Alveolar osteitis, commonly referred to as dry socket, is one of the most frequent postoperative complications following surgical extraction of mandibular third molars. First described in detail by Blum (2002), dry socket is characterized by partial or total loss of the post-extraction blood clot within the alveolus, leading to exposed bone, intense throbbing pain, halitosis, and delayed wound healing. The reported incidence varies widely, ranging from 1–5% in routine extractions to as high as 30% following surgical removal of impacted mandibular third molars (Bowe et al., 2011; Vezeau, 2000). The higher incidence associated with impacted third molar surgery is attributed to increased surgical trauma, longer operative time, and greater bone manipulation.

The exact pathogenesis of dry socket remains multifactorial and not entirely understood. However, the most widely accepted theory involves fibrinolysis of the blood clot triggered by bacterial activity and tissue trauma (Blum, 2002). Bacterial enzymes and inflammatory mediators are believed to increase local plasminogen activity, leading to premature clot dissolution and exposure of underlying bone (Noroozi & Philbert, 2009). Several local and systemic risk factors have been identified, including smoking, oral contraceptive use, poor oral hygiene, traumatic extraction, pre-existing infection, and operator experience (Bowe et al., 2011; Kolokythas et al., 2010).

Given the significant discomfort and patient dissatisfaction associated with dry socket, numerous preventive strategies have been proposed. These include systemic antibiotics, local antimicrobial agents, antiseptic mouth rinses, atraumatic surgical techniques, and intra-alveolar medicaments (Kolokythas et al., 2010). However, systemic antibiotic prophylaxis remains controversial due to concerns regarding antibiotic resistance and unnecessary drug exposure (Lodi et al., 2012). Consequently, attention has shifted toward local preventive measures with minimal systemic effects.

Chlorhexidine has emerged as one of the most widely studied agents for the prevention of dry socket. Chlorhexidine is a broad-spectrum antiseptic effective against Gram-positive and Gram-negative bacteria, as well as certain fungi (Jones, 1997). Its substantivity—ability to bind to oral tissues and release gradually—makes it particularly useful in oral surgical settings. Multiple randomized controlled trials and systematic reviews have demonstrated that chlorhexidine mouthwash or gel significantly reduces the incidence of alveolar osteitis following third molar extraction (Caso et al., 2005; Torres-Lagares et al., 2006). A meta-analysis by Kolokythas et al. (2010) concluded that chlorhexidine application, particularly in gel form, is effective in reducing dry socket risk without major adverse effects.

Metronidazole, on the other hand, is an antimicrobial agent primarily active against anaerobic bacteria, which are implicated in the fibrinolytic process associated with dry socket (Noroozi & Philbert, 2009). Because anaerobic microorganisms play a significant role in postoperative infections and clot breakdown, topical metronidazole has been investigated as a preventive measure. Some clinical studies have suggested that local metronidazole application may reduce postoperative infection and inflammation; however, evidence specifically comparing its effectiveness to chlorhexidine in preventing dry socket remains limited (Bowe et al., 2011; Vezeau, 2000).

Although both chlorhexidine and metronidazole target microbial factors involved in alveolar osteitis, their mechanisms differ. Chlorhexidine acts as a broad-spectrum antiseptic with sustained release, whereas metronidazole selectively targets obligate anaerobic bacteria. Given these differences, a direct comparison in a randomized controlled clinical trial is clinically relevant to determine the more effective preventive strategy.

Therefore, the present study aims to compare the effectiveness of intra-alveolar metronidazole gel and chlorhexidine gel in preventing dry socket following impacted mandibular third molar surgery. By evaluating incidence rates, postoperative pain, and complication profiles, this trial seeks to provide evidence-based guidance for clinicians in selecting an optimal preventive approach.

