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Analgesic and adjuvant anesthetic effect of submucosal tramadol after mandibular third molar surgery
Vol. 117 No. 3 March 2014
Analgesic and adjuvant anesthetic effect of submucosal tramadol after mandibular third molar surgery Marcelo Minharro Ceccheti, DDS, Ms, PhD,a Giovana Vigário Negrato, DDS,a Maria Paula Siqueira de Melo Peres, DDS, MS,b Maria Cristina Zindel Deboni, DDS, PhD,c and Maria da Graça Naclério-Homem, DDS, PhD,c University of Sao Paulo, São Paulo, Brazil Objective. The aim of this study was to assess analgesic and adjuvant anesthetic effects of submucosal tramadol after third molar extraction. Study Design. In this double-blind, split-mouth, placebo-controlled, single-dose, crossover investigation, 52 patients underwent mandibular third molar extraction under local anesthesia. Surgical side was randomly assigned to submucosal 2 mL 100 mg tramadol injection (group T) or normal saline solution (group P) immediately after surgery. Anesthetic blockade duration, time of intake and amount of analgesic rescue drug, and postoperative pain intensity were recorded immediately after anesthesia cessation and 4, 8, 24, 48, and 72 hours after surgery. Data were submitted to analysis of variance and Wilcoxon tests. Results. Anesthetic blockade duration between groups was similar. Group T took significantly less rescue drug after 72 hours (P ⫽ .008). Time elapsed before first intake of rescue drug was longer (P ⫽ .006), and pain intensity was significantly lower (P ⫽ .001) in group T. Conclusions. Submucosal tramadol injection after oral surgery improved postoperative analgesia, but did not extend anesthetic action duration. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:e249-e254)
Removal of an impacted mandibular third molar causes swelling, trismus, and moderate to severe pain.1 In dentistry, postoperative pain relief can be efficiently achieved with various analgesics, antiinflammatory drugs, or associations thereof. It is well known that better pain control after oral surgery may lead to improved recovery in terms of lifestyle and oral function.2 However, nonsteroidal antiinflammatory drugs are associated with numerous side effects and are contraindicated in a significant number of patients, such as those with a history of peptic ulcer disease or bleeding disorders, those taking anticoagulants or corticosteroids, and those with a history of allergy or intolerance to aspirin-like drugs.3 Tramadol may be an alternative for such patients, because it lacks sedative and respiratory depressant effects. Tramadol has been found to be a suitable analgesic for use in moderate pain after day-case oral surgery.4 Furthermore, in a study addressing extremely severe postoperative pain, both tramadol and morphine were An abstrat showing preliminary result was presented as a poster during the scientific meeting of the International Association for Dental Research, 2010, Barcelona, Spain. a Oral and Maxillofacial Surgery Department, General Clinics Hospital School of Medicine. b Dentistry Division, General Clinics Hospital, School of Medicine. c Oral and Maxillofacial Surgery Department, School of Dentistry. Received for publication Mar 11, 2012; returned for revision May 1, 2012; accepted for publication May 23, 2012. © 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2012.05.015
successful in providing relief. Despite the administration of higher doses than usual, there were fewer severe side effects with tramadol than with morphine.5 All of the analgesic effects of tramadol, whether administered by the oral or parenteral route, are explained by receptor-mediated mechanisms.6 Tramadol and its active metabolite, M1, exhibit weak and selective affinity for -opioid receptors, acting as central analgesics.6,7 Tramadol also exerts indirect action on monoaminergic receptors through norepinephrine and serotonin reuptake inhibition, blocking nociceptive inputs at the spinal cord.6-8 There are many descriptions of the effects of tramadol after systemic administration. However, the local analgesic effect of tramadol was first demonstrated only in 19988; ever since then, authors have tried to explain a possible mechanism of action.9-11 Moreover, a local anesthetic effect similar to that of prilocaine12 and lidocaine13 has been reported in the literature since it has been used as an adjunct to articaine in the removal of impacted mandibular third molars.14 Combination of tramadol and ibuprofen appears to produce supra-additive antiinflam-
Statement of Clinical Relevance The submucosal injection of tramadol is an easy and suitable method of using this analgesic in outpatients. It is considered to be an additional therapeutic option, fully available to dentists because it can be performed directly in the operative field.
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matory effects that may offer clinical advantages regarding safety or efficacy for treating postsurgical dental pain15; additionally, some studies have even suggested a limited antiinflammatory effect.16 Only a few oral surgery investigations support the assertion that tramadol exerts a local effect on peripheral nerves. Some authors have shown that tramadol can be used as an analgesic adjunctive drug and improves quality of perioperative anesthesia14 in third molar surgery. Recently submucous local tramadol was shown to increase the anesthetic efficacy of mepivacaine with epinephrine in inferior alveolar nerve blockade, although duration of soft tissue anesthesia did not lengthen.17 The present prospective placebo-controlled study was designed to determine the effect of tramadol administered locally by submucosal injection on the onset and duration of analgesia and the duration of the sensory block produced by mepivacaine immediately after impacted mandibular third molar removal.
