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Table of Contents   
Year : 2021  |  Volume : 24  |  Issue : 1  |  Page : 24-28
The additive effect of clonidine to lidocaine on postoperative pain management after root canal treatment on mandibular molars with symptomatic irreversible pulpitis: A prospective randomised double-blind clinical trial

1 Department of Preventive and Restorative Dental Science, School of Dentistry, University of California, San Francisco, CA, USA
2 Department of Periodontics and Dental Hygiene, School of Dentistry at Houston, University of Texas, Houston, TX, USA
3 Torabinejad Dental Research Center, Isfahan, Iran
4 Department of Dental Medicine, New York Medical College, Valhalla, NY, USA

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Date of Submission12-Oct-2020
Date of Decision25-Nov-2020
Date of Acceptance01-Dec-2020
Date of Web Publication05-Jul-2021


Context: Postoperative pain control has been a common challenge to clinicians in endodontics.
Aims: This double-blind randomized clinical trial assessed the efficacy of clonidine added to lidocaine for postoperative pain following endodontic treatment of mandibular molars with symptomatic irreversible pulpitis (SIP).
Methods: One hundred participants with lower molars experiencing SIP were recruited and randomly assigned to two groups. 1.8 mL of 2% lidocaine with either epinephrine (1:80,000) or clonidine (15 μg/mL) was administered to each group via an inferior alveolar nerve block. A Heft–Parker Visual Analog Scale was used to rate preoperative pain and at 6, 12, 24, 36, 48, and 72 h following endodontic treatment. Their postoperative analgesic consumption was recorded.
Statistical Analysis Used: The analgesic efficacy was analyzed by Chi-square test, paired t-test, and repeated measures ANOVA (P < 0.05).
Results: Early postoperative pain was significantly lower in the lidocaine/clonidine group than the lidocaine/epinephrine group (6 h: P = 0.038; 12 h: P = 0.031). The lidocaine/clonidine group consumed a significantly lower amount of analgesics (P = 0.048).
Conclusions: The administration of clonidine added to lidocaine may reduce early postoperative pain and consumption of analgesics following endodontic treatment in lower molars with SIP.

Keywords: Clonidine; inferior alveolar nerve; irreversible pulpitis; lidocaine; postoperative pain; root canal therapy

How to cite this article:
Shadmehr E, Sarmast ND, Davoudi A, Chung YJ, Wang HH. The additive effect of clonidine to lidocaine on postoperative pain management after root canal treatment on mandibular molars with symptomatic irreversible pulpitis: A prospective randomised double-blind clinical trial. J Conserv Dent 2021;24:24-8

How to cite this URL:
Shadmehr E, Sarmast ND, Davoudi A, Chung YJ, Wang HH. The additive effect of clonidine to lidocaine on postoperative pain management after root canal treatment on mandibular molars with symptomatic irreversible pulpitis: A prospective randomised double-blind clinical trial. J Conserv Dent [serial online] 2021 [cited 2023 Jun 7];24:24-8. Available from:

   Introduction Top

Clonidine has been proposed as an adjunct to lidocaine in dentistry. Studies have demonstrated that the combination of lidocaine and clonidine decreases postoperative pain and consumption of analgesics following third molar extractions[1],[2],[3],[4],[5] and improves the success of pulpal anesthesia via inferior alveolar nerve block (IANB) for symptomatic irreversible pulpitis (SIP) cases.[6] However, the effect of clonidine on postoperative endodontic pain is poorly understood. This prospective, randomized, and double-blind trial investigated the analgesic effectiveness of an IANB of lidocaine/clonidine admixture for postoperative pain management following endodontic treatment for mandibular molars with SIP.

   Methods Top

One hundred and ninety-eight patients were recruited in this study. The sample size of 50 per group was calculated based on previous postoperative pain studies.[1],[2],[3],[4],[5] All participants were 18 years of age or older and in American Society of Anesthesiologists classification 1.

All included patients were diagnosed with SIP and normal apical tissue for mandibular molars. An electric pulp test (Elements Diagnostic Unit; SybronEndo, Glendora, CA, USA) and a cold test (Roeko Endo-Frost; Roeko, Langenau, Germany) were performed to confirm SIP. Patients who presented prolonged exaggerated responses and moderate-to-severe pain to cold testing were included. Patients who did not respond to the cold test or those with periapical pathosis (except for a widened periodontal ligament) or partial necrosis were excluded from the study [Figure 1].
Figure 1: CONSORT flow diagram

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Patients with active signs of oral infections or inflammation, a history of beta-blocker use, analgesic or opioid consumption within 24 h, and contraindications to clonidine, epinephrine, or ibuprofen were excluded. Pregnant and breastfeeding patients were excluded. Informed consent was signed by all participants based on the Declaration of Helsinki. The protocol was approved by the Ethical Committee of Isfahan University of Medical Sciences (ID No. 142287) and registered in International Standard Randomised Controlled Trial Number (ISRCTN) (ID No. ISRCTN70419178). It followed the CONSORT checklist.