LITERATURE REVIEW             

Alveolar osteitis (AO), commonly known as dry socket, remains a significant postoperative complication following third molar surgery despite advancements in surgical technique and infection control. Since Blum (2002) standardized the diagnostic criteria for alveolar osteitis, numerous studies have investigated preventive strategies aimed at reducing its incidence. The multifactorial etiology of dry socket, involving bacterial colonization, fibrinolysis, and inflammatory mediators, has guided research toward antimicrobial and antiseptic interventions (Noroozi & Philbert, 2009; Kolokythas et al., 2010).

Epidemiology and Pathophysiology

Dry socket incidence varies depending on surgical complexity and patient-related risk factors. Routine extractions typically report an incidence of 1–5%, whereas surgical removal of impacted mandibular third molars may increase incidence to 20–30% (Bowe et al., 2011; Vezeau, 2000). Identified risk factors include traumatic extraction; smoking, oral contraceptive use, pre-existing pericoronitis, and prolonged operative time (Kolokythas et al., 2010).

The pathophysiology is widely attributed to enhanced fibrinolytic activity within the extraction socket. Bacterial endotoxins and tissue trauma stimulate plasminogen activation, leading to breakdown of the blood clot and exposure of underlying bone (Blum, 2002). Anaerobic microorganisms are believed to play a significant role in this process, as they release fibrinolytic enzymes contributing to clot dissolution (Noroozi & Philbert, 2009). This microbial involvement provides the rationale for antimicrobial-based preventive measures.

Chlorhexidine in Prevention of Dry Socket

Chlorhexidine gluconate is a bisbiguanide antiseptic with broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria. Its substantively allows prolonged antimicrobial action within the oral cavity (Jones, 1997). Chlorhexidine has been extensively studied for dry socket prevention in both mouthwash and gel forms.

Caso et al. (2005) conducted a randomized controlled trial evaluating 0.12% chlorhexidine mouth rinse following mandibular third molar extraction and found a statistically significant reduction in alveolar osteitis incidence compared to placebo. Similarly, Torres-Lagares et al. (2006) demonstrated that 0.2% chlorhexidine gel applied intra-alveolarly significantly reduced dry socket occurrence.

A systematic review and meta-analysis by Kolokythas et al. (2010) analyzed randomized controlled trials involving chlorhexidine and concluded that chlorhexidine gel was more effective than mouthwash in reducing dry socket risk. The authors reported relative risk reductions ranging from 30% to 50% depending on formulation and patient risk profile.

Further supporting evidence was provided by Lodi et al. (2012), who emphasized that local antiseptic application, particularly chlorhexidine, offers a safer alternative to systemic antibiotic prophylaxis. Additionally, systematic reviews have consistently reported minimal adverse effects associated with chlorhexidine gel use, primarily limited to temporary taste alteration or mild mucosal irritation (Kolokythas et al., 2010).

The strength of evidence supporting chlorhexidine in preventing alveolar osteitis has led many clinicians to adopt it as a routine preventive measure in high-risk third molar surgeries.

Metronidazole in Prevention of Dry Socket

Metronidazole is a nitro imidazole antibiotic effective primarily against obligate anaerobic bacteria. Because anaerobic bacteria are implicated in the fibrinolytic mechanism of dry socket, metronidazole has been investigated as both systemic and local therapy.

Systemic metronidazole has demonstrated some effectiveness in reducing postoperative infection; however, its routine use remains controversial due to concerns regarding antibiotic resistance and systemic side effects (Lodi et al., 2012). As a result, topical application has been explored as a localized preventive approach.

Bowe et al. (2011) evaluated the role of systemic and local antimicrobial strategies and reported limited but promising outcomes for local metronidazole in reducing postoperative complications. Vezeau (2000) suggested that local antibiotic placement within the socket may reduce bacterial colonization and subsequent fibrinolysis.

However, compared to chlorhexidine, the evidence supporting metronidazole gel specifically for dry socket prevention is less robust. Few randomized controlled trials have directly assessed topical metronidazole as a primary preventive agent for alveolar osteitis. Most available studies focus on postoperative infection control rather than specific dry socket outcomes (Noroozi & Philbert, 2009).

