Among the various analgesics used in the dental practice, 2% lidocaine + clonidine and 0.5% bupivacaine + adrenaline showed superior effectiveness for pain management following lower third molars removal surgeries. 

The exodontia of the third molar is one of the commonly performed surgical procedure in dental practice and is also considered as an integral model to study pain. This procedure can be associated with significant levels of postoperative pain due to its consequent surgical complexity and three-dimensional display in the jawbone. The intensity of pain increases significantly 5 to 6 h after surgery, disrupting the quality of life and reducing treatment adherence. These pain levels are also sensitive to various factors including patient age, tooth position, surgeon ability, therapeutic scheme, and postoperative care.  Besides these factors, the most integral factor which evaluates the sensation of intraoperative pain is the anaesthetic product used.

In this sense, pain management is crucial following exodontia of the third molar. Local anaesthetics are widely used drugs for pain control in dental practice, known to exert short, medium, and long-term actions. These drugs either administered pre or postoperatively, blocks the nerve conduction in a certain body region reversibly. Lidocaine hydrochloride is commonly used local anaesthetics of the amide class which has been utilised for over 60 years in dental procedures. Recently, articaine hydrochloride has been researched and utilised extensively compared to lidocaine due to higher anaesthetic duration, lower latency and superior diffusion of bone tissue. Another long term anaesthetic which is researched extensively is bupivacaine hydrochloride known for its higher anaesthetic ability,  adherence to plasma proteins and prolonged action due to the high liposolubility.

Rationale behind research

A large number of local anaesthetics has been employed for pain management in dental practices but the existing literature is lacking in providing comparative data for various anaesthetics. Therefore, this systematic review and meta-analysis was conducted to compare various analgesics used for pain management after lower third molar extraction surgeries.

Objective

This study aimed to compare and provide the most effective local anaesthetic agent for better pain management after lower third molar removal surgeries.  

Literature search

Clinical databases including Scopus, PubMed, Cochrane Library, Web of Science, LILACS, Embase, and SciELO were searched to identify relevant articles. Grey literature was captured using OpenThesis and OpenGrey and also used to reduce publication and selection bias. The search descriptors were selected using Emtree (Embase Subject Headings), DeCS (Health Sciences Descriptors), and MeSH (Medical Subject Headings) resources. The search strategy was also enhanced using boolean operators AND” and “OR”.

Inclusion criteria

The studies were included if:

• it enrolled healthy (ASA I) participants (18-59 years old), who had undergone exudation of partially or completely impacted third molars
• it included any anaesthetic solution associated with vasoconstrictors or not
• it had a randomized controlled design which evaluated postoperative pain, without any language restrictions or restrictions related to publication year

Exclusion criteria

Studies were excluded if it includes:

• Patients who smoke
• Patients subjected to head and neck radiotherapy
• Patients under controlled use of bisphosphonates

Study selection and Data extraction

The study selection was performed in four steps by two reviewers. These four steps consist of:

• Identification of studies after a search from databases, export of results to the EndNote Web software and discussion of eligibility criteria
• Systematic evaluation of titles by two reviewers 
• Reading of extracts and application of eligibility criteria
• Evaluation of the full texts of the preliminary eligible studies

Risk of Bias and Quality assessment

Risk of bias and individual quality of the studies was analyzed using an assessment tool from the Joanna Briggs Institute (JBI). Each domain related to the potential risk of bias was independently evaluated by two authors. The rate of positive answers to the questions in the assessment instrument was used for categorizing studies. If the study obtained 49% of "yes" answers, the risk of bias was high; if 50% to 69% of "yes" answers, the risk of bias was moderate and if it reached 70% of "yes" score, the risk of bias was low.

Data analysis

Following the selection of studies, data related to the identification of the study (author, year, and country), sample characteristics (number of patients, age, and sex), anaesthetic drug and anaesthetic technique used, type of scale used to assess pain, compliance to CONSORT, respect to the ethical criteria and the presence of a consent form, and specific results regarding the pain reported by patients immediately after the surgical procedure was collected.

A calibration exercise was performed to maintain the consistency between the reviewers. Discussions were held to resolve any disagreement between the reviewers and if both reviewers failed to settle the disagreement, a third reviewer was consulted to make a final decision. Study results were extracted using four variables: duration of the anaesthetic effect, the intensity of pain during and after the procedure, and painkiller consumption. According to each variable, the percentage of comparisons in which each anaesthetic was more effective was calculated. Similar calculations were performed for pain intensity during and after the procedure and painkiller consumption. The authors were contacted by e-mail if any relevant information was missing for data extraction. For 5 consecutive weeks,  a weekly email was sent to the authors.

