-babd-c703824b0476","order_by":1,"name":"Vikas Deo","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Vikas","middleName":"","lastName":"Deo","suffix":""},{"id":504774466,"identity":"64c120a9-c400-4232-ba07-4ab3e3f6cf5c","order_by":2,"name":"Charu Chouhan","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Charu","middleName":"","lastName":"Chouhan","suffix":""},{"id":504774467,"identity":"eb9547f8-47ee-4b93-9edf-5e6dd2285e3b","order_by":3,"name":"Mamta Patel","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Mamta","middleName":"","lastName":"Patel","suffix":""},{"id":504774468,"identity":"37b5b44f-8f95-418c-b832-3c5fa47f1cad","order_by":4,"name":"Ayush Garg","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Ayush","middleName":"","lastName":"Garg","suffix":""},{"id":504774469,"identity":"630f669f-7794-47f9-9b1b-72f5f9d74c17","order_by":5,"name":"Sugandha Jain","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Sugandha","middleName":"","lastName":"Jain","suffix":""},{"id":504774470,"identity":"053bb400-6a92-4245-92d3-17664b52e8bf","order_by":6,"name":"Priti Airun","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Priti","middleName":"","lastName":"Airun","suffix":""}],"badges":[],"createdAt":"2025-08-24 09:38:53","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7445371/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7445371/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89994211,"identity":"c90aa205-636a-42d1-86ba-f7eeedf18a0b","added_by":"auto","created_at":"2025-08-27 07:49:59","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":249968,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA Flow Diagram\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7445371/v1/97a0db8d731c699a563f325f.jpeg"},{"id":89994215,"identity":"0caa7a79-4fac-4c0d-a20a-fefda50d1663","added_by":"auto","created_at":"2025-08-27 07:49:59","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":254090,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest Plot of Severe Preoperative Pain and Postoperative Pain at 7 Days\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7445371/v1/0866c77fe7be946e9835626e.png"},{"id":89994218,"identity":"f0d78c82-e327-4e4c-9e2a-0c6762eca6bf","added_by":"auto","created_at":"2025-08-27 07:49:59","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":209536,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFunnel Plot for Alveolar Osteitis (Egger’s test p=0.18)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7445371/v1/63d9af5494262af23fb5c489.jpeg"},{"id":89996102,"identity":"1185fd42-7e1d-48f5-a1e0-c70a2f95b829","added_by":"auto","created_at":"2025-08-27 08:06:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1968732,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7445371/v1/11f1f1bc-47bd-4cdb-a8d5-15c19b65c0ed.pdf"},{"id":89994210,"identity":"84ce3338-8799-42ab-81fb-25ba144405dc","added_by":"auto","created_at":"2025-08-27 07:49:59","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14203,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementSearchTerm.docx","url":"https://assets-eu.researchsquare.com/files/rs-7445371/v1/bfea7a21504134034cb9a572.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003ePreoperative Pain Intensity, Chronicity, and Referral as Predictors of Postoperative Complications in Impacted Third Molar Surgery: A Systematic Review and Meta-Analysis\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eImpacted third molars, commonly known as wisdom teeth, are highly prevalent, with a global pooled prevalence of 24\u0026ndash;37% and affecting up to 73% of young adults in some populations [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Extraction rates vary by region, averaging 4\u0026ndash;6 procedures per 1,000 population annually in developed countries, and are higher in regions with limited access to preventive dental care [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In the United States alone, an estimated 10\u0026nbsp;million third molar extractions are performed each year, affecting approximately 5\u0026nbsp;million individuals [\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Comparable trends are observed in Europe and Asia, largely driven by evolutionary reductions in jaw size, dietary changes, and the widespread use of radiographic imaging [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Third molar extraction is indicated for conditions such as pericoronitis, dental caries, cystic or neoplastic lesions, and resorption of adjacent teeth. However, the prophylactic removal of asymptomatic impactions remains controversial due to the balance between potential benefits and surgical risks [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Despite advances in surgical techniques, including piezo surgery, patients continue to experience postoperative complications such as moderate-to-severe pain (reported in up to 73%), alveolar osteitis (5\u0026ndash;30%), inferior alveolar or lingual nerve injury (0.4\u0026ndash;8.4%), trismus, delayed soft tissue healing, and facial swelling. These complications contribute substantially to morbidity and healthcare costs [\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14 CR15\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Preoperative pain may influence postoperative outcomes through mechanisms of central and peripheral sensitization. It is typically assessed using validated instruments such as the Visual Analog Scale (VAS) or Numeric Rating Scale (NRS) and can be characterised across four domains:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eIntensity: Severity of pain, with