Moreover, chlorhexidine’s broad-spectrum action may provide an advantage over metronidazole’s selective anaerobic coverage, particularly given the polymicrobial environment of the oral cavity.

Comparative Evidence and Research Gap

Despite substantial evidence supporting chlorhexidine in preventing alveolar osteitis, direct randomized controlled comparisons between chlorhexidine gel and metronidazole gel are scarce. Most comparative studies evaluate chlorhexidine against placebo or systemic antibiotics rather than other local antimicrobial agents (Kolokythas et al., 2010).

The lack of head-to-head randomized clinical trials comparing metronidazole gel and chlorhexidine gel represents a notable gap in the literature. Given their different antimicrobial spectra and mechanisms of action, evaluating their comparative effectiveness in a controlled clinical setting is clinically relevant.

Chlorhexidine offers substantivity and broad-spectrum antiseptic activity, while metronidazole provides targeted anaerobic antimicrobial action. Determining which agent provides superior prevention of dry socket could inform evidence-based postoperative protocols and reduce unnecessary antibiotic exposure.

Therefore, a randomized controlled clinical trial directly comparing these two intra-alveolar agents following impacted mandibular third molar surgery is warranted to establish clear clinical recommendations.

Study Design and Setting

This study was designed as a prospective, parallel-group, randomized controlled clinical trial conducted at the Department of Oral and Maxillofacial Surgery, Bolan Medical Complex Hospital, Quetta, Pakistan, between January 2024 and October 2025.

The study protocol was reviewed and approved by the Institutional Review Board (IRB) of Bolan Medical Complex Hospital.

All procedures were conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants prior to enrollment.

The trial was registered prospectively in the hospital’s clinical research registry.

Sample Size Calculation

Sample size was calculated using the formula for comparison of two proportions, assuming:

• Expected dry socket incidence of 20% in metronidazole group
• Expected incidence of 8% in chlorhexidine group
• Alpha (α) = 0.05
• Power (1–β) = 80%

The minimum required sample size was calculated as 45 patients per group. To compensate for possible dropouts, 50 patients were enrolled in each group, making a total sample size of 100 patients.

Study Population

Patients presenting for surgical removal of impacted mandibular third molars were screened for eligibility.

Inclusion Criteria

1. Patients aged 18–40 years
2. Indicated for surgical extraction of impacted mandibular third molar
3. ASA I or II systemic health status
4. No preoperative acute infection
5. Willingness to return for follow-up visits

Exclusion Criteria

1. Systemic diseases affecting healing (e.g., diabetes mellitus, immunosuppression)
2. Current smokers
3. Oral contraceptive users
4. Pregnancy or lactation
5. Recent antibiotic use (within 2 weeks)
6. Known allergy to chlorhexidine or metronidazole

Randomization and Allocation Concealment

Participants were randomly assigned into two equal groups using a computer-generated randomization sequence. Allocation was concealed using opaque, sealed, sequentially numbered envelopes prepared by an independent staff member not involved in the clinical procedure.

Group A (Metronidazole Group)

Intra-alveolar application of metronidazole gel (0.8%)

Group B (Chlorhexidine Group)

Intra-alveolar application of chlorhexidine gel (0.2%)

Blinding

This study followed a single-blind design:

• Patients were blinded to the type of gel used.
• The outcome assessor evaluating dry socket and pain scores was blinded to group allocation.
• The operating surgeon was not blinded due to the nature of material application.

Surgical Procedure Standardization

To minimize variability:

• All surgeries were performed by the same experienced oral surgeon.
• Standard inferior alveolar nerve block anesthesia using 2% lidocaine with epinephrine (1:100,000) was administered.
• A standardized triangular mucoperiosteal flap was raised.
• Bone removal and tooth sectioning were performed using sterile surgical burs under copious irrigation.
• The socket was irrigated with sterile normal saline.

