Anesth Analg 2007;104:1528-1531
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000262040.19721.26
PAIN MEDICINE
Liposome-Encapsulated Ropivacaine for Topical Anesthesia of Human Oral Mucosa
Michelle Franz-Montan, DDS, MSc*,
André L. R. Silva, PharmD
,
Karina Cogo, PharmD, MSc*,
Cristiane de C. Bergamaschi, PharmD, MSc*,
Maria C. Volpato, PhD*,
José Ranali, PhD*,
Eneida de Paula, PhD, and
Francisco C. Groppo, PhD*
From the *Department of Physiological Sciences, Dentistry School of Piracicaba, Piracicaba, SP, Brazil; and Department of Biochemistry, Institute of Biology, State University of Campinas– UNICAMP, Campinas, SP, Brazil.
Address correspondence and reprint requests to Francisco C. Groppo, PhD, Av. Limeira, 901 – Bairro Areião, CEP: 13414-903 Piracicaba, São Paulo, Brazil. Address e-mail to fcgroppo{at}fop.unicamp.br.
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Abstract
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BACKGROUND: The elimination of pain caused by needle insertion for local anesthesia would be a significant advance in dentistry.
METHODS: In this blinded cross-over study we evaluated the efficacy of liposome-encapsulated ropivacaine for topical anesthesia. Thirty healthy volunteers received 60 mg topical anesthetics: Liposome-encapsulated 1% ropivacaine, 1% plain ropivacaine, 2.5% lidocaine and 2.5% prilocaine mixture (EMLA), and 20% benzocaine gel, in the buccal fold of the upper-right canine for 2 min in different sessions. After insertion of 30-G needles, pain was rated on a visual analog scale (VAS). A pinprick test was used to measure the duration of topical anesthesia. The pulpar response was assessed by an electric pulp tester.
RESULTS: VAS median and interquartile range (in cm) were 0.8 (0.4–1.5), 1.6 (0.8–2.6), 1.1 (0.3–2.7), 2.2 (0.9–2.9) for liposome-encapsulated ropivacaine, ropivacaine, EMLA, and benzocaine groups, respectively. The liposome-encapsulated ropivacaine group showed lower VAS mean values when compared with the benzocaine group (P = 0.0205). The median values and interquartile range for the duration of soft tissue anesthesia were 11 (7–14), 6.5 (4–11), 14 (11–16), and 7 (6–9) min for liposome-encapsulated ropivacaine, ropivacaine, EMLA, and benzocaine groups, respectively. EMLA and liposome-encapsulated ropivacaine were just as efficient for reducing pain, and showed longer soft tissue anesthesia when compared to the other local anesthetics (P = 0.0001).
CONCLUSION: Liposomal-encapsulated 1% ropivacaine gel was equivalent to EMLA® for reducing pain during needle insertion and for the duration of soft tissue anesthesia. None of the topical anesthetics was effective for inducing pulpal anesthesia.
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Introduction
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Local anesthesia is one of the most feared procedures in dentistry, probably due to pain during needle insertion (1). Elimination of the needle for local anesthesia would be a great advance in dental treatment. Topical pulpal anesthesia is not yet a reliable procedure; however, this objective has been pursued by many investigators (2,3).
Liposomes have been reported to be effective drug carriers. Local anesthetics encapsulated into liposomes show longer duration of action, reduction in circulating plasma levels, reduced central nervous system toxicity, and reduced cardiovascular toxicity (4,5). In addition, liposomes facilitate the penetration of the anesthetic into the skin, carrying the encapsulated drug into the dermis and providing sustained release. Previous studies showed significant skin anesthesia induced by liposome-encapsulated local anesthetics (6–9).
The efficacy of encapsulated local anesthetics in the oral mucosa was evaluated by Zed et al., (1) who concluded that liposome-encapsulated 5% tetracaine provided more pain relief before a local anesthetic injection than 20% benzocaine gel.
The aim of this study was to evaluate liposomal ropivacaine as a topical anesthetic in the oral mucosa as well as its effect on the pulpal response.
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METHODS
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The Ethical Committee of Piracicaba Dental School, State University of Campinas Piracicaba, Brazil (#162/ 2003) approved this research. This study evaluated 30 healthy volunteers (15 women and 15 men) 18 to 26-yr-old (21.3 ± 2.31 yr). All volunteers gave written informed consent. They were in good health, and had no history of allergy to any of the local anesthetics. None of the volunteers were taking any medication that would alter pain perception, as determined by oral questioning and written health history. The tooth undergoing testing was vital and free of caries, large restorations, periodontal disease, past endodontic treatment, and history of trauma or sensitivity.