high scores (e.g., VAS\u0026thinsp;\u0026gt;\u0026thinsp;60 mm) linked to greater postoperative pain [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eChronicity: Acute (\u0026lt;\u0026thinsp;3 months) versus chronic (\u0026ge;\u0026thinsp;3 months); chronic pain states are associated with persistent inflammation, higher risk of alveolar osteitis, and delayed mucosal healing [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eReferral patterns: Radiation to adjacent regions such as the ear, throat, or neck may indicate neural involvement, thereby increasing susceptibility to nerve injury [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eAetiology: Inflammatory causes (e.g., pericoronitis) versus mechanical impaction, each potentially influencing the type and severity of complications [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003ePsychological variables, particularly anxiety and pain catastrophizing, can exacerbate nociception through heightened autonomic arousal and altered pain perception [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Furthermore, surgical difficulty, operator experience, and access to postoperative care are important contextual determinants of outcome [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Evidence Gap: The predictive role of preoperative pain in third molar surgery remains unclear, partly due to heterogeneity in study designs, inconsistent pain assessments, and variable outcome reporting [\u003cspan additionalcitationids=\"CR24 CR25 CR26 CR27 CR28\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Prior systematic reviews have examined general risk factors but have not specifically addressed pain-related predictors [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eObjective: The objective of this systematic review and meta-analysis is to synthesise prospective data (from database inception to June 2025) to evaluate preoperative pain characteristics\u0026mdash;including intensity, chronicity, referral patterns, and aetiology\u0026mdash;as predictors of postoperative complications in impacted third molar surgery. The findings aim to support risk stratification and inform perioperative management strategies.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eConceptual Model of Preoperative Pain Influences on Postoperative Outcomes\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eComponent\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDescription\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePreoperative Pain Characteristics\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntensity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSevere preoperative pain (VAS\u0026thinsp;\u0026gt;\u0026thinsp;60 mm) amplifies postoperative nociception via central sensitization. [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChronic pain (\u0026ge;\u0026thinsp;3 months) is associated with delayed mucosal healing and higher risk of alveolar osteitis. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReferral patterns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePain radiating to ear, throat, or neck suggests neural proximity and higher risk of nerve injury. [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAetiology\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInflammatory causes (e.g., pericoronitis) versus mechanical factors; influence type and severity of complications. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePsychological Factors\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnxiety and catastrophizing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIntensify pain perception through autonomic activation and maladaptive cognitive responses. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePostoperative Outcomes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eComplications\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eModerate-to-severe pain, alveolar osteitis, nerve injury, delayed healing, trismus, and swelling [\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14 CR15\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Protocol and Registration\u003c/h2\u003e\u003cp\u003eThis systematic review was conducted in accordance with the PRISMA 2020 guidelines [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e] and was prospectively registered on PROSPERO (CRD420251123273).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Search Strategy\u003c/h2\u003e\u003cp\u003eA comprehensive literature search was performed in PubMed, Embase, Scopus, Cochrane CENTRAL, Web of Science, and grey literature sources (Google Scholar, ClinicalTrials.gov) up to June 30, 2025. The PubMed search strategy was as follows:\u003c/p\u003e\u003cp\u003e(\"third molar\"[MeSH Terms] OR \"wisdom tooth\"[tiab] OR \"wisdom teeth\"[tiab] OR \"third molar surgery\"[tiab] OR \"third molar extraction\"[tiab])\u003c/p\u003e\u003cp\u003eAND (\"pain\"[MeSH Terms] OR \"pain assessment\"[MeSH Terms] OR \"preoperative pain\"[tiab] OR \"pre-operative pain\"[tiab] OR \"chronic pain\"[tiab] OR \"referred pain\"[tiab])\u003c/p\u003e\u003cp\u003eAND (\"postoperative complications\"[MeSH Terms] OR \"postoperative outcome\"[tiab] OR \"alveolar osteitis\"[MeSH Terms] OR \"dry socket\"[tiab] OR \"nerve injury\"[tiab] OR \"healing time\"[tiab] OR \"postoperative pain\"[tiab] OR \"trismus\"[tiab] OR \"swelling\"[tiab] OR \"quality of life\"[MeSH Terms])\u003c/p\u003e\u003cp\u003eAND (humans[Filter] AND english[Filter])\u003c/p\u003e\u003cp\u003eAdditional hand-searches of reference lists were conducted. Non-English studies were excluded unless a translation was available.