SCIENTIFIC REPORT

An Evaluation of Analgesic Efficacy and ClinicalAcceptability of Intravenous Tramadol as anAdjunct to Propofol Sedation for Third MolarSurgeryE. A. Shipton, FFA, FRCA, FANZCA, FFPMANZCA, D MED,* J. A. Roelofse, MBChB, MMED,PhD,t and R. J. Blignaut, PhDt*Department of Anesthesiology, Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch,New Zealand, tDepartment of Anesthesiology, Faculty of Dentistry, University of Stellenbosch, and tDepartment of Statistics,University of the Western Cape

This article details a double-blind, randomized, placebo-controlled pilot study eval-uating the analgesic efficacy and clinical acceptability of intravenous tramadol inpatients undergoing surgical removal of an impacted third molar tooth under localanesthesia and intravenous sedation with propofol. Forty-five ASA status 1 dentaloutpatients were randomly allocated to 2 groups of 22 (group A) and 23 (group B)patients each (n = 45). Group A (T/P) received intravenous tramadol 1.5 mg/kginjected over 2 minutes, followed by a bolus dose of intravenous propofol 0.4 mg/kg. Maintenance consisted of a continuous infusion of propofol 3 mg/kg/h, withan additional bolus dose of 0.4 mg/kg intravenously 2-3 minutes prior to the infil-tration of the local anesthetic solution. Group B (P/P) patients received no tramadolbut instead a saline placebo solution and an identical amount of propofol. Overall,in this study, postoperative pain was much better controlled in the group receivingtramadol 1.5 mg/kg intravenously despite there being no significant difference inthe dose of propofol administered in both groups. Intravenous tramadol, when givenwith propofol, did not affect the cardiovascular, respiratory, and sedative effects ofpropofol. Following tramadol, despite being an opioid, no nausea and vomiting werereported in the early postoperative period, indicating the value of using tramadolwith propofol. Thus, this pilot study demonstrated the potential use of intravenoustramadol with propofol in day-case dento-alveolar surgery.

Key Words: Tramadol; Propofol; Postoperative analgesia; Clinical acceptability;Third molar surgery.

Postoperative pain following surgical removal of amandibular third molar is a validated, well-docu-

mented, and highly sensitive model to assess therapeuticrelief of moderate to severe pain.1 Despite the avail-ability of potent analgesics, postoperative pain remainsa routine problem in ambulatory oral surgery. Following

Received May 18, 2002; accepted for publication December 16,2002.Address correspondence to Professor E. A. Shipton, Department

of Anesthesiology, Christchurch School of Medicine and Health Sci-ences, University of Otago, Private Bag 4345, Christchurch, NewZealand.

Anesth Prog 50:121-128 2003© 2003 by the American Dental Society of Anesthesiology

surgical removal of impacted third molar teeth, pain in-tensity is said to be maximal 3-5 hours after surgery.2At this stage, the effects of short-acting local anestheticsare usually wearing off.Tramadol [tramadol hydrochloride: (1RS, 2RS)-2-[(di-

methylamine) methyl)-1-(3 methoxyphenyl)-cyclohex-anol HCL] is a synthetic 4-phenyl-piperidine analogueof codeine.3 Tramadol's efficacy over a wide range ofacute and chronic pain states, its multiformulation avail-ability, and its low serious side-effect potential at highdoses and in prolonged therapy, combine to bestow onit a user-friendly profile for short- and long-term use in

ISSN 0003-3006/03/$9.50SSDI 0003-3006(03)

121

122 Tramadol/Propofol Sedation for Third Molar Surgery

Table 1. Demographic Data

T/P P/PNumber 22 23Age (yrs) 29 + 12 29 ± 13Weight (kg) 68 + 13 70 ± 13Operating time (min) 42 ±+ 14 43 ±+ 12SexMale 8 6Female 14 17

hospitals and communities.4 The marketed formulationsof tramadol contain a racemic mixture of 2 enantiomers(50: 50), each one displaying differing affinities for var-

ious receptors.3 The complementary and synergisticmode of action of these 2 enantiomers is both opioidand monoaminergic, so that its analgesic effect extendsto both opioid-sensitive and -insensitive pain.3

