Abstract
The main purpose of this study was to assess the clinical efficacy and haemodynamic effects of ropivacaine for infiltration anaesthesia in patients undergoing surgical removal of upper third molars. The safety profile of ropivacaine was also studied by investigating the maximal venous plasma concentration of ropivacaine and the reactivity to ropivacaine of isolated human infraorbital arteries. Ropivacaine in concentrations of 0.5, 0.75 and 1% achieved dose-dependent parameters of maxillary infiltration aneasthesia, clinically relevant in concentrations 0.75 and 1%. Postoperative needs for analgesics were observed in 67–100% of patients. Haemodynamic parameters were stable during surgery with significant changes occuring 10 min after surgery. After maxillary infiltration of 2.0 ml 1% ropivacaine, the maximum venous plasma concentration (Cmax) was 82 ± 15 μg/l. On isolated human infraorbital artery, ropivacaine (10 −4 M) induced endothelium-independent contraction. This study suggests that 0.75 and 1% ropivacaine offers adequate and safe intraoperative analgesia but not successful postoperative pain control for the surgical removal of upper third molars.
Ropivacaine is a new long-acting amide local anaesthetic with a potentially improved safety profile when contrasted with bupivacaine , for which potent cardiac and neurologic toxic effects, even in small doses, have been reported . The fact that ropivacaine may offer less cardiac and neurologic toxicity suggests a potential clinical advantage of ropivacaine over bupivacaine when large volumes of local anaesthetics are required for peripheral nerve blocks , epidural or spinal anaesthesia.
Various controlled clinical studies have demostrated that ropivacaine produces a dose-dependent peripheral anaesthetic effect. ZARIC et al. suggested that higher concentrations of ropivacaine (0.75 and 1%) were equired to provide adequate sensory block in lumbar epidural anaesthesia since the average total duration of anaesthesia was 7.5, 6 and 4.5 h for 1, 0.75 and 0.5% ropivacaine, respectively. It has also been reported that 1% ropivacaine, administered for interscalene brachial plexus anaesthesia for shoulder surgery, has a shorter onset time of anaesthesia and prolonged postoperative analgesia than 0.5% ropivacaine . It has also been suggested that the anaesthetic properties of roopivacaine were improved at higher concentrations and there was a slight vasoconstriction effect; this has been demonstrated in animals and in human blood vessels .
There is little information on the efficacy of ropivacaine in dental anaesthesia. In volunteers, not undergoing a surgical procedure, ERNBERG and KOPP found that results for maxillary infiltration (1 ml) and mandibular nerve block (1.8 ml) of 0.2, 0.5 and 0.75% ropivacaine, showed that a long-acting duration of soft tissue anaesthesia was observed only for mandibular nerve block when ropivacaine was used at a concentration of 0.75%. In similar conditions, comparable results were obtained by AXELSSON and ISACSSON . For maxillary infiltration anaesthesa in volonteeres, KENNEDY et al. reported longer duration of soft tissue anaesthesia (7 h) with short duration of pulpal anaesthesia (33 min), although 1.8 ml of 0.5% ropivacaine was injected with epinephrine (1:200.000). The effectiveness of ropivacaine in dentistry has been established for lower third molar surgery , oral surgical interventions and topical anaesthesia of the human oral mucosa .
The main purpose of this study was to assess the clinical efficacy and haemodynamic effects of 0.5, 0.75 and 1% ropivacaine for maxillary infiltration anaesthesia in a controlled double-blinded study. In addition, because the systemic side effects of local anaesthetics are directly related to their systemic plasma concentration and vasodilating properties, the authors also investigated the maximal venous plasma concentration of ropivacaine (in healthy volunteers) and the reactivity to ropivacaine of isolated human infraorbital arteries, which are responsible for blood flow at the site of maxillary infiltration anaesthesia. This information should help to establish basic principles for the effective and safe introduction of ropivacaine in clinical dental anaesthesia.