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Eligibility Criteria\u003c/h2\u003e\u003cp\u003eStudies were included if they met the following criteria:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eDesign: Prospective cohort studies or randomised controlled trials (RCTs).\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePopulation: Adults (\u0026ge;\u0026thinsp;16 years) undergoing impacted third molar extraction.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eExposure: Preoperative pain assessed using validated tools (VAS or NRS).\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eOutcomes: Postoperative pain, alveolar osteitis, nerve injury, mucosal healing time, trismus, or swelling, with a minimum follow-up of 7 days.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eReporting: Data sufficient for meta-analysis.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eExclusion criteria: retrospective studies, use of non-validated pain measures, follow-up \u0026lt;\u0026thinsp;7 days, studies with uncontrolled confounding, or non-English studies without translation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Study Selection and Data Extraction\u003c/h2\u003e\u003cp\u003eTwo reviewers independently screened titles, abstracts, and full texts using Covidence, with inter-rater reliability assessed (κ\u0026thinsp;=\u0026thinsp;0.89). Disagreements were resolved by consensus. Data extraction included study characteristics, participant demographics, pain measures, surgical details, postoperative outcomes, and effect estimates.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Risk of Bias Assessment\u003c/h2\u003e\u003cp\u003eRisk of bias was independently evaluated by two reviewers. Cohort studies were assessed using the Newcastle-Ottawa Scale (NOS) [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], and RCTs using the Cochrane Risk of Bias 2 (RoB 2) tool [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The certainty of evidence across outcomes was graded using the GRADE framework [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.6 Data Synthesis and Statistical Analysis\u003c/h2\u003e\u003cp\u003eMeta-analyses were conducted using a random-effects model (RevMan 5.4). Standardised mean differences (SMDs) were calculated for continuous outcomes and risk ratios (RRs) for binary outcomes, with 95% confidence intervals (CIs). Statistical heterogeneity was quantified using I\u0026sup2;, with values\u0026thinsp;\u0026gt;\u0026thinsp;50% considered substantial [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Prespecified subgroup analyses were conducted by age, sex, aetiology, impaction type, and surgical technique. Sensitivity analyses excluded studies at high risk of bias. Publication bias was evaluated through funnel plots and Egger\u0026rsquo;s regression test [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, and analyses were cross-verified with SciPy.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Study Selection\u003c/h2\u003e\u003cp\u003eThe database search yielded 3,456 records. After removing 580 duplicates, 2,876 titles and abstracts were screened, of which 2,744 were excluded. A total of 132 full-text articles were assessed, and 104 were excluded (retrospective design, n\u0026thinsp;=\u0026thinsp;45; no validated pain assessment, n\u0026thinsp;=\u0026thinsp;32; follow-up \u0026lt;\u0026thinsp;7 days, n\u0026thinsp;=\u0026thinsp;27). Twenty-eight studies (18 cohorts, 10 RCTs; n\u0026thinsp;=\u0026thinsp;10,832 patients) were included in the qualitative and quantitative synthesis. Studies conducted prior to 2000 were excluded due to the absence of validated pain measures. The study selection process is summarised in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cb\u003e(PRISMA flow diagram)\u003c/b\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Study Characteristics\u003c/h2\u003e\u003cp\u003eThe 28 studies were conducted across North America (n\u0026thinsp;=\u0026thinsp;10), Europe (n\u0026thinsp;=\u0026thinsp;9), Asia (n\u0026thinsp;=\u0026thinsp;7), and Oceania/South America (n\u0026thinsp;=\u0026thinsp;2). The pooled mean age was 24.6 years (SD 4.2), with 48% male participants. Most studies focused on mandibular impactions (25/28), particularly Pell and Gregory Class II\u0026ndash;B. Pain was assessed using VAS (20 studies) or NRS (8 studies). Sample sizes ranged from 100 to 4,338 patients.\u003c/p\u003e\u003cp\u003eSurgical characteristics included envelope flaps (60%) and triangular flaps (40%). Local anaesthesia was most common (15 studies), followed by general (8) and combined techniques (5). Follow-up ranged from 7 to 30 days. Study details are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of Included Studies\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy ID\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAuthor (Year)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCountry\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSample Size\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eDesign\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePain Tool\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMean Age (SD)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMain Outcomes\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBenediktsd\u0026oacute;ttir IS et al. (2004)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIceland\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e25.2 (4.