The volunteers randomly received four different topical anesthetics in a blinded, cross-over, four-period treatment design. Each treatment was performed in four different appointments spaced at least 1 wk apart. Each volunteer received 60 mg of topical anesthetic: liposome-encapsulated 1% ropivacaine gel, plain 1% ropivacaine gel, eutectic mixture of 2.5% lidocaine, and 2.5% prilocaine cream (EMLA®, AstraZeneca, Cotia, Brazil) (EMLA), and 20% benzocaine gel (Benzotop®, DFL Ind. Com. Ltd, Rio de Janeiro, Brazil). Both EMLA® and Benzotop® were kindly donated by AstraZeneca and DFL, respectively. The ropivacaine gels were prepared from ropivacaine hydrochloride (kindly donated by Cristalia Produtos Quimicos e Farmaceuticos Ltda) at the Department of Biochemistry, Institute of Biology, State University of Campinas.
Before topical application, at each session the upper right canine was tested with a pulp tester six times, at 2-min intervals (Analytic Technology, Redmond, WA) to record baseline vitality. The probe tip of the pulp-tester was placed in the center of the canine on the buccal side. Fluoride toothpaste was chosen as the conductive substance (10–12).
The gingiva at the maxillary buccal fold in the canine region was dried using sterile gauze. Topical anesthetic (previously weighed) was applied using a cotton swab. Each topical anesthetic was kept on the mucosa surface for 2 min. After topical application, the mucosa was gently wiped with sterile gauze followed by a water rinse.
After topical application, the volunteers were tested three times:
- Pain associated with needle insertion. Immediately after topical anesthetic application, a 30-G dental needle was inserted in the region of topical application, until periosteum contact. The pain perception was measured using a visual analog pain scale (VAS), consisting of a 10-cm line where 0 indicates "no pain" and 10 "unbearable pain." Subjects were asked to make a mark on the line according to their level of perceived pain. A ruler was used to measure the distance from the end-point marked "no pain" to the mark made by the volunteer.
- Duration of soft tissue anesthesia. After pain intensity was measured, all volunteers were asked to verify the duration of oral mucosa anesthesia, using a pinprick test adapted from McLean et al., (10) every 1 min, up to cessation of numbness.
- Pulpal anesthesia. After the topical anesthetic was removed, electrical stimulation was performed every 2 min for 20 min to evaluate the pulpal response. Pulpal anesthesia was defined as the absence of the subject’s response to the maximal output (300 V, 0.08 mA) of the pulp tester, indicated as the "80" reading (10).
The results were compared by the Friedman test and Wilcoxon sign-ranked test for pairwise comparison as the post hoc test (Bioestat 4.0, Mamirauá Institute, Belém, PA, Brazil). Comparisons were considered significant at P < 0.05.
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RESULTS
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There were no significant differences (P > 0.05) among groups concerning pain associated with needle insertion, except for the liposome-encapsulated ropivacaine group, which showed lower VAS values when compared to the benzocaine group (P = 0.0205). Figure 1 shows medians of VAS for all groups.
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Figure 1. Visual analog pain scale (VAS) scores rated by the volunteer after needle insertion. (Central line: median; Box: lower and upper quartiles; Whisker: maximum and minimum values; o: outlier).
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The EMLA® and liposome-encapsulated ropivacaine groups had longer soft tissue anesthesia when compared to the ropivacaine and benzocaine gels (P = 0.0001). No significant differences were found between benzocaine and ropivacaine groups (P > 0.05). Figure 2 shows the medians of soft tissue anesthesia, in min.
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Figure 2. Duration of soft tissue anesthesia in minutes (Central line: median; Box: lower and upper quartiles; Whisker: maximum and minimum values; o: outlier).
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There were no statistically significant differences concerning pulpal response (canine) among the different periods or anesthetics tested. No volunteer achieved the maximum setting of the pulp tester (300 V, 80 reading). Figure 3 shows medians of pulpal response after topical anesthetic application.
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Figure 3. Median pulpal response measured with the electrical pulp tester every 2 min from the application of topical anesthesia (the zero mark represents the baseline response).