Propofol, an emulsion formulation of isopropylphen-ol, is a suitable drug for sedation because its pharma-cokinetic profile suggests a high total body clearanceand a short elimination half-life after both bolus injectionand brief infusions.5 This suggests a rapid recovery witha low incidence of excitatory effects.6 Propofol appears

to be safe and efficacious for use during outpatient oralsurgical procedures.78

This pilot study was designed in a double-blind, ran-

domized, placebo-controlled manner to evaluate the an-

algesic efficacy and clinical acceptability of intravenoustramadol/propofol versus placebo/propofol in patientsundergoing surgical removal of an impacted third molartooth under local anesthesia and intravenous sedation.

METHODS

Forty-five healthy male or female patients aged 18-55years scheduled to undergo surgical removal of an im-pacted mandibular third molar were eligible for partici-pation in the study (see Table 1 for demographic data).All patients required bone removal and suturing. Exclu-sion criteria were as follows: pregnancy or lactation; use

of anticoagulants, analgesics, or any central nervous sys-

tem depressants; hypersensitivity to opioids or any oth-er medication likely to interfere with the study drugs.Treatment with any analgesic whatsoever was forbiddenfor 24 hours prior to surgery. Ethical approval was ob-tained from the Hospital and University Ethical Com-mittee and written informed consent from all the pa-

tients involved in the study.At a presurgery visit, patients were evaluated for in-

clusion, and baseline assessments (including a medicalhistory) were performed. Patients were randomly allo-cated before surgery according to a computer-generatedrandomization list to 1 of the 2 treatment groups.

Thus, 45 ASA status 1 dental outpatients undergoingelective surgical removal (with bone removal and toothextraction) of 1 impacted third molar under local anes-thesia, were allocated by randomization to 2 groups of22 (group A) and 23 (group B) patients each (n = 45)(see Table 1 for demographic data). Neither group hadreceived any premedication beforehand. One of the au-thors (JAR) had recently found that tramadol drops 1.5mg/kg before multiple dental extractions in childrenaged 4-7 years resulted in significantly better analgesiafor up to 120 minutes postoperatively.9 As the absoluteoral bioavailability of tramadol drops is 70.6 (1.13)%,1°it was decided that Group A (T/P) receive intravenoustramadol 1.5 mg/kg injected over 2 minutes, followedby a bolus dose of intravenous propofol 0.4 mg/kg.Maintenance consisted of a continuous infusion of pro-pofol 3 mg/kg/h, with an additional bolus dose of 0.4mg/kg intravenously 2-3 minutes prior to the infiltra-tion of the local anesthetic solution.Group B (P/P) patients received no tramadol but in-

stead a saline placebo solution and an identical amountof propofol. The study was blinded by means of a salineplacebo solution with identical packaging to the trama-dol and only the particular patient's number as identifier.All treatments were carried out by the same anesthesi-ologist and the same maxillo-facial surgeon, and all as-sessments by a single research nurse. In both groups,2-3 minutes after the propofol bolus, 4 mL of mepiv-acaine 2% was injected appropriately in all patients toprovide local anesthesia. Ten minutes after the comple-tion of effective local anesthetic blockade (as assessedby numbness of the mucous membranes to pin pricks),the surgical procedure was started.

Monitoring consisted of a DinamapR adult/pediatricnoninvasive blood pressure monitor, an Ohmeda BioxIIIR pulse oximeter for measuring oxygen saturation, anda continuous electrocardiogram. Blood pressures (sys-tolic, diastolic, mean), pulse and respiratory rates, oxy-gen saturations, and anxiety scores (observed scale: 1 =very anxious; 2 = alert, moderately anxious, 3 = calm,indifferent, not anxious) were recorded at the followingtime intervals: before the start of sedation, 15 minutesafter the propofol bolus and start of the infusion butbefore the start of the surgery, and at the end of theprocedure.