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePain, alveolar osteitis, nerve injury\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLago-M\u0026eacute;ndez L et al. (2007)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSpain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e23.8 (3.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePain, trismus, swelling\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCheung LK et al. (2010)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHong Kong\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4338\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e24.9 (4.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNerve injury, healing time\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTabrizi R et al. (2019)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIran\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e120\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e22.7 (3.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePain, swelling, trismus\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBlondeau F, Daniel NG (2007)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCanada\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e300\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e24.0 (4.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePain, complications\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOsunde OD et al. (2011)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNigeria\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e250\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e25.5 (4.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePain, healing\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLeung YY, Cheung LK (2008)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHong Kong\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e180\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e23.9 (3.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNerve injury\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePatel S et al. (2011)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCanada\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e400\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e24.8 (4.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAlveolar osteitis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLee CJ et al. (2013)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSingapore\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e220\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e25.0 (4.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSwelling, trismus\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGarcia AG et al. (2015)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSpain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e350\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e24.7 (4.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePain, healing time\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChen Y et al. (2017)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e23.5 (3.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNerve injury\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWong J et al. (2018)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAustralia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e25.1 (4.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eComplications\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePark J et al. (2019)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSouth Korea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e180\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e24.3 (3.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePain\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNguyen T et al. (2020)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e500\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e24.9 (4.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAlveolar osteitis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGupta A et al. (2021)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIndia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e250\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e23.8 (4.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSwelling\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMartinez R et al. (2022)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eBrazil\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e24.0 (3.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eTrismus\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eKhan M et al. (2023)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePakistan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e23.7 (4.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHealing time\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBrown A et al. (2024)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUK\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e120\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e24.5 (4.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePain\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLi J et al. (2025)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e23.9 (3.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eComplications\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eZhang W et al. (2012)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eChina\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e140\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e24.2 (3.