One milliliter of clonidine (Catapressan amp., Boehringer-Ingelheim, Germany) was added to 9 mL of 2% lidocaine plain (2% Lignodic, Caspian Tamin, Rasht, Iran), which made the clonidine concentration 15 μg/mL. The solution was inserted into a unloaded carpule (Darupakhsh, Tehran, Iran) using a 30G insulin syringe (Henke-Sass, Wolf, Tuttlingen, Germany) through the rubber diaphragm of the dental cartridge. The total concentrations of lidocaine and clonidine in one cartridge were 34.2 μg and 27 μg, respectively. All preparations were performed under sterile conditions by a pharmacologist who was not involved in the study. All carpules looked identical in order to blind the clinician and the patient.

Anesthetic carpules were randomly assigned a five-digit number by a blinded research assistant. Patients were instructed to pick one of the separately sealed envelopes with individual numbers, which were then transferred to a data collection document without revealing the identification of administered anesthetics. The list of the five-digit number was not accessible to any clinicians performing evaluation or treatment.

Patients were randomly assigned to two groups based on the anesthetic solution administered. Each patient received an IANB of either:

  • Group 1 (lidocaine/epinephrine): 1.8 mL of 2% lidocaine with 1:80,000 epinephrine (Persicaine, Darupakhsh, Tehran, Iran)
  • Group 2 (lidocaine/clonidine): 1.8 mL of 2% lidocaine with 15 μg/mL clonidine.

All blocks were administered by a single endodontist. Before injection, preoperative pain was rated on a Heft–Parker Visual Analog Scale (VAS). A topical anesthetic (20% benzocaine, Denti-Care, Medicom, Canada) was placed for 1 min. A standard IANB using either solution was administered using a 27G needle (Monoject; Sherwood Services, Mansfield, MA, USA). A long buccal supplemental infiltration was given using 0.4 mL of 2% lidocaine with 1:80,000 epinephrine. Lip numbness was assessed after 15 min. After rubber dam isolation, endodontic treatment was initiated. Following access preparation, chemo-mechanical preparation was performed using ProTaper Universal (Dentsply Maillefer, Ballaigues, Switzerland) and 5.25% sodium hypochlorite. Canals were obturated using the cold lateral compaction technique. Treatments were performed and data were collected at the Endodontic Department of Isfahan University of Medical Sciences. All root canal treatments were completed in a single visit by either an endodontist or a postgraduate resident. Patients who did not report lip numbness within 15 min and needed another block administration, and those that showed radiographic evidence of overfill or were treated in multiple visits were excluded.

Following treatment, the participants recorded their pain intensity on a Heft‒Parker VAS at 6, 12, 24, 36, 48, and 72 h. The VAS scale was grouped into four classifications:

  • No pain: 0 mm
  • Mild pain: >0 mm and ≤54 mm
  • Moderate pain: >54 mm and ≤114 mm
  • Severe pain: >114 mm.

In case of postoperative pain, participants were directed to take 400 mg ibuprofen every 6 h and to document the amount consumed. The data were collected and analyzed using Chi-square test, paired t-test, and repeated measures ANOVA. All statistical analyses used SPSS 20 (IBM Corp., Armonk, NY, USA) at a significance level of 0.05.

   Results Top

One hundred and eight patients were initially included. Eight patients were further excluded due to inability to achieve numbness, overfilling, or missing VAS forms [Figure 1]. One hundred patients (42 males and 58 females) with 50 patients in each group were included in the final analysis. The two groups did not differ significantly in gender, age, tooth type, or preoperative mean intensity of pain (P > 0.05) [Table 1]. No correlations were found between pain and gender, age, or tooth type at any time interval. The lidocaine/clonidine group experienced significantly less pain at 6 and 12 h following treatment (P = 0.038 and 0.031, respectively). The mean intensity of pain was lower in the lidocaine/clonidine at all the other time intervals, with no statistically significance (P > 0.05) [Figure 2]. The lidocaine/clonidine group consumed a significantly less amount of ibuprofen postoperatively (59 tablets) than the other group (111 tablets) (P = 0.048) [Figure 3].
Figure 2: Pain levels at different time intervals

