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Pain relief of oral ulcer by dibucaine-film
Pain 83 (1999) 625±626
Clinical Note
www.elsevier.nl/locate/pain
Pain relief of oral ulcer by dibucaine-®lm Keiko Yamamura a,*, Toshihisa Yotsuyanagi b, Tomomitsu Okamoto c, Toshitaka Nabeshima a a
Department of Hospital Pharmacy, Nagoya University School of Medicine, Tsuruma-cho, Showa-ku, Nagoya 466, Japan b Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya 467, Japan c Department of Obstetrics and Gynecology, Nagoya University School of Medicine, Tsuruma-cho, Showa-ku, Nagoya 466, Japan Received 7 December 1998; received in revised form 6 June 1999; accepted 23 June 1999
Abstract A water-soluble three-layered oral mucosa-adhesive ®lm made from hydroxypropyl cellulose containing dibucaine (0.25 mg of drug/cm 2) was designed for alleviation of severe pain due to oral ulcers, caused by chemotherapy and/or radiotherapy. We report two patients with constant severe pain ulcers treated with the dibucaine ®lm. Patients were asked to record the time that pain was relieved while chewing following ®rst application of the ®lm. Pain relief lasted for 2±5 h after application of the dibucaine ®lm. q 1999 International Association for the Study of Pain. Published by Elsevier Science B.V. Keywords: Oral ulcer; Dibucaine; Mucosa-adhesive ®lm; Hydroxyproply cellulose
1. Introduction Oral ulceration is common in patients who have undergone chemotherapy and/or radiotherapy. It often causes severe discomfort, interferes with the ability to sleep, interferes with eating and drinking, and may require interruption of therapy until the pain becomes tolerable (Sonis and Clark, 1991). Topical treatment is an effective and safe method delivering anesthetic agents to the mucosal area (Toth et al., 1995). The present commercial local anesthetic preparations such as lotions, gels or ointments are easily displaced from the affected area and demonstrate limited effectiveness due to their brief activity (Matthews et al., 1987). Several studies have examined oral mucosal adhesive systems containing lidocaine to prolong pain relief. However, the systems may cause irritation to the damaged mucosa because they must be removed from the application site after extraction of lidocaine (Brook et al., 1989; Hersh et al., 1996; Taware et al., 1997). To solve this problem, we designed and a three-layered hydroxypropyl cellulose (HPC) ®lm that consisted of a non-adhesive layer, an intermediate drug-containing layer and an adhesive layer (Fig. 1). This water-soluble ®lm slowly dissolves in saliva, so it does not have to be removed after application. The ®lm was * Corresponding author. Department of Neuropsycho-pharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Tsuruma-cho, Showa-ku, Nagoya 466, Japan. Tel.: 181-52-744-2673; fax: 181-52-7442979.
prepared as follows: to obtain the non-adhesive layer, a homogeneous solution of HPC (0.6 g), ethyl cellulose (0.6 g) and polyethylene glycol 400 (PEG, 0.44 g) in ethanol (20 ml) was poured into a 6 £ 10 cm 2 Te¯on-coated cast and dried. Then, a solution of HPC (5.8 g), PEG (0.11 g) and dibucaine (DC: 0.11 g) in ethanol (130 ml) was applied on the non-adhesive layer and dried. Finally, HPC (0.5 g) and PEG (0.01 g) were dissolved in ethanol (20 ml) in which pectin (1.9 g) was dispersed to form a suspension. Then the suspension was applied to the above double-layered ®lm and dried to form the adhesive layer. The thickness of the DC ®lm (0.25 mg of drug/cm 2) was 0.2 mm. We present two cases in whom application of the dibucaine ®lms resulted in effective relief of oral pain. 2. Case reports 2.1. Patient 1 A 82 year old woman with a cancer of the right maxilla had received radiotherapy in conjunction with chemotherapy which included cisplatin and ¯uorouracil. She developed oral ulcers on tongue and gingival with severe pain on any contact. Thus, she could not take a solid meal and was restricted to liquids. She applied the ®lm that was cut in an appropriate size, typically 1.5±2 cm in diameter, to affected sites 30 mm before taking a meal. She was asked to record the duration that she did not feel pain while chewing following the ®rst application of the ®lm. The pain relief
0304-3959/99/$20.00 q 1999 International Association for the Study of Pain. Published by Elsevier Science B.V. PII: S 0304-395 9(99)00164-5
626
K. Yamamura et al. / Pain 83 (1999) 625±626
Fig. 1. Schematic illustration of a 3-layered mucosa-adhesive ®lm.