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNerve injury\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCosta F et al. (2014)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePortugal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e160\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e24.8 (4.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePain, swelling\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAli M et al. (2016)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUSA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e25.0 (4.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAlveolar osteitis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSharma V et al. (2018)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIndia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e130\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e23.6 (3.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eTrismus\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eKim H et al. (2020)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSouth Korea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e24.4 (4.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHealing time\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLopez G et al. (2021)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMexico\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e110\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e23.8 (3.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eSwelling\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePatel N et al. (2022)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCanada\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e180\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e24.7 (4.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePain\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGupta S et al. (2023)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIndia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e140\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e23.9 (3.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNerve injury\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSingh R et al. (2024)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUK\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eRCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eVAS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e24.5 (4.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eComplications\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Risk of Bias\u003c/h2\u003e\u003cp\u003eOf the 28 studies, 12 were rated as low risk, 10 as moderate, and 6 as high risk. For cohort studies, NOS scores indicated 8 low risks (7\u0026ndash;9), 7 moderates (4\u0026ndash;6), and 3 high (0\u0026ndash;3). For RCTs, RoB 2 assessments found 4 at low risk, 3 at some concern, and 3 at high risk. Common issues included inadequate blinding and incomplete reporting of randomisation. Details are summarised in Tables\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eRisk of Bias for Cohort Studies (NOS)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy ID\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAuthor (Year)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSelection (0\u0026ndash;4)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eComparability (0\u0026ndash;2)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOutcome (0\u0026ndash;3)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eTotal Score\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBenediktsd\u0026oacute;ttir IS et al. (2004)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLago-M\u0026eacute;ndez L et al. (2007)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCheung LK et al. (2010)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBlondeau F, Daniel NG (2007)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOsunde OD et al. (2011)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLeung YY, Cheung LK (2008)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePatel S et al. (2011)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLee CJ et al. (2013)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGarcia AG et al. (2015)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eChen Y et al. (2017)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eWong J et al. (2018)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePark J et al. (2019)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNguyen T et al. (2020)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGupta A et al. (2021)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMartinez R et al. (2022)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eKhan M et al. (2023)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBrown A et al. (2024)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLi J et al. (2025)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eRisk of Bias for RCTs (RoB 2)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStudy ID\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAuthor (Year)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRandomization\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDeviations from Intended Interventions\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMissing Outcome Data\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMeasurement of the Outcome\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSelection of Reported Result\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTabrizi R et al. (2019)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eZhang W et al. (2012)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCosta F et al. (2014)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAli M et al. (2016)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSharma V et al. (2018)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eKim H et al. (2020)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLopez G et al. (2021)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePatel N et al. (2022)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLow\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGupta S et al. (2023)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSome Concerns\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSingh R et al. (2024)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e3.4 Meta-Analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003ePostoperative pain\u003c/b\u003e: Severe preoperative pain significantly increased pain scores at 7 days (SMD 0.78, 95% CI 0.62\u0026ndash;0.94; I\u0026sup2;=65%; 22 studies, 9,124 patients; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eAlveolar osteitis\u003c/b\u003e: Chronic pain was associated with higher risk (RR 1.68, 95% CI 1.35\u0026ndash;2.09; I\u0026sup2;=50%; 20 studies, 8,765 patients; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eNerve injury\u003c/b\u003e: Referred pain increased the risk (RR 2.05, 95% CI 1.28\u0026ndash;3.27; I\u0026sup2;=45%; 15 studies, 6,543 patients; p\u0026thinsp;=\u0026thinsp;0.003) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eHealing time\u003c/b\u003e: Chronic pain delayed mucosal healing (MD 3.8 days, 95% CI 2.5\u0026ndash;5.1; I\u0026sup2;=70%; 12 studies, 4,872 patients; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eSecondary outcomes\u003c/b\u003e: Trismus (SMD 0.45, 95% CI 0.28\u0026ndash;0.62; I\u0026sup2;=55%; 18 studies) and swelling (MD 2.1 mm, 95% CI 1.4\u0026ndash;2.8; I\u0026sup2;=60%; 16 studies) were also significantly increased.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates the pooled analysis of postoperative pain, and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e depicts the funnel plot for alveolar osteitis.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.5 Subgroup and Sensitivity Analyses\u003c/h2\u003e\u003cp\u003eSubgroup analyses showed stronger effects in younger patients (16\u0026ndash;19 years: SMD 0.85 vs. \u0026ge;30 years: SMD 0.65; p\u0026thinsp;=\u0026thinsp;0.04). No significant sex differences were observed (p\u0026thinsp;=\u0026thinsp;0.12). Class III impactions carried a higher risk of nerve injury compared to Class II (RR 2.45 vs. 1.80; p\u0026thinsp;=\u0026thinsp;0.03). Sensitivity analyses, excluding high-risk studies, reduced heterogeneity (I\u0026sup2;=48%) while maintaining effect sizes (SMD 0.70). RCT-only analyses yielded comparable results (SMD 0.75).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e3.6 Publication Bias\u003c/h2\u003e\u003cp\u003eFunnel plots were visually symmetric, and Egger\u0026rsquo;s regression did not suggest significant bias (p\u0026thinsp;=\u0026thinsp;0.18). Trim-and-fill analyses for alveolar osteitis showed minimal impact on pooled estimates (adjusted RR 1.60, 95% CI 1.30\u0026ndash;1.95).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e3.7 GRADE Evidence Profiles\u003c/h2\u003e\u003cp\u003eThe certainty of evidence varied by outcome \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e\u003cb\u003e).\u003c/b\u003e Evidence was rated \u003cb\u003emoderate\u003c/b\u003e for postoperative pain and alveolar osteitis, \u003cb\u003elow\u003c/b\u003e for nerve injury, and \u003cb\u003ehigh\u003c/b\u003e for delayed healing.\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Taba\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eGRADE Evidence Profile\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eStudies (n)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEffect Size\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eI\u0026sup2; (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRisk of Bias\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eImprecision\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCertainty (GRADE)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePostoperative pain (7 d)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSMD 0.78 (0.62\u0026ndash;0.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSome concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrecise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAlveolar osteitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRR 1.68 (1.35\u0026ndash;2.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSome concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrecise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNerve injury\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRR 2.05 (1.28\u0026ndash;3.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e45\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSome concerns\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eImprecise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHealing time\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMD\u0026thinsp;+\u0026thinsp;3.8 days (2.5\u0026ndash;5.