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Figure 3: The number of analgesic tablets consumed in two groups

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Table 1: Age, gender, tooth type, and initial pain level distributions between lidocaine/clonidine and lidocaine/epinephrine groups

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   Discussion Top

Our study highlights the role of clonidine added to lidocaine in reducing postoperative pain following single-visit endodontic treatment. It was prospective, randomized, and double-blind trial, which provides the highest level of evidence in clinical research. There was no difference between the two groups regarding patients' age, sex, tooth, and preoperative pain, which allowed standardization and proper evaluation of the efficacy of both solutions in controlling postoperative pain and analgesic consumption. This study only included those with moderate-to-severe preoperative pain. Torabinejad et al.[7] showed a correlation between pre- and postoperative pain after endodontic treatment in incidence and severity. Since all individuals included in our study reported preoperative pain, it can be assumed that they were more likely to develop postoperative pain. Therefore, the patient population in this study appears to be ideal to assess postoperative pain management.[8] Patients with overfillings or multiple visits were excluded. These factors have been associated with postoperative symptoms[9] and may affect the outcome. Patients were instructed to take ibuprofen in case of pain, similar to previous reports.[3],[8] Although the use of analgesics may have impacted our results, the ethical practice mandates prescribing analgesics for patients in pain.

Lidocaine with epinephrine is the most common anesthetic solution used in practice. However, it fails to provide adequate analgesia to control postoperative pain. In order to enhance the analgesic efficacy of lidocaine, previous studies have attempted to search for an additive to lidocaine.[10],[11],[12] In various fields of dentistry including pediatric dentistry,[13] oral surgery,[1],[2],[3],[4] and endodontics,[6] clonidine has been proposed as a great additive to local anesthetic agents.

Clonidine has analgesic effects by hyperpolarizing cation channels and suppressing action potentials.[14] It induces peripheral vasoconstriction by activation of postsynaptic alpha-2 adrenoceptors.[15] This results in slowing down vascular uptake of the local anesthetic agent, which increases duration and depth of anesthesia.[16] Postoperative pain is reported to be more prevalent in apprehensive patients.[17] Clonidine has sedative effects which can decrease patient's anxiety and apprehension.[18] It is plausible to assume that the anti-anxiety effect of clonidine may also play a role in decreasing postoperative pain. Clonidine may produce some systemic side effects.[19],[20] However, these side effects are directly correlated to its concentrations. Brkovic et al.[2] demonstrated that 15 μg/mL of clonidine was an effective and safe concentration to be used for intraoral block anesthesia. In other subsequent studies that used clonidine for intraoral block anesthesia, 15 μg/mL of clonidine was used without any reported side effects.[1],[3],[4],[5] Therefore, 15 μg/mL was chosen as the clonidine concentration in the present study. None of the participants experienced side effects. Our study further corroborates the previous studies that 15 μg/mL is a safe concentration of clonidine.[1],[2],[3],[4],[5]

Pain scores have emerged as reliable measures of assessing pain and response to treatment. The Heft–Parker VAS is commonly used in pain studies to determine pain levels.[21],[22],[23],[24] Our study showed that the overall mean of preoperative pain was 104 mm, which correlates to moderate pain. These values are consistent with other reports assessing pain in patients with SIP.[21],[22] The level of postoperative pain was assessed for the first 72 h. The same timeline has been previously used and appears to be sufficient to determine the efficacy of anesthetic solutions in postoperative pain.[8] Most patients in our study experienced the greatest postoperative pain in the early postoperative time intervals. After these early stages, the frequency of moderate and severe pain decreased, as mild and no pain increased. At the first 6 h, 62% of the patients reported mild-to-severe pain. This number dropped to 33% after 48 h. At 72 h, 79% of the patients were asymptomatic. These findings are consistent with previous reports that the incidence of postoperative pain can be up to 40% within the first 48 h and drops over time.[8],[25] The postoperative pain experienced by the lidocaine/clonidine group was significantly less compared to the control group at 6 and 12 h after treatment. At 6 h posttreatment, the frequency of moderate or severe pain was almost three times greater in the lidocaine/epinephrine group (34%) than the lidocaine/clonidine group (12%) (P < 0.05). The lidocaine/clonidine group also consumed significantly fewer analgesics than the lidocaine/epinephrine group (P < 0.05) (59 and 111 tablets, respectively). The number of patients who took no analgesics was higher in the lidocaine/clonidine group than the lidocaine/epinephrine group (30 patients and 17 patients, respectively). These findings demonstrate that clonidine may be effective in managing postoperative pain after endodontic treatment.