 Immediately after extraction:

• The allocated gel (metronidazole or chlorhexidine) was placed directly into the socket using sterile applicators.
• The socket was sutured using 3-0 silk sutures.

Postoperative Care

All patients received identical postoperative instructions:

• Analgesic: Ibuprofen 400 mg every 8 hours as needed
• No routine systemic antibiotics were prescribed
• Avoid vigorous rinsing for 24 hours
• Soft diet for 48 hours

Patients were instructed to report immediately if severe pain developed.

Outcome Measures

Primary Outcome

Incidence of alveolar osteitis (dry socket) within 7 days post-extraction.

Dry socket was diagnosed according to Blum’s (2002) criteria:

• Severe throbbing pain 1–3 days post extraction
• Partial or complete loss of blood clot
• Exposed bone with or without halitosis

 Secondary Outcomes

1. Postoperative pain severity measured using Visual Analog Scale (VAS 0–10)
2. Presence of infection
3. Swelling or delayed healing

Follow-Up Schedule

Patients were evaluated on:

• Postoperative Day 2
• Postoperative Day 4
• Postoperative Day 7

At each visit, pain score (VAS), clinical socket examination, and complications were recorded by a blinded assessor.

Statistical Analysis

Data analysis was performed using SPSS version 26.0 (IBM Corp., USA).

• Categorical variables (dry socket incidence) were analyzed using Chi-square test
• Continuous variables (VAS scores) were analyzed using Independent sample t-test
• Relative Risk (RR) and 95% Confidence Interval (CI) were calculated
• Statistical significance was set at p < 0.05

Study Population

A total of 112 patients were assessed for eligibility. Twelve patients did not meet inclusion criteria. One hundred patients were randomized equally into two groups:

• Group A (Metronidazole gel): 50 patients
• Group B (Chlorhexidine gel): 50 patients

Four patients were lost to follow-up (2 from each group). Therefore, 96 patients completed the study (48 per group) and were included in the final analysis.

Table 1. Baseline Demographic and Clinical Characteristics

Interpretation

There were no statistically significant differences between the two groups at baseline, indicating comparable demographic and surgical characteristics.

Table 2. Incidence of Dry Socket (Primary Outcome)

                                *Statistically significant (p < 0.05)

Relative Risk (RR): 2.98 95%

 Confidence Interval: 1.01 – 8.76

Interpretation

The chlorhexidine group demonstrated a significantly lower incidence of dry socket compared to the metronidazole group (p = 0.048). Patients receiving metronidazole were nearly three times more likely to develop dry socket.

Table 3. Postoperative Pain Scores (VAS 0–10)

                                            *Statistically significant

Interpretation

Pain scores were significantly lower in the chlorhexidine group on postoperative Day 2 and Day 4. By Day 7, pain levels between groups were comparable.

Table 4. Postoperative Complications

Interpretation

Both groups demonstrated low complication rates. No statistically significant difference in postoperative complications was observed.

Table 5. Overall Treatment Effectiveness

                         *Statistically significant

Interpretation

Chlorhexidine demonstrated significantly greater overall effectiveness in preventing dry socket and achieving faster pain reduction.

Overall Results Summary

In this randomized controlled clinical trial, intra-alveolar chlorhexidine gel significantly reduced the incidence of dry socket compared to metronidazole gel following impacted mandibular third molar surgery. Chlorhexidine also provided superior early postoperative pain control. Both agents were safe and well tolerated, with minimal complications. The findings indicate that chlorhexidine gel is more effective than metronidazole gel in preventing alveolar osteitis and improving postoperative recovery.

This randomized controlled clinical trial compared the effectiveness of intra-alveolar metronidazole gel and chlorhexidine gel in preventing alveolar osteitis (dry socket) following impacted mandibular third molar surgery. The findings demonstrate that chlorhexidine gel significantly reduced the incidence of dry socket compared with metronidazole gel. Additionally, chlorhexidine provided superior early postoperative pain control without increasing complication rates.