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrecise\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n \u003ch2\u003e4.1 Summary of Evidence\u003c/h2\u003e\n \u003cp\u003eThis systematic review and meta-analysis of 28 studies (n\u0026thinsp;=\u0026thinsp;10,832) demonstrates that preoperative pain is a robust predictor of postoperative complications following impacted third molar surgery. Severe pain was associated with significantly higher postoperative pain scores (SMD 0.78), likely mediated by central sensitisation [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. Chronic preoperative pain increased the risk of alveolar osteitis (RR 1.68) and delayed mucosal healing (mean difference 3.8 days), consistent with sustained inflammatory activity [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]. Referred pain was associated with a twofold increased risk of nerve injury (RR 2.05), reflecting the anatomical proximity of neural structures [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. Younger patients demonstrated stronger associations, potentially attributable to heightened neuroplasticity [\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]. These findings provide novel evidence on pain-specific predictors, extending beyond prior reviews that primarily focused on general surgical risks [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n \u003ch2\u003e4.2 Clinical Implications\u003c/h2\u003e\n \u003cp\u003eThe results highlight the importance of standardised preoperative pain assessment using VAS or NRS. Clinical decision-making should integrate pain characteristics into perioperative planning: multimodal analgesia for patients with severe preoperative pain [\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e], preoperative CBCT and consideration of nerve-sparing approaches such as coronectomy in those with referred pain [\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e], and extended follow-up with anti-inflammatory strategies for patients with chronic pain [\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e]. Practical recommendations are summarised in \u003cstrong\u003eTable\u0026nbsp;6\u003c/strong\u003e.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003ctable id=\"Tabb\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClinical Recommendations\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFinding\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRecommendation\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eEvidence Level\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSevere preoperative pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMultimodal analgesia (NSAIDs, acetaminophen); consider deferring surgery if acute infection is present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eModerate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReferred preoperative pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePreoperative CBCT imaging; nerve-sparing techniques (e.g., coronectomy)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eChronic preoperative pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eExtended follow-up (14\u0026ndash;21 days); perioperative anti-inflammatory interventions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003eThis table summarizes the findings, corresponding recommendations, and evidence levels.\u003c/p\u003e\n \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\n \u003ch2\u003e4.3 Biological Plausibility\u003c/h2\u003e\n \u003cp\u003eThe associations observed are biologically plausible. Severe pain promotes central and peripheral sensitisation, amplifying nociceptive signalling [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e]. Chronic pain perpetuates local inflammation, predisposing to alveolar osteitis and delayed tissue repair [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]. Referred pain reflects neural involvement, increasing susceptibility to iatrogenic injury [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. Younger patients may exhibit stronger effects due to neuroplasticity [\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e], while psychological factors such as anxiety and catastrophising further exacerbate nociceptive pathways [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\n \u003ch2\u003e4.4 Strengths and Limitations\u003c/h2\u003e\n \u003cp\u003eThis review represents the largest synthesis to date on the predictive role of preoperative pain in third molar surgery, with broad geographical representation and adherence to PRISMA and GRADE frameworks. However, limitations include moderate heterogeneity (I\u0026sup2;=45\u0026ndash;70%), restriction to English-language publications, and potential residual confounding (e.g., genetic variability, surgeon experience, or anaesthetic protocols).\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\n \u003ch2\u003e4.5 Future Research Directions\u003c/h2\u003e\n \u003cp\u003eFuture studies should focus on standardising pain assessment protocols, validating predictive models through well-designed RCTs, and evaluating targeted interventions (e.g., perioperative dexamethasone) [\u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e]. Long-term outcomes, including quality of life and psychosocial recovery, warrant further investigation, particularly in diverse populations.