Material and Method
Patients and parameters of infiltration anaesthesia
After institutional approval (Ethical Committee of Faculty of Dentistry, University of Belgrade) and informed written consent, 66 adult patients (22 in each group), scheduled for upper third molar surgery, were studied. The patients were classified as having physical status 1 in the American Society of Anesthesiologists (ASA) classification. Exclusion criteria were: allergy to study medications; contraindications to maxillary infiltration anaesthesia; presence of any dental procedure 24 h previously; medication given 48 h previously; presence of acute or chronic infection in the oral cavity especially in the region of the upper molars; history of chronic pain; pregnancy and nursing mothers; and an inability to comply with the study assessment.
Patients were studied using a double-blind, controlled design and randomized by a computer-generated list to receive 2.5 ml of 0.5%, 0.75% or 1% ropivacaine plain, without a vasoconstrictor (Naropine ® , AstraZeneca, Sodertalje, Sweden) for maxillary infiltration anaesthesia (MIA; 2.0 ml) and palatal infiltration anaesthesia (PIA; 0.5 ml). The study solutions were prepared for injection by an independent clinical pharmacist not involved in the study. No premedication was given.
The onset and duration of anaesthesia were investigated using pinprick testing and numbness of soft tissue. Sensory changes for pinprick testing were recorded bilaterally at the buccal attached gingiva of the area where the upper third molars were impacted, using sharp pinprick testing with a 26-gauge needle directly through the gingiva into the periosteum, and at the palatal mucosa at the site of palatal injection. The onset of anaesthesia was tested every minute until the pinprick did not induce any sensation. If onset was not obtained within the first 15 min, simultaneously for both MIA and PIA, additional anaesthesia (to complete the surgical procedure) was applied only for the failed anaesthesia site, which was classified as an unsuccessful event. After the completion of surgery, the duration of anaesthesia was evaluated by pinprick testing every 30 min until the patient felt blunt sensation, and continuing every 10 min until sensation was re-established. Onset and duration of anaesthesia were also evaluated from subjective statements by the patients about the presence of soft tissue numbness using the same time protocol.
A 100-mm visual analogue scale (VAS) and six-pointed verbal rating scale (VRS), (marked with no pain, just noticeable pain, weak, moderate, severe and excruciate pain) were used to assess the intensity of anaesthesia during the surgical procedure determined by the patients at the end of surgery. If additional anaesthesia was given during the surgery (to complete the surgical procedure), as a result of unacceptable pain being reported, the anaesthesia was considered as unsuccessful only for the failed site.
Postoperative analgesia was provided with ibuprofen (Brufen ® 400 mg, Galenika, Belgrade, Serbia). All patients had routine follow-up, carried out by an independent anaesthetist on the day of surgery, and by an oral surgeon during the first 7 days after surgery. Patients were instructed to report any complications and discomfort.
Haemodynamic parameters
Patients, with successful MIA and PIA, had standard monitoring, including continuous electrocardiography and measurement of systolic blood pressure (SP), diastolic blood pressure (DP), mean arterial pressure (MAP), heart rate (HR) before administration of anaesthesia, during administration of anaesthesia, and 5 min after administration of anaesthesia. The surgery began 5 min after the last recording. Afterwards recordings were repeated 5 min into the surgical extraction (corresponding to 15 min after injection) according to the protocol of Meechan et al . The last reading of haemodynamic parameters was 30 min after the administration of anaesthesia (approximately 10 min after surgery).
Vascular effects
Segments of human infraorbital arteries were obtained during surgery for craniofacial deformities, after obtaining informed consent from five patients. The Local Ethical Committee of School of Dentistry, University of Belgrade approved the procedure. The isolated segments were carefully dissected free from surrounding connective tissue and cut into 3 mm long circular rings. All vessel segments were immediately placed in Krebs–Ringer–bicarbonate solution (composition in mM: NaCl 118.3; KCl 4.7; CaCl 2 2.5; MgSO 4 1.2; KH 2 PO 4 1.2; NaHCO 3 25.0; glucose 11.1). In separate experiments, the endothelium was removed by gently rubbing the intimal surface with a stainless-steel wire. Ring preparations were mounted between two stainless-steel triangles in an organ bath containing 10 ml Krebs–Ringer–bicarbonate solution (37 °C), aerated with 95% O 2 and 5% CO 2 , which produced a solution pH of 7.4. One of the triangles was attached to a displacement transducer (K30; Hugo Sachs, Freiburg, Germany). Isometric tension was recorded on a Hugo Sachs model MC 6621 recorder.