Sedation scores (according to Ramsay et al1l were 1= fully awake, orientated; 2 = drowsy; 3 = eyes closed,arousable to command; 4 = eyes closed, arousable toshoulder shaking; 5 = unarousable to shoulder-tip shak-ing) were assessed at the following time intervals: beforethe start of sedation, 15 minutes after the propofol bo-lus and start of the infusion but before the start of thesurgery, and at the end of the procedure.

Postoperative pain scores were performed by the pa-

Anesth Prog 50:121-128 2003

Anesth Prog 50:121-128 2003

tients filling in visual analogue scales (VAS; marking on

a continuous line of 10 cm with 0 = no pain; 10 =

intolerable pain) at the following time intervals after sur-

gery: 1, 2, 3, and 4 hours (in the recovery room) andat 6, 8, and 10 hours (at home). If any patients expe-rienced pain between 2-10 hours postoperatively, es-

cape analgesia was provided as oral tramadol 50-100mg (1 to 2 capsules) every 4 hours. Time to escapeanalgesia was recorded.The pegboard test was used as a measure of recovery

following propofol/tramadol.12 Control times were ob-tained prior to drug administration, then immediatelybefore surgery, and at the end of surgery. Each patientwas asked to move as many pegs as they could in 45seconds from one side of the board to the other andback again (after familiarization with this technique).

Operating conditions were graded by the maxillo-fa-cial surgeon at the end of the procedure according tothe movement during surgery as follows: continuousmovement making treatment difficult, some movementbut no interference with surgery, and no movement. Atthe end of the procedure, the surgeon rated the overalleffectiveness of the sedation as follows: very poor se-

dation making surgery impossible, poor sedation buttreatment partially completed or completed with diffi-culty, good sedation but limited difficulty in completingprocedure, and very good sedation with procedurescompleted without any difficulties. Patients remained inthe recovery room for 4 hours after surgery, where re-

covery was assessed according to the Aldrete's postan-esthetic recovery score.13

After discharge, nausea and vomiting as reported bypatients were recorded. Patients returned to the hospitalthe following day. Clinical acceptability of the medica-tion was made by means of a 5-point Verbal RatingScale (VRS: 1 = excellent, 2 = good, 3 = moderate,4 = poor, 5 = very poor).

Statistical AnalysisAll tests of the significance of differences were 2-tailedand a probability of .05 or less was accepted as signif-icant. Various tests such as the Chi-square tests, FisherExact tests, and the Mann-Whitney tests were applied.Repeated measures using general linear models as-

sessed the pain differences over time in the 2 groups.

All statistical modeling and significance testing was per-

formed using the SAS statistical package (CMS version5.18).

RESULTS

Patients in the 2 groups were similar with respect toage, height, weight, gender distribution, and length of

surgery (Table 1). There were no significant differences(P = .05) in age, weight, blood pressures (systolic, dia-stolic, mean arterial), pulse oximetry oxygen saturation,pegboard tests between the 2 groups at the various timeintervals measured (Table 2). With regard to the peri-operative sedation and anxiety levels at the different in-tervals, no significant differences were found betweenthe 2 groups (P = .05). Analysis of the propofol ad-ministered revealed that almost equal amounts were giv-en in both groups during surgery (tramadol group 206.8mg ± 66.9; placebo group 206.0 + 48.7). No or min-imal technical difficulties were experienced by the sur-geon in patients in either group. No nausea, vomiting,and dizziness were noted in either group, and similarrecovery-room scores were obtained in both groups dur-ing the first 4 hours postoperatively. No significant (P< .05) cardiovascular depression or fall in oxygen sat-urations were found in either group during the first 4hours postoperatively. However, 3 patients self-reportednausea and vomiting after discharge, all being in thetramadol group. The 2 patients in the tramadol groupthat did not receive rescue analgesia reported no nauseaor vomiting.