MATERIALS AND METHODS The study was designed as a prospective, randomized, placebo-controlled, double-blinded, split-mouth crossover trial. All patients were informed of the experimental methodology and signed an institutionally approved consent form. The study was conducted in compliance with Declaration of Helsinki (1989), and was reviewed and approved by the Institutional Ethical Committee (protocol 95/08). The inclusion criteria considered healthy subjects of any sex, ⬎18 years of age, with symmetric bilateral bone-impacted mandibular third molars requiring surgical removal, and with no history of psychiatric illness or allergy to the drugs used in this study. Exclusion criteria included the use of analgesic or antiinflammatory drugs 24 hours before treatment, history of seizure disorders, pregnancy, or lactation. Fiftytwo patients were included in the research. Third molar position was classified according to Pell and Gregory (1933)18 as evaluated in a panoramic radiograph. The same surgeon performed both extractions on each patient, with a minimum interval of 1 week between them. Surgery was carried out under local anesthesia, using a maximum of 3 1.8-mL cartridges of 2% mepivacaine with 1:20,000 levonorfedrin as a local anesthetic. A mucoperiosteal flap was elevated distally to the second molar providing access to the third molar from the buccal aspect. Osteotomy was achieved under continuous sterile saline solution irrigation. When necessary, sectioning of crown and roots was performed with a fissure bur. After extraction, the alveolus was inspected, curetted, and irrigated with sterile saline solution. Primary closure was achieved
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with 4-0 silk suture. Difficulties of extraction procedures were regarded to be grade I when extraction was performed by forceps only, grade II when extraction included osteotomy, grade III when extraction included osteotomy and coronal sectioning, and grade IV when extraction included extensive osteotomy and crown and root sectioning. In all cases, the operating time and the duration of the local anesthesia effect were recorded. Patients were allocated into 2 treatment regimens according to a computer-generated randomization schedule prepared before the study: Group T received 2 mL 100 mg tramadol, injected into the buccal mucosa adjacent to the third molar alveolus immediately after extraction; and group P received 2 mL normal saline solution in the same manner. All of the patients were randomized to the T or P group for the first surgery and then received the protocol of the opposite group for the second surgery. Medications were administered by another surgeon in charge of randomization control, thus ensuring double blindness. Patients were given routine postoperative instructions and were asked to fill out a 3-part questionnaire: 1) evaluation of pain intensity with the use of a 100-mm visual analog scale (VAS) at 4, 8, 24, 48, and 72 hours after surgery, with 0 anchored by “no pain” and 100 anchored by “very intense pain”; 2) amount of analgesic consumption and time of intake; and 3) duration of anesthetic blockade, considering the moment of lip numbness cessation perception by the patient compared with the same sensation on the contralateral lip, as the time the anesthetic wore off. The following standardized postoperative medication was prescribed to prevent any postoperative infection from interfering with the pain assessment made by patients: 500 mg amoxicillin orally every 8 hours for 7 days or 500 mg erythromycin orally every 8 hours for 7 days for patients allergic to penicillin. A mouth rinse with 15 mL 0.2% chlorhexidine solution was used before surgery for 1 minute and at home, twice a day, for 1 week. A dose of 500 mg metamizole was prescribed as a rescue medication for mild and moderate postoperative pain. Patients were instructed to record the number of analgesic pills they took, if any, and the time at which they took them. Patients were also instructed to return to the clinic in case of intolerable pain. Analgesic efficacy was assessed based on 4 end points: pain intensity as recorded on VAS; mean time elapsed before first intake of the rescue medication; total dose of analgesic consumed during the first 72 hours after surgery; and overall evaluation of the pain experience. Furthermore, the potential adjuvant anesthetic effect of tramadol presumably added to mepivacaine for the mandibular blockade was evaluated in both groups by comparing the patients’ reports regarding the duration of the anesthetic perception as indi-
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Table I. Demographic data and surgical characteristics Measured variable
All samples
Sex (female/male) Age (y) Weight (kg) Duration of surgery (min) Mepivacaine anesthetic cartridges Adverse events Duration of sensory block (min)
36/16 22.10 ⫾ 3.84 (18-33) 60.27 ⫾ 8.71(47-86)
Group P
Group T
P value
35.73 ⫾ 19.40 (7–100) 2.21 ⫾ 0.42 (1.5-3) 2 199.13 ⫾ 65.48 (35-342)
34.35 ⫾ 18.49 (5-90) 2.34 ⫾ 0.47 (1.5-4*) 4 208.85 ⫾ 63.78 (90-340)
.47 (NS) .066 (NS) .32 (NS)
Values are mean ⫾ SD (range). P, placebo; T, tramadol; NS, not significant. *The third cartridge broke during insertion into the carpule syringe and was replaced by other anesthetic cartridge, but keeping the same amount of drug used throughout the sample.
cated by the moment of lip numbness cessation realized by patients. The time interval between the onsets of the anesthetic effect to the lip normal sensation was considered to be the duration of the sensory blockade. Adverse effects of tramadol, such as vomiting, nausea, dizziness, dry mouth, and sweating, were recorded when present. Patient demographic data was expressed as mean and range and submitted to analysis of variance. The Wilcoxon test was used for statistical analysis and comparison among groups for continuous variables. A P value of ⬍.05 was considered to be significant (2001 Statistic version 6; StatSoft, Tulsa, OK).
RESULTS Data from 52 patients were included in the study. As presented in Table I, demographic data and surgical characteristics were similar in both groups. There were no differences in the extent of sensory block, number of anesthetic cartridges used, or duration of surgery between the groups. Preoperative classification of dental impaction was based on panoramic radiography and was found to be similar in both groups. There were no significant differences in surgery extraction complexity between the groups. Adverse effects were mild and did not complicate the postoperative course or delay the patient’s return to normal activities. There were nausea and vomiting (1 in group P and 3 in group T) and slight surgical bleeding easily controlled by local pressure and postoperative guidelines (1 case in each group). Consumption of rescue analgesics was used to evaluate the analgesic effect of tramadol. Nine patients in
the tramadol group did not require rescue medication after either surgery during the study period, whereas only 1 in the placebo group required metamizole after both extractions. Patients in the tramadol group made less use of the rescue analgesic than those in the placebo group (P ⫽ .008 [Wilcoxon test]). The mean time until the first analgesic requirement in the tramadol group was significantly longer than in the placebo group (P ⫽ .006 [Wilcoxon test]; Table II). Pain intensity over the 72-hour observation period was assessed with a 100-mm VAS and was found to differ significantly between the 2 groups only when patients felt that anesthesia had worn off (P ⬍ .001). Later evaluations showed no differences in mean pain values between both groups (Figure 1). Patients’ overall assessment related to pain showed that more patients in the placebo group (75%) than in the tramadol group (23%) scored the postoperative period of the control contralateral molar extraction as being worse than the postoperative period of the tramadol-medicated molar extraction (2 test: P ⬍ .001). Only 1 patient reported equal distress after both surgeries. Comparison of VAS mean scores between groups and surgical difficulty scale records showed a significant difference only for grade III surgery (P ⬍ .001). Differences in VAS means observed for grade IV surgery were practically the same as those observed for grade III (1.23 and 1.14, respectively), with no significant difference (Figure 2). Mean postoperative pain scores after the first procedure were lower in patients who had received tramadol
Table II. Mean dose of analgesic rescue drug taken within 72 hours of surgery and time to first metamizole tablet required Group P No. of analgesic tablets consumed (500 mg each) Time to first dose of rescue analgesic (min)
4.4 ⫾ 3.71 (0-20) 185.4 ⫾ 59.4 (60-343)
Data expressed as mean ⫾ SD (range). *Statistically significant versus control (Wilcoxon test).