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DISCUSSION
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There is a clear need to develop newer and better topical anesthetics, especially for the pediatric dental population (13). Although EMLA® has been reported to be the most effective topical anesthetic (2,14,15), Primosch and Rolland-Asensi (16) observed in children that EMLA® in an oral adhesive form showed no superior effectiveness for reducing the pain response during palatal infiltration when compared to benzocaine 20% in either oral adhesive or gel formulation. The present study, evaluating the buccal fold, showed similar results. All topical anesthetics tested had a similar ability to reduce the pain response, with lower pain scores obtained with liposome-encapsulated ropivacaine compared to benzocaine.
Liposome-encapsulated ropivacaine and EMLA produced better results because they produced longer soft tissue anesthesia when compared to the other anesthetics tested. When EMLA was applied, soft tissue anesthesia duration was similar to that obtained by Haasio et al. (17) but less than that reported by McMillan et al. (15). This could have been related to the dose and time of application as previously reported (15,17,18). McMillan et al. (15) applied 500 mg of EMLA for 10 min, Haasio et al. (17) applied 200 mg, whereas in the present study only 60 mg of local anesthetic was applied for 2 min.
Bitter taste (pH = 9.0), low viscosity, cost, and subjects’ preference are among the many disadvantages of EMLA® use in the oral mucosa (3). In addition, the manufacturer does not recommend its oral use because safe dosing amounts for mucosal application are unknown (16,19).
The lack of an effective topical anesthetic, along with the disadvantages of EMLA®, has further encouraged the search for the ideal topical anesthetic. In the present study, ropivacaine was chosen due to its characteristics, e.g., it is a long-acting amide local anesthetic, available in pure S-isomeric form, thus having decreased potential for cardiac and central nervous system toxicity (12,20,21). Ropivacaine also has less potential for causing allergenic reactions when compared to benzocaine (19). Methemoglobinemia is a rare but serious complication of local anesthetics. Literature reports on this condition are related to prilocaine, benzocaine, procaine, and lidocaine (22), but not ropivacaine.
Liposomal encapsulation of local anesthetics enhances penetration through the epidermal barrier, carrying the encapsulated drug into the skin and providing sustained release. The permeability of the oral mucosa is estimated to be 4–4000 times more than that of skin (21). The better penetration of liposomal formulations and better mucosa permeability could suggest that some liposomal-encapsulated local anesthetics applied to the oral mucosa surface could penetrate the cortical bone and pulpal tissue. However, the topical liposome-encapsulated formulation evaluated in the present study was not effective for inducing pulpal anesthesia.
Similar results were obtained by Meechan and Donaldson (3), who observed no significant differences for reducing the pulpal response of maxillary primary teeth (anterior maxillary buccal fold) after a 5-min application of EMLA® or placebo.
However, Vickers and Punnia-Moorthy (2) observed an absence of pulpal response after application of 500 mg of EMLA® cream for 15–30 min in 13 subjects. Twelve subjects (92%) reported no pain at the maximum setting of the pulp tester. In the present study, 60 mg of each topical anesthetic was used for a 2-min application on the oral mucosa. These methodological differences probably affected the effectiveness of pulpal anesthesia of the topical anesthetics evaluated. Further studies will be necessary to test the pulpal response after topical use of ropivacaine under similar conditions, i.e., higher doses and longer mucosal contact time. The similarity between EMLA® and liposome-encapsulated ropivacaine with regard to soft tissue anesthesia could be considered a good indicator that larger amounts could produce pulpal anesthesia. Liposome-encapsulated ropivacaine also had similar efficacy for reducing the pain response (VAS), indicating that ropivacaine could replace EMLA for oral use.
In conclusion, liposome-encapsulated ropivacaine was equivalent to EMLA for reducing pain during needle insertion and with respect to the duration of soft tissue anesthesia. However, none of the topical anesthetics was effective for inducing pulpal anesthesia in a 2-min application time.
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ACKNOWLEDGMENTS
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We thank AstraZeneca (Brazil), DFL (Brazil) and Cristalia (Brazil) for the kind donation of EMLA® cream, Benzotop® and ropivacaine hydrochloride, respectively.
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Footnotes
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Accepted for publication February 21, 2007.
The author, M. Franz-Montan was supported (scholarship) by Conselho Nacional de Desenvolvimento Científico e Tecnológico– CNPq.
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Abstract
Introduction