Analysis of the pain scores showed significant differ-ences between the 2 groups. The development of post-operative pain, as reflected by the VAS, is shown inFigures 1 and 2. The values displayed were derived fromdata recorded prior to the administration of rescue med-ication as well as from results obtained after the admin-istration of the tramadol capsules. But in each patientthat received rescue medication, all assessments record-ed after the intake of the tramadol capsules were re-placed by the last observation carried forward (LOCF).This approach can be seen in Figure 2.When the continual-pain assessments and the carry-

over effects were tested for normality, it was found thatthese measurements were approximately normally dis-tributed and therefore generalized linear models couldbe applied. Pain assessments were made at 1, 2, 3, 4,6, 8, and 10 hours postoperatively. The 2 groups dif-fered significantly at each individual time period (P =.0001). The average pain value of the tramadol groupwas significantly lower than that of the placebo group.Repeated measures using general linear models werealso used to compare the LOCF effect between the 2groups at the different time intervals. The 2 groups dif-fered significantly at each individual time period (P =.0001). At each time period, the level of pain was lowerin the tramadol group.The primary efficacy variable is the area under the

curve (AUC) of the postoperative pain assessments asmeasured using the VAS. The smaller values indicateless overall pain. The AUCs were calculated in 2 differ-ent ways. In the first method, assessments made after a

Shipton et al 123

124 Tramadol/Propofol Sedation for Third Molar Surgery

Table 2. Blood Pressure, Heart Rate, Respiratory Rate, Blood Oxygen Saturation Levels, and Pegboard Test*

Tramadol Propofol Placebo PropofolMean SD Mean SD

Systolic pressure (mm Hg)BD 132.0 16.7 127.3 15.4BS 140.1 14.9 133.5 24.4AS 130.3 14.4 131.0 18.1

Diastolic pressure (mm Hg)BD 77.5 11.3 77.1 12.1BS 80.9 8.8 77.8 15.8AS 78.6 10.1 78.5 10.3

Mean pressure (mm Hg)BD 97.6 15.8 93.4 13.3BS 98.4 11.5 98.3 17.6AS 93.3 9.9 95.3 14.1

Heart rate (beats/min)BD 78.5 13.7 81.5 13.3BS 75.6 12.1 79.6 10.1AS 71.2 10.6 77.0 11.1

Respiratory rate (breaths/min)BD 20.0 2.2 20.8 2.7BS 19.4 2.2 19.3 2.2AS 18.7 2.0 19.5 1.0

Oxygen saturation (%)BD 98.5 1.0 98.4 1.1BS 98.3 1.2 97.9 4.3AS 97.9 1.7 96.6 8.2

Pegboard testBD 36.8 5.3 39.1 5.7BS 30.9 6.5 35.0 7.0AS 35.0 4.6 35.9 7.6* Abbreviations: BD indicates before drug; BS, before surgery; AS, after surgery.

I 1 1 2 1 3 1 4 1 6 1 8 10

-4- Tramadol

I Placebo

6

0

ITramadol 0.36: 0.72 1.86 1.48 3.45 t2.53 | 3.59 2.26 | 2.72 t 2.00 2.13 t 2.14 1.77 1.68

IPlacebo |1.91 2.71 3.89 3.22 5.52 t 3.28 5.30 2.94 4.56 2.93 4.52 2.23 3.82 t 2.65

HOURS POST-OPFigure 1. Postoperative pain over time.

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Anesth Prog 50:121-128 2003

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Anesth Prog 50:121-128 2003

I-- Tramadol -4- Placebo

3 4 6 8 10

Tramadol 0.36 t 0.72 1.86 i 1.48 3.59 + 2.44 3.82 +2.61 4.05 , 2.39 3.95 * 2.51 3.95 * 2.51Placebo 1.91 * 2.71 3.96 +3.15 5.57 3.30 5.91 2.96 6.04 t 3.09 6.13 t 3.03 8.17 3.02

HOURS POSTOPFigure 2. Postoperative pain last observation carried forward.

patient had taken postoperative analgesia were analyzedas if the analgesia had not been taken. In the secondmethod, assessments made after a patient had takenpostoperative analgesia were assumed to be missing andall missing assessments were substituted using LOCF.Using the first method, the mean AUC was 15.9 in thetramadol group as compared with 29.5 in the placebogroup (P = .002). Using substitution for missing data(LOCF), the AUCs were 21.5 and 37.5 in the tramadoland placebo groups, respectively (P = .01). In Table 3,the AUCs are summarised by presenting the medianand range for each treatment.