Group T 3.37 ⫾ 4.65 (0-25) 303.72 ⫾ 416.01 (60-2,880)
P value .008* .006*
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Fig. 1. Visual analog scale (VAS) of pain at different moments of the evaluation. Data are expressed as mean with standard deviation.
Fig. 2. Visual analog scale (VAS) scores of tramadol and saline solution groups according to surgical difficulty grade.
compared with placebo (P ⫽ .036). The order of administration of tramadol or placebo during the first or second surgery had an effect on experience of pain (carryover effect). The same result was not observed when tramadol and placebo effects were compared during the second operation (Table III).
DISCUSSION This study showed that 2 mL 100 mg tramadol injected locally into the submucosa after impacted third molar extraction was superior to placebo for adequate analgesic coverage for 208.85 ⫾ 63.78 minutes (⬃3.5 hours). Tramadol is a centrally acting synthetic analgesic composite that is structurally related to codeine and morphine. Parenteral and oral are the most common administration routes, and its effectiveness for managing of moderate to severe postoperative pain has been demonstrated in both in- and outpatients.19 Furthermore, tramadol has proved to be an effective analgesic after dentoalveolar surgery, and has been shown to be significantly superior to placebo.4
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In addition to tramadol’s established central action, it is suggested that the drug may be suitable for local administration by acting through a combination of known and unknown peripheral mechanisms of action.20 Some investigations demonstrated that local application of drugs, e.g., in tissue wound, can maximize its level at the site of action, minimizing systemic exposure. The superior analgesic effect for the peripheral route is most probably due to the achievement of a higher drug concentration at the site of wound without loss due to its body distribution or elimination.21 We observed that the more complex the surgical procedure, the more the local administration of tramadol in relieving postoperative pain after third molar extraction seemed to be effective. Surgical difficulty grade III showed lower VAS mean values than other grades, although grade IV difficulty tended slightly toward statistical significance (P ⫽ .06). This was observed probably because of a small sample size; only 6 subjects in group P and 8 in group T were grade IV. This result confirmed the relationship mentioned above between increased pain and increased difficulty, notably in the operations that required the raising of a mucoperiosteal flap.22 An important finding of this study was that patients in the locally administered tramadol group required less intake of analgesics, providing evidence of the analgesic effectiveness of this kind of intervention. Moreover, the mean time until intake of the first dose of the rescue medication was longer in the tramadol group than in the placebo group, which is consistent with earlier studies.4,23 Likewise, it was demonstrated that preemptive ketorolac plus submucosal tramadol resulted in the decrease of postoperative analgesics use.24 We think that a patient’s choice to take a rescue medication is a better indicator of pain than any numeric scale. This method provides more sensitive behavioral information during the period of recovery after third molar extraction. The present investigation provides evidence of the benefit of tramadol administered into the surgical site alone in dental surgical procedures, but the peripheral mechanism of action of this otherwise centrally acting analgesic drug remains unclear. A number of theories have arisen in an attempt to explain possible mechanisms of action. Some have suggested that tramadol is an atypical opioid that acts on voltage-dependent Na⫹ channels (as do local anesthetics) and adrenergic pathways (as do vasoconstrictors).25 Recent experiments claimed that nonspecific voltage-dependent K⫹ channels and the nitric oxide system influence the antinociceptive effect of tramadol.23 It is also thought that tramadol may possess weak antiinflammatory properties not involved with the arachidonic acid path-
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ORIGINAL ARTICLE Ceccheti et al. e253
Table III. Operating conditions when tramadol or placebo (saline) was administered during the first or second operation: VAS scores on a 0-10 cm scale reported by patients Surgical order First surgery Second surgery
Group
Mean
SD
Median
Min.
Max.
n
P value
Saline Tramadol Saline Tramadol
2.82 1.86 2.70 1.89
1.63 1.32 2.08 1.25
2.50 1.67 2.00 1.58
0.75 0.00 0.67 0.00
6.00 5.67 9.42 5.00
28 24 24 28
.036
way.15,16 It seems that tramadol has independent systemic and peripheral mechanisms of action, because it improves the quality of postoperative analgesia when both routes are used in combination.26 A synergistic effect between local and systemic mechanisms of action is also conjectured.20 Administration of tramadol during mandibular third molar extraction improved the quality of operating conditions during the first operation, delaying and decreasing the need for postoperative analgesics owing to the carryover effect. The same conclusion was proposed by Kanto et al.27 in a crossover study. When tramadol is used during the first surgery, patients have a positive pain experience, and less preoperative anxiety leads to a reduced need for analgesia. This was clearly observed when global pain assessment was analyzed and compared on a pain scale. The VAS showed analgesic action for only 3.5-4 hours following surgery. However, 75% of the sample reported a worse postoperative experience when placebo was used as local medication. The adverse effects that are generally reported include vomiting, nausea, dizziness, dry mouth, and profuse sweating.19 The submucosal route of administration could be advantageous over systemic analgesics or nonsteroidal antiinflammatory