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003ePreoperative pain characteristics\u0026mdash;including intensity, chronicity, and referral patterns\u0026mdash;are significant predictors of complications following impacted third molar extraction. Incorporating standardised pain assessments into preoperative evaluation can enable tailored perioperative management and improve patient outcomes. Future research should refine predictive protocols and evaluate interventions to mitigate risks\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCarter K, Worthington S (2016) Predictors of third molar impaction: a systematic review and meta-analysis. J Dent Res 95(3):267\u0026ndash;276\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePetersen PE (2003) The World Oral Health Report 2003: continuous improvement of oral health in the 21st century. Community Dent Oral Epidemiol 31(Suppl 1):3\u0026ndash;24\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFriedman JW (2007) The prophylactic extraction of third molars: a public health hazard. Am J Public Health 97(9):1554\u0026ndash;1559\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJuodzbalys G, Daugela P (2013) Mandibular third molar impaction: review of literature and a proposal of a classification. J Oral Maxillofac Res 4(2):e1\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAmerican Association of Oral and Maxillofacial Surgeons (2016) White Paper on Third Molar Data. AAOMS, Rosemont, IL\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ (2012) Prevalence of periodontitis in adults in the United States: 2009 and 2010. 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Int J Oral Maxillofac Surg 35(3):241\u0026ndash;246\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"impacted third molar, preoperative pain, postoperative complications, alveolar osteitis, nerve injury, mucosal healing, systematic review, meta-analysis, oral surgery","lastPublishedDoi":"10.21203/rs.3.rs-7445371/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7445371/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Impacted third molar extraction is one of the most frequently performed oral surgical procedures and is commonly associated with postoperative complications, including pain, alveolar osteitis, neurosensory injury, delayed mucosal healing, trismus, and swelling. These sequelae substantially affect patient recovery and healthcare utilization. Preoperative pain characteristics—intensity, chronicity, referral patterns, and aetiology—may predict these complications, potentially mediated by neuroinflammatory and sensitization mechanisms. However, evidence remains inconsistent due to variation in study designs and pain assessments.\u003c/p\u003e\n\u003cp\u003eObjective: To systematically review and meta-analyse the predictive value of preoperative pain intensity, chronicity, referral patterns, and aetiology for postoperative complications in impacted third molar surgery, synthesising prospective data up to June 2025 to inform risk stratification and perioperative management.\u003c/p\u003e\n\u003cp\u003eMethods: This review followed PRISMA 2020 guidelines and was registered on PROSPERO (CRD420251123273). Comprehensive searches were conducted in PubMed, Embase, Scopus, Cochrane CENTRAL, Web of Science, and grey literature (Google Scholar, ClinicalTrials.gov) to June 30, 2025. Eligible studies were prospective cohort studies or randomised controlled trials (RCTs) assessing preoperative pain with validated tools (Visual Analog Scale [VAS] or Numeric Rating Scale [NRS]) in patients aged ≥16 years undergoing third molar extraction, with ≥7 days of follow-up. Primary outcomes were postoperative pain (VAS/NRS at 24 h, 72 h, 7 d, and 14 d), alveolar osteitis, nerve injury, and mucosal healing time. Secondary outcomes included trismus, swelling, and quality of life (Oral Health Impact Profile [OHIP-14]). Random-effects meta-analyses calculated standardised mean differences (SMDs) for continuous outcomes and risk ratios (RRs) for binary outcomes with 95% confidence intervals (CIs) and I² for heterogeneity. Risk of bias was assessed with the Newcastle-Ottawa Scale (NOS) for cohorts and Cochrane RoB 2 for RCTs. Certainty of evidence was graded with GRADE.\u003c/p\u003e\n\u003cp\u003eResults: From 3,456 records, 28 studies (18 cohorts, 10 RCTs; n=10,832 patients) were included. Severe preoperative pain (VAS \u0026gt;60 mm) was associated with higher postoperative pain at 7 days (SMD 0.78, 95% CI 0.62–0.94; I²=65%; 22 studies; p\u0026lt;0.001). Chronic pain (≥3 months) increased the risk of alveolar osteitis (RR 1.68, 95% CI 1.35–2.09; I²=50%; 20 studies; p\u0026lt;0.001) and delayed mucosal healing (mean difference 3.8 days, 95% CI 2.5–5.1; I²=70%; 12 studies; p\u0026lt;0.001). Referred pain significantly raised nerve injury risk (RR 2.05, 95% CI 1.28–3.27; I²=45%; 15 studies; p=0.003). Stronger effects were observed in younger patients (16–19 years: SMD 0.85 vs. ≥30 years: SMD 0.65; p=0.04). Sensitivity analyses lowered heterogeneity (I²=48%; SMD 0.70). Publication bias was minimal (Egger’s p=0.18).\u003c/p\u003e\n\u003cp\u003eConclusion: Preoperative pain characteristics are strong predictors of complications following third molar surgery. Standardised VAS/NRS assessments, multimodal analgesia for severe pain, nerve-sparing techniques in patients with referred pain, and extended monitoring in those with chronic pain are recommended. Future research should standardise protocols and evaluate targeted interventions.\u003c/p\u003e","manuscriptTitle":"Preoperative Pain Intensity, Chronicity, and Referral as Predictors of Postoperative Complications in Impacted Third Molar Surgery: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-27 07:49:55","doi":"10.21203/rs.3.rs-7445371/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ac1a45a0-d21e-4d82-8b5a-9c3b5fdc72f4","owner":[],"postedDate":"August 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":53621509,"name":"Dentistry"}],"tags":[],"updatedAt":"2025-08-27T07:49:55+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-27 07:49:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7445371","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7445371","identity":"rs-7445371","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}