Consistent with our study, Brkovic et al.[2] investigated the postoperative analgesic efficacy of clonidine for mandibular third molar extraction and found that 85% of the lidocaine/epinephrine group reported postoperative pain compared to 50% patients in the lidocaine/clonidine group. The lidocaine/clonidine group needed a significantly lower number of postoperative analgesics as well. Patil and Patil[5] reported that postoperative pain after maxillary molar surgery was significantly lower in patients treated with lidocaine/clonidine (36%) than the lidocaine/epinephrine group (76%). The number of analgesics taken in the 24-h postoperative period was significantly lower in the lidocaine/clonidine group. Chowdhury et al.[3] reported that postoperative analgesic efficacy of lidocaine/clonidine after third molar extraction was higher than lidocaine/epinephrine. A significantly lower number of analgesics were taken in the lidocaine/clonidine group.

Our study reported contradictory results to some previous studies. Brkovic et al.[1] evaluated the pain control ability of clonidine versus epinephrine as an adjunct to lidocaine for maxillary third molar surgery and found no difference in postoperative pain and the amount of analgesic consumption between the lidocaine/clonidine group and the lidocaine/epinephrine group. Jimson et al.[4] showed that although both admixtures of clonidine and epinephrine to lidocaine provided significantly longer postoperative analgesia, they reported no statistically significant difference between lidocaine/clonidine and lidocaine/epinephrine. The difference in results from our study may stem from different sample sizes, pharmaceutical agents, and the kind of treatment procedures. In general, extraction is a more traumatic procedure than an endodontic procedure. Patients who were enrolled in the extraction studies may have experienced more postoperative complications and, as a result, exhibited more postoperative pain and analgesic needs than those who participated in our study.

   Conclusions Top

Clonidine at 15 μg/mL may be safely used as an additive to lidocaine to manage postoperative pain and reduce analgesics following endodontic treatment on mandibular molars in patients with SIP. The application of clonidine in endodontic pain management should be further investigated in future research studies.


We sincerely thank Dr. Adham A. Azim for his contributions.

Financial support and sponsorship

This study was financially supported by Torabinejad Research Center.

Conflicts of interest

There are no conflicts of interest.