drugs because they entail reducing the risk of side effects.21 In the present research, no major adverse effects were observed in the tramadol group. Only gastrointestinal disturbances were seen, all of which occurred in the first 2 hours after surgery. This observation is in agreement with other study outcomes which described only minor sideeffects.3,4,27 As with other authors,28 dizziness was not reported at any time by the patients in the present study. Furthermore, every tooth alveolus repaired uneventfully. It is important to note that there was no local reaction, such as inflammatory process exacerbations, delayed healing, or necrosis, even though tramadol was submucosally injected. Recently it was shown that submucous tramadol can augment the anesthetic efficiency of mepivacaine with epinephrine in the inferior alveolar nerve blockage.17 Conversely, no adjuvant anesthetic action was seen in this study. The injection of 100 mg tramadol immediately after dental extractions did not increase the duration of sensory blockage of 2% mepivacaine with levonorfedrin. Similar results were described with tra-
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madol and 7.5 mg/mL ropivacaine for brachial plexus block and were related to the choice of a long-acting local anesthetic.29 The possible explanation for the lack of effect of tramadol in lengthening the postoperative anesthetic period could be based on the methods employed in this study. Probably, because tramadol was administered after completion of the procedure, the anesthetic effect of mepivacaine was at its peak, with all peripheral nerve ion channels occupied by the anesthetic salt. If the local mechanism of action of tramadol involves binding to sensory nerves, as suspected,18,19 this would possibly have prevented its action. Our results could provide an indirect argument in favor of this hypothesis. In conclusion, the present study suggests that local administration of 100 mg tramadol contributes to provide a pain-free period of 3.5-4 hours after mandibular third molar extraction, with rare adverse effects and good patient acceptance. Moreover, there was a relationship between more complicated interventions and pain relief after local administration of tramadol. Nevertheless no beneficial effect of tramadol in lengthening the sensory blockade produced with mepivacaine was observed. Additional studies comparing the effects of tramadol with those of other local anesthetics or systemic analgesic drugs are desirable. Molecular investigations could be conducted to verify if tramadol acts either directly or indirectly modifying the action of local anesthetic. The authors thank Aparecida Conceição de Souza for technical assistance. REFERENCES 1. Grossi GB, Maiorana C, Garramone RA, Borgonovo A, Creminelli L, Santoro F. Assessing postoperative discomfort after third molar surgery: a prospective study. J Oral Maxillofac Surg 2007;65:901-4. 2. Snyder M, Shugars DA, White RP Jr, Phillips C. Pain medication as an indicator of interference with lifestyle and oral function during recovery after third molar surgery. J Oral Maxillofac Surg 2005;63:1130-7. 3. Broome IJ, Robb HM, Raj N, Girgis Y, Wardall GJ. The use of tramadol following day-case oral surgery. J Anesth 1999;54: 266-96. 4. Collins M, Young I, Sweeney P, Fenn GC, Stratford ME, Wilson A, Harris M. The effect of tramadol on dento-alveolar surgical pain. Br J Oral Maxillofac Surg 1997;35:54-8. 5. Wiebalck A, Tryba M, Hoell T, Strumpf M, Kulka P, Zenz M.
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Efficacy and safety of tramadol and morphine in patients with extremely severe postoperative pain. Acute Pain 2000;3:22-8. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004;43:879-923. Raffa RB, Friderichs E. The basic science aspect of tramadol hydrochloride. Pain Rev 1996;3:249-71. Pang WW, Mok MS, Chang DP, Huang MH. Local anesthetic effect of tramadol, metoclopramide, and lidocaine following intradermal injection. Reg Anesth Pain Med 1998;23:580-3. Pang WW, Huang PY, Chang DP, Huang MH. The peripheral analgesic effect of tramadol in reducing propofol injection pain: a comparison with lidocaine. Reg Anesth Pain Med 1999;24: 246-9. Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL, et al. Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol. J Pharmacol Exp Ther 1993;267:331-40. Tsai YC, Chang PJ, Jou IM. Direct tramadol application on sciatic nerve inhibits spinal somatosensory evoked potentials in rats. Anesth Analg 2001;92:1547-51. Altunkaya H, Ozer Y, Kargi E, Babuccu O. Comparison of local anaesthetic effects of tramadol with Prilocaine for minor surgical procedures. Br J Anaesth 2003;90:320-2. Soltanimohammadi S, Seyedi M. Comparison of postoperative analgesic effect of tramadol with lidocaine when used as subcutaneous local anesthetic. Int J Pharmacol 2007;3:207-9. Pozos AJ, Martinez R, Aguirre P, Perez J. The effects of tramadol added to articaine on anesthesia duration. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102:614-7. El-Sharrawy EA, Hakim IE, Sameeh E. Attenuation of C-reactive protein increases after exodontia by tramadol and ibuprofen. Anesth Prog 2006;53:78-82. Sousa AM, Franco PAB, Ashmawi HA, Posso IP. Local effect of tramadol on formalin evoked flinching behaviour in rats. Rev Bras Anestesiol 2008;58:371-9. Isiodia-Espinoza MA, Orosco-Solis M, Tobías-Azúa FJ, M’nedez-Gutiérrez EP. Submucous tramadol increases the anesthetic efficacy of mepivacaine with epinephrine in the inferior alveolar nerve block. Br J Oral Maxillofac Surg 2012;50:157-60. Pell GJ, Gregory GT. Impacted third molars: classification and modified technique for removal. Dent Dig 1933;39:330-8. Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain. Drugs 2000;60:139-76. Wang JT, Chung CC, Whitehead RA, Schwarz SK, Ries CR, MacLeod BA. Effects of local tramadol administration on peripheral glutamate-induced nociceptive behaviour in mice. Can J Anaesth 2010;57:659-63.