The artery segments were allowed to equilibrate for 60 min in Krebs–Ringer–bicarbonate solution. After this recovery period, preparations were given a preload of 2.0 g. Once at their optimal length, the segments were allowed to equilibrate for 30 min before experimentation. Contractions induced by ropivacaine in vascular rings under basal tension were expressed as percentages relative to the maximal contraction induced by KCl (60 mM).
C max and t max of ropivacaine
The single-dose pharmacokinetic study of ropivacaine was carried out on five healthy male volunteers (without any dental treatment), aged 25–33 years. The study was approved by the Local Ethical Committee of School of Dentistry, University of Belgrade and informed written consent was obtained from all subjects. All subjects were in the normal weight range for their height. Alcohol, caffeine-containing drinks, cigarettes and medications were not allowed during the study and for 24 h before it began. An injection of 2 ml of 1% ropivacaine was given for maxillary infiltration anaesthesia on the buccal side in the area of upper third molar.
Peripheral venous blood samples (10 ml) were collected from the antecubital vein immediately before the injection of the local anaesthetic and 5, 10, 15, 20, 30 and 45 min after the single dose of ropivacaine. All blood samples were centrifuged at room temperature immediately after collection and the plasma was stored at –20 °C. Ropivacaine was determined by liquid chromatography (Waters 2695 Separation Module, Milford, USA) with mass spectrometry (Waters Micromass Detector ZQ, Micromass Technology, Milford, USA).
Maximum peak ropivacaine concentration (C max ) and the time to reach the peak (t max ) were measured. The results were analyzed using the IBM MassLynx 4.0 Software System (Milford, USA).
Statistics
The study was designed to have 80% power to detect possible significant differences between groups. The analysis of variance (ANOVA) was used to compare patients’ data and the values of the anaesthetic parameters between three groups. Tukey test was used for post hoc comparisons. Analysis of variance for repeated measures was used to analyse changes over time. The χ 2 test was used for comparison of non-parametric values. To compare differences between two groups an unpaired type sample equal variance t-test with two-tailed distribution was used. The results of the clinical and experimental studies were given as mean ± SD. A level of p < 0.05 was considered to represent a statistically significant difference.
Results
Demographic data and details of the surgical procedure did not differ among study groups ( Table 1 ). 54 sites (14 MIA in 0.5%, 20 MIA in 0.75%, 20 MIA in 1% ropivacaine) with maxillary infiltration anaesthesia and 58 sites (14 PIA in 0.5%, 22 PIA in 0.75%, 22 PIA in 1% ropivacaine) with palatal infiltration anaesthesia were evaluated ( Table 1 ).
| Parameters | 0.5% Rop | 0.75% Rop | 1% Rop | Significance |
|---|---|---|---|---|
| Age (years) * | 24.7 ± 3.8 | 28.6 ± 10.4 | 25.6 ± 4.4 | NS |
| n (MIA) | 14 | 20 | 20 | NS |
| n (PIA) | 14 | 22 | 22 | NS |
| Gender (F/M) | 7/7 | 12/10 | 14/8 | NS |
| Weight (kg) * | 63 ± 9 | 66 ± 13 | 65 ± 12 | NS |
| Height (cm) * | 175 ± 23 | 181 ± 12 | 180 ± 17 | NS |
| Duration of surgery (min) * | 11.4 ± 2.2 | 13.6 ± 3.9 | 11.9 ± 2.1 | NS |
| Imp/PImp molars | 10/4 | 15/7 | 18/4 | NS |
Parameters of infiltration anaesthesia
Maxillary infiltration anaesthesia was effective in 60, 90 and 90% of 0.5, 0.75 and 1% ropivacaine, respectively. Only the complete success (100%) of infiltration anaesthesia was recorded for PIA in the 0.75 and 1% ropivacaine groups. For both infiltration anaesthesia techniques significant difference was observed between 0.5% ropivacaine and higher concentrations of ropivacaine (p < 0.05) ( Table 2 .).