Statistical analysis and certainty of the evidence

After the inclusion of relevant studies, a meta-analysis was performed to compare the efficacy of different anaesthetics for pain management following surgical procedure by using the standardized mean difference (SMD). Stata 16.1 software was used to perform statistical analyses. The certainty of the evidence of treatment effect estimates for network meta-analyses was rated using the GRADE approach. The certainty of the evidence was classified as high, moderate, low, and very low. 

The study outcomes included the comparison of pain score reported by each patient using different anaesthetics with the pain score of patients subjected to the use of 4% articaine + adrenaline (reference treatment)

Outcomes

Study characteristics: 

• A total of 16 studies were included in the quantitative analysis
• Out of these 16 studies, only 13 studies with 574 patients were included in the meta-analysis

Study quality: 

• The certainty of evidence varied between moderate and very low

Effect of intervention on the outcome:

• Two anaesthetic groups (2% lidocaine + clonidine and 0.5% bupivacaine + adrenaline) has significantly lower pain scores than the reference group
• Out of all the 8 anaesthetic groups,  2% lidocaine + clonidine showed a 51.2% probability of being considered the best anaesthetic, followed by 0.5% bupivacaine + adrenaline (44.0% probability), whereas 1% ropivacaine showed highest probability (94.3%) of being the worst anaesthetic among all
  

The present systematic review and network meta-analysis determine the most effective anaesthetic solution for pain management immediately after the surgeries for extubation of lower third molars. 

Among 8 different anesthetic solutions (Lidocaine 2% + adrenaline, Articaine 4% + adrenaline, Bupivacaine 0.5% + adrenaline, Lidocaine 2% + Clonidine, Lidocaine 4% + Adrenaline, Mepivacaine 2% + Adrenaline, Ropivacaine 1% and Ropivacaine 1% + Lidocaine 2%) enrolled,  2% lidocaine + clonidine showed superior efficacy for pain control in dental surgery.

The mapping of the results of the various studies found that levobupivacaine 0.5% and ropivacaine 0.75% were most effective in managing intraoperative and postoperative pain, respectively but satisfactory results in the duration of the analgesic effect. Both these solutions were considered as effective anaesthetic options, especially when the use of vasoconstrictors was contraindicated. These anaesthetic solutions were also more effective compared to short-term anaesthetics (2% lido + adrenaline and mepi 3% + adrenaline) but the efficacy of these solutions compared to long term anaesthetics such as bupivacaine was not estimated yet.

The findings of meta-analysis also reported that 1% of ropivacaine had the highest pain scores therefore least effective for pain management. Compared to bupivacaine, it has prolonged action, less lipophilic, the lower penetration rate in large myelinated motor fibers, thereby improved safety profile and less risk of cardiovascular and central nervous system adverse events.

As per the quantitative analysis of this study, 2% lidocaine + clonidine reported lower pain scores after the surgical procedure and the highest probability for being the best anaesthetic. A study conducted by Brkovic et al. indicated that groups using clonidine effectively reduced postoperative pain in 33% of patients in the group using clonidine compared to treated with epinephrine. The consumption of total analgesic dose was also significantly lower in patients treated with clonidine compared to those using epinephrine. Clonidine with central activation of presynaptic alpha-2 adrenoceptors and postsynaptic alpha-2 adrenoceptors produces peripheral vasoconstriction, promotes central analgesia and sedation.

Another anaesthetic solution found effective for pain management immediately after surgery was 0.5% bupivacaine + adrenaline. A study by Lee et al. assessed the analgesic quality of 0.5% bupivacaine, 2% lidocaine with epinephrine and 0.5% levobupivacaine following removal of third molars. The findings reported better analgesic effects between 4 and 48 h and a reduction in doses of postoperative analgesia with long-term anaesthetics compared to lidocaine. These benefits of levobupivacaine and bupivacaine may be attributed to the coefficient of protein link, which was 96% of bupivacaine and levobupivacaine compared to only 64% for lidocaine. This property allows molecules to bind to tissue proteins and provide greater anaesthetic molecules at the injection site, thereby increasing the duration of analgesia.

Based on the above results, 2% lidocaine + clonidine should be recommended for pain reduction after third molar extraction compared to 4% articaine but it should be used with caution due to low certainty of evidence. The main reason for lower certainty of evidence in this comparison was the risk of bias and imprecision. However, 0.5% bupivacaine when compared to 4% articaine resulted in favourable results in pain reduction with moderate certainty of evidence. The addition of these two factors supports the use of 0.5% bupivacaine to reduce postoperative pain in third molar surgeries with a  strong recommendation. There is a need to perform future studies with larger samples size to reduce imprecision of estimates. Also, there is a need to apply stricter methodologies related to randomization and blindness of participants and researchers.