OOOO March 2014 21. Dionne RA, Haynes D, Brahim JS, Rowan JS, Guivarc’h P-H. Analgesic effect of sustained-release flurbiprofen administered at the site of tissue injury in the oral surgery model J. Clin Pharmacol 2004;44:1418-24. 22. Lago-Méndez L, Diniz-Freitas M, Senra-Rivera C, Gude-Sampedro F, Rey JMG, García-García A. Relationships between surgical difficulty and postoperative pain in lower third molar extractions. J Oral Maxillofac Surg 2007;65:979-83. 23. Yalcin I, Aksu F. Involvement of potassium channels and nitric oxide in tramadol antinociception. Pharmacol Biochem Behav 2005;80:69-75. 24. Isiordia-Espinoza MA, Pozos-Guillén AJ, Martínez-Rider R, Herrera-Abarca JE, Pérez-Urizar J. Preemptive analgesic effectiveness of oral ketorolac plus local tramadol alter mandibular third molar urgery. Med Oral Patol Oral Cir Bucal 2011; 16:e776-80. 25. Mert T, Gunes Y, Gunay I. Local analgesic efficacy of tramadol following intraplantar injection. Eur J Pharmacol 2007;558: 68-72. 26. Pozos-Guillen A, Martinez-Rider R, Aguirre-Banuelos P, PerezUrizar J. Pre-emptive analgesic effect of tramadol after mandibular third molar extraction: a pilot study. J Oral Maxillofac Surg 2007;65:1315-20. 27. Kanto D, Salo M, Happonen RP, Vahlberg T, Kanto J. Tramadol premedication in operative extraction of the mandibular third molar: a placebo-controlled crossover study. Acta Odontol Scand 2005;63:43-9. 28. da Costa újo FA, de Santana Santos T, de Morais HH, Laureano Filho JR, de Oliveira e Silva ED, Vasconcellos RJ. Comparative analysis of preemptive analgesic effect of tramadol chlorhydrate and nimesulide following third molar surgery. J Craniomaxillofac Surg. doi.org/10.1016/j.jcms.2012.01.018. 29. Kesimci E, Izdes S, Gozdemir M, Kanbak O. Tramadol does not prolong the effect of ropivacaine 7.5 mg/mL for axillary branchial plexus block. Acta Anaesthesiol Scand 2007;51:736-41.
Reprint requests: Maria Cristina Zindel Deboni, MSc, DDS, PhD Department of Oral Surgery Dental School University of São Paulo Av. Prof. Lineu Prestes 2227 Butantã, São Paulo Brazil [email protected]
Analgesic and adjuvant anesthetic effect of submucosal tramadol after mandibular third molar surgery Marcelo Minharro Ceccheti, DDS, Ms, PhD,a Giovana Vigário Negrato, DDS,a Maria Paula Siqueira de Melo Peres, DDS, MS,b Maria Cristina Zindel Deboni, DDS, PhD,c and Maria da Graça Naclério-Homem, DDS, PhD,c University of Sao Paulo, São Paulo, Brazil Objective. The aim of this study was to assess analgesic and adjuvant anesthetic effects of submucosal tramadol after third molar extraction. Study Design. In this double-blind, split-mouth, placebo-controlled, single-dose, crossover investigation, 52 patients underwent mandibular third molar extraction under local anesthesia. Surgical side was randomly assigned to submucosal 2 mL 100 mg tramadol injection (group T) or normal saline solution (group P) immediately after surgery. Anesthetic blockade duration, time of intake and amount of analgesic rescue drug, and postoperative pain intensity were recorded immediately after anesthesia cessation and 4, 8, 24, 48, and 72 hours after surgery. Data were submitted to analysis of variance and Wilcoxon tests. Results. Anesthetic blockade duration between groups was similar. Group T took significantly less rescue drug after 72 hours (P ⫽ .008). Time elapsed before first intake of rescue drug was longer (P ⫽ .006), and pain intensity was significantly lower (P ⫽ .001) in group T. Conclusions. Submucosal tramadol injection after oral surgery improved postoperative analgesia, but did not extend anesthetic action duration. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:e249-e254)
Removal of an impacted mandibular third molar causes swelling, trismus, and moderate to severe pain.1 In dentistry, postoperative pain relief can be efficiently achieved with various analgesics, antiinflammatory drugs, or associations thereof. It is well known that better pain control after oral surgery may lead to improved recovery in terms of lifestyle and oral function.2 However, nonsteroidal antiinflammatory drugs are associated with numerous side effects and are contraindicated in a significant number of patients, such as those with a history of peptic ulcer disease or bleeding disorders, those taking anticoagulants or corticosteroids, and those with a history of allergy or intolerance to aspirin-like drugs.3 Tramadol may be an alternative for such patients, because it lacks sedative and respiratory depressant effects. Tramadol has been found to be a suitable analgesic for use in moderate pain after day-case oral surgery.4 Furthermore, in a study addressing extremely severe postoperative pain, both tramadol and morphine were An abstrat showing preliminary result was presented as a poster during the scientific meeting of the International Association for Dental Research, 2010, Barcelona, Spain. a Oral and Maxillofacial Surgery Department, General Clinics Hospital School of Medicine. b Dentistry Division, General Clinics Hospital, School of Medicine. c Oral and Maxillofacial Surgery Department, School of Dentistry. Received for publication Mar 11, 2012; returned for revision May 1, 2012; accepted for publication May 23, 2012. © 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2012.05.015
successful in providing relief. Despite the administration of higher doses than usual, there were fewer severe side effects with tramadol than with morphine.5 All of the analgesic effects of tramadol, whether administered by the oral or parenteral route, are explained by receptor-mediated mechanisms.6 Tramadol and its active metabolite, M1, exhibit weak and selective affinity for -opioid receptors, acting as central analgesics.6,7 Tramadol also exerts indirect action on monoaminergic receptors through norepinephrine and serotonin reuptake inhibition, blocking nociceptive inputs at the spinal cord.6-8 There are many descriptions of the effects of tramadol after systemic administration. However, the local analgesic effect of tramadol was first demonstrated only in 19988; ever since then, authors have tried to explain a possible mechanism of action.9-11 Moreover, a local anesthetic effect similar to that of prilocaine12 and lidocaine13 has been reported in the literature since it has been used as an adjunct to articaine in the removal of impacted mandibular third molars.14 Combination of tramadol and ibuprofen appears to produce supra-additive antiinflam-
Statement of Clinical Relevance The submucosal injection of tramadol is an easy and suitable method of using this analgesic in outpatients. It is considered to be an additional therapeutic option, fully available to dentists because it can be performed directly in the operative field.
e249
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matory effects that may offer clinical advantages regarding safety or efficacy for treating postsurgical dental pain15; additionally, some studies have even suggested a limited antiinflammatory effect.16 Only a few oral surgery investigations support the assertion that tramadol exerts a local effect on peripheral nerves. Some authors have shown that tramadol can be used as an analgesic adjunctive drug and improves quality of perioperative anesthesia14 in third molar surgery. Recently submucous local tramadol was shown to increase the anesthetic efficacy of mepivacaine with epinephrine in inferior alveolar nerve blockade, although duration of soft tissue anesthesia did not lengthen.17 The present prospective placebo-controlled study was designed to determine the effect of tramadol administered locally by submucosal injection on the onset and duration of analgesia and the duration of the sensory block produced by mepivacaine immediately after impacted mandibular third molar removal.