lasted 4±5 h, and she could take a solid meal without feeling discomfort and pain. Two applications per day were required. 2.2. Patient 2 A 29 year old woman with choriocarcinoma had received chemotherapy including methotrexate and daunorubicin. She developed ulcers on the mucobuccal with constant severe pain. She could only manage liquids and complained that she could not sleep at night due to pain. She applied the ®lm to affected sites before taking a meal and before sleep. She was asked to record the duration she was pain free while chewing following the ®rst application of the ®lm. The pain relief lasted 2±3 h. She reported that she could apply the ®lm mucosa, and that was not displaced by chewing or movements of her tongue. She did not feel that her mouth was obstructed and she could sleep thereafter. The intensity of her pain changed from constant, severe pain to mild while chewing only for a period of 7 days. No serious or unexpected adverse effects were observed during the course of this treatment. 3. Conclusion The mucosa-adhesive ®lm has to be moderately watersoluble and pliant, because it is intended to be applied to highly irritable areas of the oral mucosa and/or tongue. We reported previously that a single layered HPC ®lm was
suf®ciently pliant to be applied the oral lesion sites (Yotsuyanagi et al., 1985). However, it did not have a suf®cient adhesive strength. When the affected site was highly moist due to the ulceration, the ®lm fell off the affected sites or was moved from its initial position due to uncontrolled slipping. The three-layered HPC ®lm reported here has improved the clinical applicability of this preparation. The addition of ethyl cellulose prevented sticking to the ®ngers during application; the addition of pectin increased its adhesive strength to the mucous. Dibucaine did not give rise to any complaints about the taste of the ®lm. In conclusion, this dibucaine three-layered ®lm was easy to use and welltolerated. It provided effective pain relief when used on oral ulcers and we consider that this ®lm may improve the quality of life of patients with eating dysfunction and help maintain their physical strength. References Brook IM, Tucker GT, Tuckley EC, Boyes RN. A lignocaine patch for dental analgesia and early pharmacology. J Controlled Release 1989;10:183±188. Hersh EV, Houpt MI, Cooper SP, Feldman RS, Wolff MS, Levin ML. Analgesic ef®cacy and safety of an intraoral lidocaine patch. J Am Dent Assoc 1996;127:1626±1634. Matthews RW, Scully CM, Levers BGH. Clinical evaluation of benzydamine, chlorhexidine, and placebo mouthwashes in the management of recurrent aphthous stomatitis. Oral Surg. Oral Med. Oral Pathol 1987;63:189±191. Sonis S, Clark J. Prevention and management of oral mucositis induced by antineoplastic therapy. Oncology 1991;5:18±22. Taware CP, Mazumdar S, Pendharkar M, Adani MH, Devarajan PV. A bioadhesive delivery systems as an alternative to in®ltration anesthesia. Oral Surg. Oral Med. Oral Pathol 1997;84:609±615. Toth BB, Chambers MS, Fleming TJ. Minimizing oral complications of cancer treatment. Oncology 1995;9:851±866. Yotsuyanagi T, Yamamura K, Akao Y. Mucosa-adhesive ®lm containing local analgesic. Lancet 1985;14:613.
Clinical Note
www.elsevier.nl/locate/pain
Pain relief of oral ulcer by dibucaine-®lm Keiko Yamamura a,*, Toshihisa Yotsuyanagi b, Tomomitsu Okamoto c, Toshitaka Nabeshima a a
Department of Hospital Pharmacy, Nagoya University School of Medicine, Tsuruma-cho, Showa-ku, Nagoya 466, Japan b Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya 467, Japan c Department of Obstetrics and Gynecology, Nagoya University School of Medicine, Tsuruma-cho, Showa-ku, Nagoya 466, Japan Received 7 December 1998; received in revised form 6 June 1999; accepted 23 June 1999
Abstract A water-soluble three-layered oral mucosa-adhesive ®lm made from hydroxypropyl cellulose containing dibucaine (0.25 mg of drug/cm 2) was designed for alleviation of severe pain due to oral ulcers, caused by chemotherapy and/or radiotherapy. We report two patients with constant severe pain ulcers treated with the dibucaine ®lm. Patients were asked to record the time that pain was relieved while chewing following ®rst application of the ®lm. Pain relief lasted for 2±5 h after application of the dibucaine ®lm. q 1999 International Association for the Study of Pain. Published by Elsevier Science B.V. Keywords: Oral ulcer; Dibucaine; Mucosa-adhesive ®lm; Hydroxyproply cellulose
1. Introduction Oral ulceration is common in patients who have undergone chemotherapy and/or radiotherapy. It often causes severe discomfort, interferes with the ability to sleep, interferes with eating and drinking, and may require interruption of therapy until the pain becomes tolerable (Sonis and Clark, 1991). Topical treatment is an effective and safe method delivering anesthetic agents to the mucosal area (Toth et al., 1995). The present commercial local anesthetic preparations such as lotions, gels or ointments are easily displaced from the affected area and demonstrate limited effectiveness due to their brief activity (Matthews et al., 1987). Several studies have examined oral mucosal adhesive systems containing lidocaine to prolong pain relief. However, the systems may cause irritation to the damaged mucosa because they must be removed from the application site after extraction of lidocaine (Brook et al., 1989; Hersh et al., 1996; Taware et al., 1997). To solve this problem, we designed and a three-layered hydroxypropyl cellulose (HPC) ®lm that consisted of a non-adhesive layer, an intermediate drug-containing layer and an adhesive layer (Fig. 1). This water-soluble ®lm slowly dissolves in saliva, so it does not have to be removed after application. The ®lm was * Corresponding author. Department of Neuropsycho-pharmacology and Hospital Pharmacy, Nagoya University School of Medicine, Tsuruma-cho, Showa-ku, Nagoya 466, Japan. Tel.: 181-52-744-2673; fax: 181-52-7442979.