All patients in the placebo group received rescue an-

algesia, while 2 patients in the tramadol group did notreceive rescue analgesia. Patients in the tramadol group

also took significantly longer to take rescue analgesia(192.2 52.6 min) than those in the placebo group

(159.5 48.1 min) (P = .02). The consumption ofrescue analgesia was significantly lower at all time inter-vals measured in the tramadol group.

Patient movement causing difficulty in completing thesurgery was significantly more in the placebo group (8patients), whereas in the tramadol group, only 1 of thepatients moved and made the procedure difficult tocomplete (P = .02). At follow-up the next day, clinical

acceptability of the medications received were rated by17 patients as "excellent" (VRS = 1) in the tramadolgroup, as compared with 9 patients in the placebogroup (P = .02). In the tramadol group, only 1 patientrated their postoperative analgesia as "moderate topoor" (VRS = 3 and 4) as compared with 4 patients inthe placebo group.

The consumption of tramadol capsules from 3-10hours is shown in Figure 3. The consumption of rescue

analgesia was significantly lower at all time intervalsmeasured in the tramadol group. Average capsule con-sumption in the tramadol group was 7.2 ± 2.2 as com-pared with 15.8 ± 4.9 in the placebo group (P = .01).

DISCUSSION

Sedation combined with local anesthesia is a safe alter-native to general anesthesia because spontaneous re-

flexes and patient cooperation are retained while fearand apprehension (common reasons to delay dentalcare) are reduced.3 Local anesthetic techniques are of-ten complemented by the balanced use of low doses ofanalgesic and sedative/hypnotic drugs to provide anal-gesia, anxiolysis, and sedation. Recovery is then more

Table 3. Area Under the Curve

Variable Statistic Tramadol/Propofol Placebo/PropofolTotal pain Mean 15.91 ±+ 10.43 29.52 ± 14.64

Median 15 30Range 33 53

Last observation carried forward (LOCF) Mean 21.29 ± 13.07 35.70 ± 19.00Median 20 37Range 48 56

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Shipton et al 125

126 Tramadol/Propofol Sedation for Third Molar Surgery

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rapid and patients are more clear-headed, making thistechnique invaluable for outpatient medical and surgicalprocedures. Mepivacaine 2% (with 1/20,000 levonor-defrin) has been successfully used intraosseously to sup-plement inferior alveolar dental blocks for molar extrac-tion.14 Newer dental local anaesthetics (such as arti-caine)15 and especially more longer-acting local anaes-thetics (such as levobupivicaine)16 have the capacity forbetter postoperative pain control and for longer periods.

Postoperatively, intravenous and intramuscular tra-madol has been used with good efficacy.17 Orally, inpostsurgical pain, tramadol 50, 100, and 150 mg hadnumbers needed to treat for >50% maximal total painrelief of 7.1 (95% confidence intervals, 4.6-18), 4.8(3.4-8.2), and 2.4 (2.0-3.1), comparable with aspirin650 mg plus codeine 60 mg (numbers needed to treat3.6 [2.5-6.3]) and paracetamol 650 mg plus propoxy-phene 100 mg (numbers needed to treat 4.0 [3.0-5.7]). 18

Tramadol has recently been evaluated as a postop-erative analgesic in dento-alveolar pain.'1920 It shows a

dose-response for analgesia in patients undergoing den-tal surgery.'8 In this study of dento-alveolar pain, theaverage pain value of the tramadol group was signifi-cantly lower than that of the placebo group. The 2groups differed significantly at each individual time pe-riod (P = .0001). At each time period, the level of painwas lower in the tramadol group (Figure 1). In bothgroups, the degree of pain experienced peaked between3 and 4 hours.