MATERIALS AND METHODS The study was designed as a prospective, randomized, placebo-controlled, double-blinded, split-mouth crossover trial. All patients were informed of the experimental methodology and signed an institutionally approved consent form. The study was conducted in compliance with Declaration of Helsinki (1989), and was reviewed and approved by the Institutional Ethical Committee (protocol 95/08). The inclusion criteria considered healthy subjects of any sex, ⬎18 years of age, with symmetric bilateral bone-impacted mandibular third molars requiring surgical removal, and with no history of psychiatric illness or allergy to the drugs used in this study. Exclusion criteria included the use of analgesic or antiinflammatory drugs 24 hours before treatment, history of seizure disorders, pregnancy, or lactation. Fiftytwo patients were included in the research. Third molar position was classified according to Pell and Gregory (1933)18 as evaluated in a panoramic radiograph. The same surgeon performed both extractions on each patient, with a minimum interval of 1 week between them. Surgery was carried out under local anesthesia, using a maximum of 3 1.8-mL cartridges of 2% mepivacaine with 1:20,000 levonorfedrin as a local anesthetic. A mucoperiosteal flap was elevated distally to the second molar providing access to the third molar from the buccal aspect. Osteotomy was achieved under continuous sterile saline solution irrigation. When necessary, sectioning of crown and roots was performed with a fissure bur. After extraction, the alveolus was inspected, curetted, and irrigated with sterile saline solution. Primary closure was achieved
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with 4-0 silk suture. Difficulties of extraction procedures were regarded to be grade I when extraction was performed by forceps only, grade II when extraction included osteotomy, grade III when extraction included osteotomy and coronal sectioning, and grade IV when extraction included extensive osteotomy and crown and root sectioning. In all cases, the operating time and the duration of the local anesthesia effect were recorded. Patients were allocated into 2 treatment regimens according to a computer-generated randomization schedule prepared before the study: Group T received 2 mL 100 mg tramadol, injected into the buccal mucosa adjacent to the third molar alveolus immediately after extraction; and group P received 2 mL normal saline solution in the same manner. All of the patients were randomized to the T or P group for the first surgery and then received the protocol of the opposite group for the second surgery. Medications were administered by another surgeon in charge of randomization control, thus ensuring double blindness. Patients were given routine postoperative instructions and were asked to fill out a 3-part questionnaire: 1) evaluation of pain intensity with the use of a 100-mm visual analog scale (VAS) at 4, 8, 24, 48, and 72 hours after surgery, with 0 anchored by “no pain” and 100 anchored by “very intense pain”; 2) amount of analgesic consumption and time of intake; and 3) duration of anesthetic blockade, considering the moment of lip numbness cessation perception by the patient compared with the same sensation on the contralateral lip, as the time the anesthetic wore off. The following standardized postoperative medication was prescribed to prevent any postoperative infection from interfering with the pain assessment made by patients: 500 mg amoxicillin orally every 8 hours for 7 days or 500 mg erythromycin orally every 8 hours for 7 days for patients allergic to penicillin. A mouth rinse with 15 mL 0.2% chlorhexidine solution was used before surgery for 1 minute and at home, twice a day, for 1 week. A dose of 500 mg metamizole was prescribed as a rescue medication for mild and moderate postoperative pain. Patients were instructed to record the number of analgesic pills they took, if any, and the time at which they took them. Patients were also instructed to return to the clinic in case of intolerable pain. Analgesic efficacy was assessed based on 4 end points: pain intensity as recorded on VAS; mean time elapsed before first intake of the rescue medication; total dose of analgesic consumed during the first 72 hours after surgery; and overall evaluation of the pain experience. Furthermore, the potential adjuvant anesthetic effect of tramadol presumably added to mepivacaine for the mandibular blockade was evaluated in both groups by comparing the patients’ reports regarding the duration of the anesthetic perception as indi-
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Table I. Demographic data and surgical characteristics Measured variable
All samples
Sex (female/male) Age (y) Weight (kg) Duration of surgery (min) Mepivacaine anesthetic cartridges Adverse events Duration of sensory block (min)
36/16 22.10 ⫾ 3.84 (18-33) 60.27 ⫾ 8.71(47-86)
Group P
Group T
P value
35.73 ⫾ 19.40 (7–100) 2.21 ⫾ 0.42 (1.5-3) 2 199.13 ⫾ 65.48 (35-342)
34.35 ⫾ 18.49 (5-90) 2.34 ⫾ 0.47 (1.5-4*) 4 208.85 ⫾ 63.78 (90-340)
.47 (NS) .066 (NS) .32 (NS)
Values are mean ⫾ SD (range). P, placebo; T, tramadol; NS, not significant. *The third cartridge broke during insertion into the carpule syringe and was replaced by other anesthetic cartridge, but keeping the same amount of drug used throughout the sample.
cated by the moment of lip numbness cessation realized by patients. The time interval between the onsets of the anesthetic effect to the lip normal sensation was considered to be the duration of the sensory blockade. Adverse effects of tramadol, such as vomiting, nausea, dizziness, dry mouth, and sweating, were recorded when present. Patient demographic data was expressed as mean and range and submitted to analysis of variance. The Wilcoxon test was used for statistical analysis and comparison among groups for continuous variables. A P value of ⬍.05 was considered to be significant (2001 Statistic version 6; StatSoft, Tulsa, OK).