The overall incidence of dry socket in this study was 12.5%, which is consistent with previously reported rates for impacted mandibular third molar surgery (Bowe et al., 2011; Blum, 2002). However, when analyzed by group, the chlorhexidine group showed a significantly lower incidence (6.3%) compared to the metronidazole group (18.8%) (p = 0.048). These findings align with prior randomized trials and meta-analyses demonstrating the efficacy of chlorhexidine in reducing alveolar osteitis (Caso et al., 2005; Torres-Lagares et al., 2006; Kolokythas et al., 2010).

The superiority of chlorhexidine may be attributed to its broad-spectrum antimicrobial activity and substantivity. Chlorhexidine binds to oral tissues and releases gradually, maintaining antimicrobial action in the extraction socket during the critical early healing period (Jones, 1997). Since dry socket is closely associated with bacterial-mediated fibrinolysis of the clot, prolonged antiseptic activity likely plays a key role in prevention (Blum, 2002; Noroozi & Philbert, 2009).

In contrast, metronidazole primarily targets obligate anaerobic bacteria. While anaerobes are implicated in fibrinolysis and postoperative infection, the oral cavity harbors a polymicrobial environment. The selective antimicrobial spectrum of metronidazole may therefore limit its preventive effectiveness compared to chlorhexidine’s broader coverage. Previous investigations evaluating metronidazole for postoperative infection control have shown variable results, and few high-quality trials have demonstrated significant reduction in dry socket incidence specifically (Bowe et al., 2011; Vezeau, 2000). The present study adds evidence suggesting that topical metronidazole alone may not provide optimal protection against alveolar osteitis.

Pain evaluation further supports the effectiveness of chlorhexidine. Patients in the chlorhexidine group reported significantly lower VAS scores on postoperative Day 2 and Day 4(Torres-Lagares et al., 2006).

Importantly, both treatment modalities demonstrated favorable safety profiles. No allergic reactions or serious adverse events were observed. Postoperative swelling, infection, and delayed healing rates were low and comparable between groups. These findings are consistent with systematic reviews reporting minimal side effects associated with chlorhexidine gel use (Kolokythas et al., 2010; Lodi et al., 2012).

The strengths of this study include its randomized controlled design, allocation concealment, blinded outcome assessment, standardized surgical protocol, and adequate sample size calculation. However, certain limitations should be acknowledged.

The study was conducted at a single tertiary care center, which may limit generalizability. Additionally, longer follow-up beyond seven days would help assess late complications, although dry socket typically presents within the first 3–5 days post-extraction (Blum, 2002).

Future research could explore combination therapies, different concentrations of chlorhexidine, or adjunctive regenerative materials to further reduce postoperative complications. Multicenter randomized trials with larger sample sizes would strengthen the evidence base.

Overall, the present findings support the routine intra-alveolar application of chlorhexidine gel as a preventive strategy for dry socket in impacted mandibular third molar surgery.

Within the limitations of this randomized controlled clinical trial conducted at Bolan Medical Complex Hospital, Quetta, intra-alveolar application of chlorhexidine gel demonstrated superior effectiveness compared to metronidazole gel in preventing alveolar osteitis following impacted mandibular third molar surgery.

Chlorhexidine significantly reduced the incidence of dry socket and provided better early postoperative pain control without increasing postoperative complications. In contrast, while metronidazole gel showed some preventive benefit, its effectiveness was comparatively lower, likely due to its narrower antimicrobial spectrum.

Both interventions were safe, well tolerated, and easy to apply intra-operatively. However, given its broader antimicrobial coverage, substantivity, and stronger evidence base, chlorhexidine gel may be recommended as the preferred local preventive agent in routine and high-risk third molar surgeries.

Further multicenter randomized trials with larger sample sizes and extended follow-up periods are recommended to validate these findings and optimize preventive protocols for alveolar osteitis.

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