   References Top

Brkovic B, Gardasevic M, Roganovic J, Jovic N, Todorovic L, Stojic D. Lidocaine+clonidine for maxillary infiltration anaesthesia: Parameters of anaesthesia and vascular effects. Int J Oral Maxillofac Surg 2008;37:149-55.  Back to cited text no. 1
Brkovic B, Todorovic L, Stojic D. Comparison of clonidine and epinephrine in lidocaine anaesthesia for lower third molar surgery. Int J Oral Maxillofac Surg 2005;34:401-6.  Back to cited text no. 2
Chowdhury S, Singh M, Shah A. Efficacy of lignocaine with clonidine and adrenaline in minor oral surgical procedure. Contemp Clin Dent 2012;3:227-9.  Back to cited text no. 3
[PUBMED]  [Full text]  
Jimson S, Ranjani SS, Lenka S, Jimson S. Comparative effects of clonidine and adrenaline with lignocaine during maxillary infiltration anaesthesia for dental extraction. J Clin Diagn Res 2015;9:ZC85-8.  Back to cited text no. 4
Patil PM, Patil SP. Is clonidine an adequate alternative to epinephrine as a vasoconstrictor in patients with hypertension? J Oral Maxillofac Surg 2012;70:257-62.  Back to cited text no. 5
Shadmehr E, Aminozarbian MG, Akhavan A, Mahdavian P, Davoudi A. Anaesthetic efficacy of lidocaine/clonidine for inferior alveolar nerve block in patients with irreversible pulpitis. Int Endod J 2017;50:531-9.  Back to cited text no. 6
Torabinejad M, Cymerman JJ, Frankson M, Lemon RR, Maggio JD, Schilder H. Effectiveness of various medications on postoperative pain following complete instrumentation. J Endod 1994;20:345-54.  Back to cited text no. 7
Parirokh M, Yosefi MH, Nakhaee N, Manochehrifar H, Abbott PV, Reza Forghani F. Effect of bupivacaine on postoperative pain for inferior alveolar nerve block anesthesia after single-visit root canal treatment in teeth with irreversible pulpitis. J Endod 2012;38:1035-9.  Back to cited text no. 8
Contreras-Domínguez V, Carbonell-Bellolio P, Sanzana Salamanca E, Ojeda-Grecie A. Addition of sodium bicarbonate and/or clonidine to mepivacaine: Influence on axillary brachial plexus block characteristics. Rev Esp Anestesiol Reanim 2006;53:532-7.  Back to cited text no. 9
Haeseler G, Foadi N, Ahrens J, Dengler R, Hecker H, Leuwer M. Tramadol, fentanyl and sufentanil but not morphine block voltage-operated sodium channels. Pain 2006;126:234-44.  Back to cited text no. 10
Albrecht E, Kern C, Kirkham KR. A systematic review and meta-analysis of perineural dexamethasone for peripheral nerve blocks. Anaesthesia 2015;70:71-83.  Back to cited text no. 11
Singh V, Thepra M, Kirti S, Kumar P, Priya K. Dexmedetomidine as an additive to local anesthesia: A step to development in dentistry. J Oral Maxillofac Surg 2018;76:2091.e1-7.  Back to cited text no. 12
Mel'nikova AV, Shugaĭlov IA, Garus IaN. Efficiency of teeth local anesthesia by articaine-containing formulation with adrenaline and clonidine in pediatric dentistry. Stomatologiia (Mosk) 2014;93:43-6.  Back to cited text no. 13
Kroin JS, Buvanendran A, Beck DR, Topic JE, Watts DE, Tuman KJ. Clonidine prolongation of lidocaine analgesia after sciatic nerve block in rats is mediated via the hyperpolarization-activated cation current, not by alpha-adrenoreceptors. Anesthesiology 2004;101:488-94.  Back to cited text no. 14
Lee TS, Hou X. Dual effect of clonidine on isolated rabbit pulmonary arteries. Chest 1995;107:793-7.  Back to cited text no. 15
Mazoit JX, Benhamou D, Veillette Y, Samii K. Clonidine and or adrenaline decrease lignocaine plasma peak concentration after epidural injection. Br J Clin Pharmacol 1996;42:242-5.  Back to cited text no. 16
Stanley W, Drum M, Nusstein J, Reader A, Beck M. Effect of nitrous oxide on the efficacy of the inferior alveolar nerve block in patients with symptomatic irreversible pulpitis. J Endod 2012;38:565-9.  Back to cited text no. 17
Ise T, Yamashiro M, Furuya H. Clonidine as a drug for intravenous conscious sedation. Odontology 2002;90:57-63.  Back to cited text no. 18
Kaur P, Kundra TS, Sood D. Comparative efficacy of clonidine versus magnesium sulfate as an adjunct to lignocaine in intravenous regional anesthesia for postoperative analgesia: A prospective, randomized, double-blind study. J Anaesthesiol Clin Pharmacol 2017;33:387-90.  Back to cited text no. 19
[PUBMED]  [Full text]  
Sivaramakrishnan G, Sridharan K. Effect of clonidine on the efficacy of lignocaine local anesthesia in dentistry: A systematic review and meta-analysis of randomized, controlled trials. J Investig Clin Dent 2018;9:e12296.  Back to cited text no. 20
Oleson M, Drum M, Reader A, Nusstein J, Beck M. Effect of preoperative ibuprofen on the success of the inferior alveolar nerve block in patients with irreversible pulpitis. J Endod 2010;36:379-82.  Back to cited text no. 21
Simpson M, Drum M, Nusstein J, Reader A, Beck M. Effect of combination of preoperative ibuprofen/acetaminophen on the success of the inferior alveolar nerve block in patients with symptomatic irreversible pulpitis. J Endod 2011;37:593-7.  Back to cited text no. 22
Shetkar P, Jadhav GR, Mittal P, Surapaneni S, Kalra D, Sakri M, et al. Comparative evaluation of effect of preoperative alprazolam and diclofenac potassium on the success of inferior alveolar, Vazirani-Akinosi, and Gow-Gates techniques for teeth with irreversible pulpitis: Randomized controlled trial. J Conserv Dent 2016;19:390-5.  Back to cited text no. 23
[PUBMED]  [Full text]  
Singh S, Garg A. Incidence of post-operative pain after single visit and multiple visit root canal treatment: A randomized controlled trial. J Conserv Dent 2012;15:323-7.  Back to cited text no. 24
[PUBMED]  [Full text]  
Ng YL, Glennon JP, Setchell DJ, Gulabivala K. Prevalence of and factors affecting post-obturation pain in patients undergoing root canal treatment. Int Endod J 2004;37:381-91.  Back to cited text no. 25

Correspondence Address:
Dr. Elham Shadmehr
707 Parnassus Avenue, D3214, San Francisco, CA 94143-0758
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCD.JCD_523_20

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