RESULTS Data from 52 patients were included in the study. As presented in Table I, demographic data and surgical characteristics were similar in both groups. There were no differences in the extent of sensory block, number of anesthetic cartridges used, or duration of surgery between the groups. Preoperative classification of dental impaction was based on panoramic radiography and was found to be similar in both groups. There were no significant differences in surgery extraction complexity between the groups. Adverse effects were mild and did not complicate the postoperative course or delay the patient’s return to normal activities. There were nausea and vomiting (1 in group P and 3 in group T) and slight surgical bleeding easily controlled by local pressure and postoperative guidelines (1 case in each group). Consumption of rescue analgesics was used to evaluate the analgesic effect of tramadol. Nine patients in
the tramadol group did not require rescue medication after either surgery during the study period, whereas only 1 in the placebo group required metamizole after both extractions. Patients in the tramadol group made less use of the rescue analgesic than those in the placebo group (P ⫽ .008 [Wilcoxon test]). The mean time until the first analgesic requirement in the tramadol group was significantly longer than in the placebo group (P ⫽ .006 [Wilcoxon test]; Table II). Pain intensity over the 72-hour observation period was assessed with a 100-mm VAS and was found to differ significantly between the 2 groups only when patients felt that anesthesia had worn off (P ⬍ .001). Later evaluations showed no differences in mean pain values between both groups (Figure 1). Patients’ overall assessment related to pain showed that more patients in the placebo group (75%) than in the tramadol group (23%) scored the postoperative period of the control contralateral molar extraction as being worse than the postoperative period of the tramadol-medicated molar extraction (2 test: P ⬍ .001). Only 1 patient reported equal distress after both surgeries. Comparison of VAS mean scores between groups and surgical difficulty scale records showed a significant difference only for grade III surgery (P ⬍ .001). Differences in VAS means observed for grade IV surgery were practically the same as those observed for grade III (1.23 and 1.14, respectively), with no significant difference (Figure 2). Mean postoperative pain scores after the first procedure were lower in patients who had received tramadol
Table II. Mean dose of analgesic rescue drug taken within 72 hours of surgery and time to first metamizole tablet required Group P No. of analgesic tablets consumed (500 mg each) Time to first dose of rescue analgesic (min)
4.4 ⫾ 3.71 (0-20) 185.4 ⫾ 59.4 (60-343)
Data expressed as mean ⫾ SD (range). *Statistically significant versus control (Wilcoxon test).
Group T 3.37 ⫾ 4.65 (0-25) 303.72 ⫾ 416.01 (60-2,880)
P value .008* .006*
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Fig. 1. Visual analog scale (VAS) of pain at different moments of the evaluation. Data are expressed as mean with standard deviation.
Fig. 2. Visual analog scale (VAS) scores of tramadol and saline solution groups according to surgical difficulty grade.
compared with placebo (P ⫽ .036). The order of administration of tramadol or placebo during the first or second surgery had an effect on experience of pain (carryover effect). The same result was not observed when tramadol and placebo effects were compared during the second operation (Table III).
DISCUSSION This study showed that 2 mL 100 mg tramadol injected locally into the submucosa after impacted third molar extraction was superior to placebo for adequate analgesic coverage for 208.85 ⫾ 63.78 minutes (⬃3.5 hours). Tramadol is a centrally acting synthetic analgesic composite that is structurally related to codeine and morphine. Parenteral and oral are the most common administration routes, and its effectiveness for managing of moderate to severe postoperative pain has been demonstrated in both in- and outpatients.19 Furthermore, tramadol has proved to be an effective analgesic after dentoalveolar surgery, and has been shown to be significantly superior to placebo.4
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In addition to tramadol’s established central action, it is suggested that the drug may be suitable for local administration by acting through a combination of known and unknown peripheral mechanisms of action.20 Some investigations demonstrated that local application of drugs, e.g., in tissue wound, can maximize its level at the site of action, minimizing systemic exposure. The superior analgesic effect for the peripheral route is most probably due to the achievement of a higher drug concentration at the site of wound without loss due to its body distribution or elimination.21 We observed that the more complex the surgical procedure, the more the local administration of tramadol in relieving postoperative pain after third molar extraction seemed to be effective. Surgical difficulty grade III showed lower VAS mean values than other grades, although grade IV difficulty tended slightly toward statistical significance (P ⫽ .06). This was observed probably because of a small sample size; only 6 subjects in group P and 8 in group T were grade IV. This result confirmed the relationship mentioned above between increased pain and increased difficulty, notably in the operations that required the raising of a mucoperiosteal flap.22 An important finding of this study was that patients in the locally administered tramadol group required less intake of analgesics, providing evidence of the analgesic effectiveness of this kind of intervention. Moreover, the mean time until intake of the first dose of the rescue medication was longer in the tramadol group than in the placebo group, which is consistent with earlier studies.4,23 Likewise, it was demonstrated that preemptive ketorolac plus submucosal tramadol resulted in the decrease of postoperative analgesics use.24 We think that a patient’s choice to take a rescue medication is a better indicator of pain than any numeric scale. This method provides more sensitive behavioral information during the period of recovery after third molar extraction. The present investigation provides evidence of the benefit of tramadol administered into the surgical site alone in dental surgical procedures, but the peripheral mechanism of action of this otherwise centrally acting analgesic drug remains unclear. A number of theories have arisen in an attempt to explain possible mechanisms of action. Some have suggested that tramadol is an atypical opioid that acts on voltage-dependent Na⫹ channels (as do local anesthetics) and adrenergic pathways (as do vasoconstrictors).25 Recent experiments claimed that nonspecific voltage-dependent K⫹ channels and the nitric oxide system influence the antinociceptive effect of tramadol.23 It is also thought that tramadol may possess weak antiinflammatory properties not involved with the arachidonic acid path-
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Table III. Operating conditions when tramadol or placebo (saline) was administered during the first or second operation: VAS scores on a 0-10 cm scale reported by patients Surgical order First surgery Second surgery
Group
Mean
SD
Median
Min.