prepared as follows: to obtain the non-adhesive layer, a homogeneous solution of HPC (0.6 g), ethyl cellulose (0.6 g) and polyethylene glycol 400 (PEG, 0.44 g) in ethanol (20 ml) was poured into a 6 £ 10 cm 2 Te¯on-coated cast and dried. Then, a solution of HPC (5.8 g), PEG (0.11 g) and dibucaine (DC: 0.11 g) in ethanol (130 ml) was applied on the non-adhesive layer and dried. Finally, HPC (0.5 g) and PEG (0.01 g) were dissolved in ethanol (20 ml) in which pectin (1.9 g) was dispersed to form a suspension. Then the suspension was applied to the above double-layered ®lm and dried to form the adhesive layer. The thickness of the DC ®lm (0.25 mg of drug/cm 2) was 0.2 mm. We present two cases in whom application of the dibucaine ®lms resulted in effective relief of oral pain. 2. Case reports 2.1. Patient 1 A 82 year old woman with a cancer of the right maxilla had received radiotherapy in conjunction with chemotherapy which included cisplatin and ¯uorouracil. She developed oral ulcers on tongue and gingival with severe pain on any contact. Thus, she could not take a solid meal and was restricted to liquids. She applied the ®lm that was cut in an appropriate size, typically 1.5±2 cm in diameter, to affected sites 30 mm before taking a meal. She was asked to record the duration that she did not feel pain while chewing following the ®rst application of the ®lm. The pain relief
0304-3959/99/$20.00 q 1999 International Association for the Study of Pain. Published by Elsevier Science B.V. PII: S 0304-395 9(99)00164-5
626
K. Yamamura et al. / Pain 83 (1999) 625±626
Fig. 1. Schematic illustration of a 3-layered mucosa-adhesive ®lm.
lasted 4±5 h, and she could take a solid meal without feeling discomfort and pain. Two applications per day were required. 2.2. Patient 2 A 29 year old woman with choriocarcinoma had received chemotherapy including methotrexate and daunorubicin. She developed ulcers on the mucobuccal with constant severe pain. She could only manage liquids and complained that she could not sleep at night due to pain. She applied the ®lm to affected sites before taking a meal and before sleep. She was asked to record the duration she was pain free while chewing following the ®rst application of the ®lm. The pain relief lasted 2±3 h. She reported that she could apply the ®lm mucosa, and that was not displaced by chewing or movements of her tongue. She did not feel that her mouth was obstructed and she could sleep thereafter. The intensity of her pain changed from constant, severe pain to mild while chewing only for a period of 7 days. No serious or unexpected adverse effects were observed during the course of this treatment. 3. Conclusion The mucosa-adhesive ®lm has to be moderately watersoluble and pliant, because it is intended to be applied to highly irritable areas of the oral mucosa and/or tongue. We reported previously that a single layered HPC ®lm was
suf®ciently pliant to be applied the oral lesion sites (Yotsuyanagi et al., 1985). However, it did not have a suf®cient adhesive strength. When the affected site was highly moist due to the ulceration, the ®lm fell off the affected sites or was moved from its initial position due to uncontrolled slipping. The three-layered HPC ®lm reported here has improved the clinical applicability of this preparation. The addition of ethyl cellulose prevented sticking to the ®ngers during application; the addition of pectin increased its adhesive strength to the mucous. Dibucaine did not give rise to any complaints about the taste of the ®lm. In conclusion, this dibucaine three-layered ®lm was easy to use and welltolerated. It provided effective pain relief when used on oral ulcers and we consider that this ®lm may improve the quality of life of patients with eating dysfunction and help maintain their physical strength. References Brook IM, Tucker GT, Tuckley EC, Boyes RN. A lignocaine patch for dental analgesia and early pharmacology. J Controlled Release 1989;10:183±188. Hersh EV, Houpt MI, Cooper SP, Feldman RS, Wolff MS, Levin ML. Analgesic ef®cacy and safety of an intraoral lidocaine patch. J Am Dent Assoc 1996;127:1626±1634. Matthews RW, Scully CM, Levers BGH. Clinical evaluation of benzydamine, chlorhexidine, and placebo mouthwashes in the management of recurrent aphthous stomatitis. Oral Surg. Oral Med. Oral Pathol 1987;63:189±191. Sonis S, Clark J. Prevention and management of oral mucositis induced by antineoplastic therapy. Oncology 1991;5:18±22. Taware CP, Mazumdar S, Pendharkar M, Adani MH, Devarajan PV. A bioadhesive delivery systems as an alternative to in®ltration anesthesia. Oral Surg. Oral Med. Oral Pathol 1997;84:609±615. Toth BB, Chambers MS, Fleming TJ. Minimizing oral complications of cancer treatment. Oncology 1995;9:851±866. Yotsuyanagi T, Yamamura K, Akao Y. Mucosa-adhesive ®lm containing local analgesic. Lancet 1985;14:613.