Onset of anaesthesia was not significantly different between the three groups for MIA and PIA measured by subjective soft tissue signs of numbness. A concentration-dependent relationship and significant difference between 0.5 and 1% ropivacaine in MIA, and 0.75 and 1% ropivacaine against 0.5% ropivacaine for PIA was recorded after pinprick evaluation of onset time ( Table 3 ). Duration of anaesthesia increased in a concentration-dependent fashion with significant differences when MIA was measured by numbness and pinprick testing. Although the mean duration time was longer with the 1% ropivacaine given in PIA, this difference was not statistically significant compared with duration times obtained with 0.5 or 0.75% ropivaciane solutions ( Table 3 ).
| Parameters (mean ± SD) | ||||||||
|---|---|---|---|---|---|---|---|---|
| Treatment | Onset (s) | Duration (min) | ||||||
| MIA | PIA | MIA | PIA | |||||
| numbness | pinprick | numbness | pinprick | numbness | pinprick | numbness | pinprick | |
| 0.5% Rop | 3.3 ± 1.0 | 2.2 ± 0.7 | 2.1 ± 0.6 | 1.7 ± 0.3 | 210 ± 49 | 143 ± 24 | 140 ± 44 | 110 ± 26 |
| 0.75% Rop | 2.2 ± 1.1 | 1.7 ± 0.8 | 1.3 ± 1.0 | 1.0 ± 0.5 | 25 ± 46 | 163 ± 46 | 158 ± 44 | 122 ± 31 |
| 1% Rop | 2.6 ± 1.7 | 1.5 ± 0.9 | 1.8 ± 0.8 | 1.0 ± 0.4 | 310 ± 43 | 213 ± 30 | 170 ± 52 | 135 ± 32 |
| Statistic | p < 0.05 * | p < 0.05 † | p < 0.05 § | p < 0.05 £ | ||||
There was no statistically significant difference between the three groups when the authors evaluated the intensity of PIA using the VAS and VRS scale although a dose-related effect was observed. The difference was significant when VRS was analyzed for MIA and a dose-dependent relationship was observed ( Table 4 ). Also in MIA, 64% of patients treated with 0.5% ropivacaine experienced intraoperative pain, compared with patients who received 0.75% ropivacaine (30% patients with pain) or 1% ropivacaine (25% patients with pain) ( Table 4 ).
| Parameters (mean ± SD) | ||||||
|---|---|---|---|---|---|---|
| MIA | PIA | |||||
| Treatment | Pain | Pain | ||||
| yes/no | VAS | VRS | yes/no | VAS | VRS | |
| (n) | (mm) | (n) | (mm) | |||
| 0.5% Rop | 9/5 | 6.6 ± 9.9 | 1.9 ± 0.9 | 3/11 | 0.7 ± 1.6 | 1.2 ± 0.4 |
| (14) | (14) | |||||
| 0.75% Rop | 6/14 | 1.6 ± 4.1 | 1.5 ± 0.8 | 2/20 | 0.4 ± 1.7 | 1.1 ± 0.2 |
| (20) | (22) | |||||
| 1% Rop | 5/15 | 2.5 ± 6.9 | 1.4 ± 0.8 | 0/22 | 0 | 1.0 ± 0.0 |
| (20) | (22) | |||||
| Statistic | X 2 = 13.201 | p < 0.05 * | NS | NS | NS | |
| p = 0.005 | ||||||
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