Max.
n
P value
Saline Tramadol Saline Tramadol
2.82 1.86 2.70 1.89
1.63 1.32 2.08 1.25
2.50 1.67 2.00 1.58
0.75 0.00 0.67 0.00
6.00 5.67 9.42 5.00
28 24 24 28
.036
way.15,16 It seems that tramadol has independent systemic and peripheral mechanisms of action, because it improves the quality of postoperative analgesia when both routes are used in combination.26 A synergistic effect between local and systemic mechanisms of action is also conjectured.20 Administration of tramadol during mandibular third molar extraction improved the quality of operating conditions during the first operation, delaying and decreasing the need for postoperative analgesics owing to the carryover effect. The same conclusion was proposed by Kanto et al.27 in a crossover study. When tramadol is used during the first surgery, patients have a positive pain experience, and less preoperative anxiety leads to a reduced need for analgesia. This was clearly observed when global pain assessment was analyzed and compared on a pain scale. The VAS showed analgesic action for only 3.5-4 hours following surgery. However, 75% of the sample reported a worse postoperative experience when placebo was used as local medication. The adverse effects that are generally reported include vomiting, nausea, dizziness, dry mouth, and profuse sweating.19 The submucosal route of administration could be advantageous over systemic analgesics or nonsteroidal antiinflammatory drugs because they entail reducing the risk of side effects.21 In the present research, no major adverse effects were observed in the tramadol group. Only gastrointestinal disturbances were seen, all of which occurred in the first 2 hours after surgery. This observation is in agreement with other study outcomes which described only minor sideeffects.3,4,27 As with other authors,28 dizziness was not reported at any time by the patients in the present study. Furthermore, every tooth alveolus repaired uneventfully. It is important to note that there was no local reaction, such as inflammatory process exacerbations, delayed healing, or necrosis, even though tramadol was submucosally injected. Recently it was shown that submucous tramadol can augment the anesthetic efficiency of mepivacaine with epinephrine in the inferior alveolar nerve blockage.17 Conversely, no adjuvant anesthetic action was seen in this study. The injection of 100 mg tramadol immediately after dental extractions did not increase the duration of sensory blockage of 2% mepivacaine with levonorfedrin. Similar results were described with tra-
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madol and 7.5 mg/mL ropivacaine for brachial plexus block and were related to the choice of a long-acting local anesthetic.29 The possible explanation for the lack of effect of tramadol in lengthening the postoperative anesthetic period could be based on the methods employed in this study. Probably, because tramadol was administered after completion of the procedure, the anesthetic effect of mepivacaine was at its peak, with all peripheral nerve ion channels occupied by the anesthetic salt. If the local mechanism of action of tramadol involves binding to sensory nerves, as suspected,18,19 this would possibly have prevented its action. Our results could provide an indirect argument in favor of this hypothesis. In conclusion, the present study suggests that local administration of 100 mg tramadol contributes to provide a pain-free period of 3.5-4 hours after mandibular third molar extraction, with rare adverse effects and good patient acceptance. Moreover, there was a relationship between more complicated interventions and pain relief after local administration of tramadol. Nevertheless no beneficial effect of tramadol in lengthening the sensory blockade produced with mepivacaine was observed. Additional studies comparing the effects of tramadol with those of other local anesthetics or systemic analgesic drugs are desirable. Molecular investigations could be conducted to verify if tramadol acts either directly or indirectly modifying the action of local anesthetic. The authors thank Aparecida Conceição de Souza for technical assistance. REFERENCES 1. Grossi GB, Maiorana C, Garramone RA, Borgonovo A, Creminelli L, Santoro F. Assessing postoperative discomfort after third molar surgery: a prospective study. J Oral Maxillofac Surg 2007;65:901-4. 2. Snyder M, Shugars DA, White RP Jr, Phillips C. Pain medication as an indicator of interference with lifestyle and oral function during recovery after third molar surgery. J Oral Maxillofac Surg 2005;63:1130-7. 3. Broome IJ, Robb HM, Raj N, Girgis Y, Wardall GJ. The use of tramadol following day-case oral surgery. J Anesth 1999;54: 266-96. 4. Collins M, Young I, Sweeney P, Fenn GC, Stratford ME, Wilson A, Harris M. The effect of tramadol on dento-alveolar surgical pain. Br J Oral Maxillofac Surg 1997;35:54-8. 5. Wiebalck A, Tryba M, Hoell T, Strumpf M, Kulka P, Zenz M.
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OOOO March 2014 21. Dionne RA, Haynes D, Brahim JS, Rowan JS, Guivarc’h P-H. Analgesic effect of sustained-release flurbiprofen administered at the site of tissue injury in the oral surgery model J. Clin Pharmacol 2004;44:1418-24. 22. Lago-Méndez L, Diniz-Freitas M, Senra-Rivera C, Gude-Sampedro F, Rey JMG, García-García A. Relationships between surgical difficulty and postoperative pain in lower third molar extractions. J Oral Maxillofac Surg 2007;65:979-83. 23. Yalcin I, Aksu F. Involvement of potassium channels and nitric oxide in tramadol antinociception. Pharmacol Biochem Behav 2005;80:69-75. 24. Isiordia-Espinoza MA, Pozos-Guillén AJ, Martínez-Rider R, Herrera-Abarca JE, Pérez-Urizar J. Preemptive analgesic effectiveness of oral ketorolac plus local tramadol alter mandibular third molar urgery. Med Oral Patol Oral Cir Bucal 2011; 16:e776-80. 25. Mert T, Gunes Y, Gunay I. Local analgesic efficacy of tramadol following intraplantar injection. Eur J Pharmacol 2007;558: 68-72. 26. Pozos-Guillen A, Martinez-Rider R, Aguirre-Banuelos P, PerezUrizar J. Pre-emptive analgesic effect of tramadol after mandibular third molar extraction: a pilot study. J Oral Maxillofac Surg 2007;65:1315-20. 27. Kanto D, Salo M, Happonen RP, Vahlberg T, Kanto J. Tramadol premedication in operative extraction of the mandibular third molar: a placebo-controlled crossover study. Acta Odontol Scand 2005;63:43-9. 28. da Costa újo FA, de Santana Santos T, de Morais HH, Laureano Filho JR, de Oliveira e Silva ED, Vasconcellos RJ. Comparative analysis of preemptive analgesic effect of tramadol chlorhydrate and nimesulide following third molar surgery. J Craniomaxillofac Surg. doi.org/10.1016/j.jcms.2012.01.018. 29. Kesimci E, Izdes S, Gozdemir M, Kanbak O. Tramadol does not prolong the effect of ropivacaine 7.5 mg/mL for axillary branchial plexus block. Acta Anaesthesiol Scand 2007;51:736-41.
Reprint requests: Maria Cristina Zindel Deboni, MSc, DDS, PhD Department of Oral Surgery Dental School University of São Paulo Av. Prof. Lineu Prestes 2227 Butantã, São Paulo Brazil [email protected]