The prevention of postoperative pain is based on 2phenomena:21 (a) that the effective blockade of noxiousstimuli generated during surgery and during the initialpostoperative period (inflammatory phases) reduces sub-sequent postoperative pain (phenomenon of pre-emp-tive analgesia in the broad sense), and (b) that an anti-nociceptive treatment started before surgery is more ef-fective in the reduction of postoperative pain than thetreatment given on recovery from general anesthesia(phenomenon of pre-emptive analgesia in the narrowsense). It was found that both phenomena can be in-duced by neural blockade with local anesthetics and bysystemic or epidural opioids. Clinically impressive resultsare observed when the blockade of noxious stimuli iscomplete and extended into the initial postoperative pe-riod (a combination of both phenomena).2' Opioid pre-

medication has been found to reduce the sustained hy-perexcitability of the central nervous system to intra-operative stimuli, prolonging the pain-free period im-mediately postoperatively and decreasing the frequencyof analgesic demands.22

For third molar extractions, both patient-controlledand operator-controlled sedation with propofol havebeen used successfully with minimal changes in respi-ratory function and with the return of psychomotorfunctions to normal by 60 minutes.23A weakness of the pilot study that will be corrected

in future studies was that no direct assessment of thedifficulty of surgical removal was performed. Differently

Mean: T/P 7.2 i 2.2PIP 15.St4.9

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Anesth Prog 50:121-128 2003 Shipton et al 127

impacted third molars may cause varying degrees ofpain.Although predominantly mild in nature, data from

short-term multiple-dose studies show tramadol mostcommonly to cause nausea, tiredness, vomiting,sweating, drowsiness, and postural hypotension.2425These were significantly higher after dental surgerydue possibly to the acute dosing in awake patients andrapid mobilization.25 Despite tramadol being an opi-oid, there was a low incidence of nausea and vomitingin the early postoperative period in the tramadolgroup in this study. This is probably due to the anti-emetic effect of the propofol as there is strong evi-dence for its antiemetic efficacy in the postanesthesiacare unit.26

Overall, in this study, postoperative pain was muchbetter controlled in the group receiving tramadol 1.5mg/kg intravenously despite there being no significantdifference in the dose of propofol administered in bothgroups. Intravenous tramadol, when given with propo-fol, did not affect the cardiovascular, respiratory, andsedative effects of propofol. With tramadol, despite be-ing an opioid, no nausea and vomiting were reported inthe early postoperative period, indicating the value ofusing tramadol Awith propofol.

Dental health-care professionals have used a varietyof drugs to control pain after oral surgery.27 Strongopioids are still being used, but fears concerning the riskof opioid dependence-adverse effects such as respira-tory depression, excess sedation, and postoperativenausea and vomiting-still result in some reluctance toprescribe them.28 Many patients cannot tolerate nonste-roidal anti-inflammatory drugs due to a history of aller-gy, peptic ulceration, or bleeding disorders.20 Tramadolwould therefore appear to lend itself particularly to usein the day-case surgical environment.29 When combinedwith propofol for third molar surgery, tramadol providedsafe monitored-anesthetic care with good postoperativeanalgesia and minimal postoperative nausea and vom-iting. In this pilot study, its potential use with propofolin the day-case dento-alveolar surgery has been dem-onstrated.

REFERENCES

1. Forbes JA. Oral surgery. In: Max M, Portenay R, LaskaE, eds. Advances in Pain Research and Therapy. New York:Raven Press; 1991:347-374.

2. Fisher SE, Frame JW, Rout PJG, McEntegart DJ. Fac-tors affecting the onset and severity of pain following the sur-gical removal of unilateral impacted mandibular third molarteeth. Br J Dent. 1988;164:351-354.

3. Dayer P, Desmeules J, Collart L. Pharmacology of tra-madol. Drugs. 1997;53(suppl 2):18-24.

4. Shipton EA. Tramadol-present and future. AnaesthIntensive Care. 2000;28:363-374.

5. Oei-Lim VL, White M, Kalkman CJ, et al. Pharmaco-kinetics of propofol during conscious sedation using target-controlled infusion in anxious patients undergoing dental treat-ment. Br J Anaesth. 1998;80:324-331.

6. Mackenzie N, Grant IS. Propofol for intravenous seda-tion. Anaesthesia. 1987;42:3-6.

7. Parworth LP, Frost DE, Zuniga JR, Bennett T. Propofoland fentanyl compared with midazolam and fentanyl duringthird molar surgery. J Oral Maxillofac Surg. 1998;56:447-454.

8. Ruiz K, Coldwell SA, Hitchin N, Dresner-Black E. Pro-pofol sedation in dental practice: the first 100 patients. DentUpdate. 2000;27:16-20.

9. Roelofse JA, Payne KA. Oral tramadol: analgesic effi-cacy in children following multiple dental extractions. Eur JAnaesthesiol. 1999;16:441-447.

10. Lintz W, Becker R, Gerloff J, Terlinden R. Pharmocoki-netics of tramadol and bioavailability of enteral tramadol for-mulations. 4th communication: drops (without alcohol). Arz-neimittel-Forschung. 2000;50:99-108.

11. Ramsay MAE, Savage TM, Simpson BRJ, Goodwin R.Controlled sedation with alphaxolone-alphadolone. Br Med J.1974;2:656.

12. Vickers MD. The measurement of recovery from an-aesthesia. Br J Anaesth. 1965;37:296.

13. Aldrete A. Post-anaesthetic recovery score. Anesth An-aig. 1970;49:924-933.

14. Guglielmo A, Reader A, Nist R, Beck M, Weaver J.Anesthetic efficacy and heart rate effects of the supplementalintraosseus injection of 2% mepivacaine with 1: 20,000 le-vonordefrin. Oral Surg Oral Med Oral Pathol Oral RadiolEndodont. 1999;87:284-293.

15. Malamed SF, Gagnon S, Leblanc D. Articaine hydro-chloride: a study of safety of a new amide local anesthetic. JAm Dent Assoc. 2001;132:177-185.

16. Mather LE, Chang DH. Cardiotoxicity with modern lo-cal anaesthetics: is there a safer choice? Drugs. 2001;61:333-342.

17. Radbruch L, Grond S, Lehmann KA. A risk-benefit as-sessment of tramadol in the management of pain. Drug Saf.1996; 15:8-29.

18. Moore RA, McQuay HJ. Single-patient data meta-anal-ysis of 3453 postoperative patients: oral tramadol versus pla-cebo, codeine and combination analgesics. Pain. 1997;69:287-294.

19. Lewis KS, Han NH. Tramadol: a new centrally actinganalgesic. Am J Health Syst Pharm. 1997;54:643-652.

20. Collins M, Young I, Sweeney P, et al. The effect oftramadol on dento-alveolar surgical pain. Br J Oral MaxillofacSurg. 1997;35:54-58.

21. Kissin I. Preemptive analgesia: why its effect is not al-ways obvious. Anesthesiology. 1996;84:1015-1019.

22. Kiss IE, Kilian M. Does opiate premedication influencepostoperative analgesia? Pain. 1992;48:157-158.

23. Zacharias M, Bridgman J, Parkinson R. Two methods

128 Tramadol/Propofol Sedation for Third Molar Surgery Anesth Prog 50:121-128 2003

of administration of propofol for dental sedation. Br J OralMaxillofac Surg. 1998;36:19-23.

24. Cossmann M, Kohnen C. General tolerability and ad-verse profile of tramadol hydrochloride. Rev Contemp Phar-macother. 1995;6:513-531.

25. McQuay HJ, Moore RA. Oral tramadol versus placebo,codeine, and combination analgesics. In: McQuay HJ, MooreRA, eds. An Evidence-Based Resource for Pain Relief. Ox-ford: Oxford University Press; 1998;22:138-146.

26. Soppitt AJ, Glass PS, Howell S, Weatherwax K, GanTJ. The use of propofol for its antiemetic effect: a survey of

clinical practice in the United States. J Clin Anesth. 2000;12:263-268.

27. Cowan FF. New ways to handle pain: a discussion ofnonsteroidal anti-inflammatory agents. J Oregon Dent Assoc.1989;58:26-29.

28. Dayer P, Collart L, Desmeules J. The pharmacology oftramadol. Drugs. 1994;47(suppl 1):3-7.

29. Coulthard P, Snowdon AT, Rood JP. The efficacy andsafety of postoperative pain management with tramadol forday case surgery. Ambul Surg. 1996;4:25-29.