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Report CopyRight/DMCA Form For : Treatment Of Oral Mucositis Pain Following Radiation
1558 Support Care Cancer 2014 22 1557 1562, Recommended evidence based management of oral muco mucosa including exposed nerve endings Fig 1 The liquid. sitis in patients with head and neck cancer consists of crystalline film formation occurs by molecular self assembly. implementing an oral care protocol regularly assessing pa of the lipid components and ambient water molecules present. tients for oral symptoms and empiric short term analgesics 1 in saliva and does not involve any chemical reaction The film. 9 10 Gentle brushing and flossing and the use of bland oral adheres to the palate the inside of the cheeks gums and the. rinses are common features of oral care protocols Although a rim of the tongue In the formulation containing benzydamine. number of interventions are available to relieve pain associat the drug was slowly released into the oral mucosa with the. ed with oral mucositis there is currently a lack of well aim of conferring rapid onset and prolonged analgesia. supported therapies According to a recent Cochrane review Additional effects of the bioadhesive lipid formulation may. 11 randomized clinical trials of oral mucositis treatments are include lubrication and mechanical protection of the sore. few and offer little clinical guidance The existing evidence mucosa and possibly a moistening effect. has not shown mouthwashes containing analgesics or antisep The present study was conducted with the primary objec. tics to be superior to placebo or to unmedicated preparations tive of testing the analgesic effect of CAM2028 with. Behavioral approaches relaxation and imagery or hypno benzyd amine compared w ith CAM2028 without. sis were also not superior to control treatments There is a benzydamine the FDA approved prescription formulation of. need for effective rapid acting treatment that can be easily episil over an 8 h period An additional objective was to. deployed in the clinic as needed assess the safety and tolerability of a single dose of the new. Benzydamine is among the agents frequently recommend formulation. ed for pain relief in oral mucositis in patients undergoing. moderate dose radiation therapy for head and neck cancer. 1 9 10 Benzydamine is a nonsteroidal antiinflammatory Patients and methods. drug with a long history of safe use in patients Results of. clinical trials of benzydamine in oral mucositis have been CAM2028 with and without benzydamine was evaluated in. mixed two studies showed no greater effects on pain than a crossover double blind placebo controlled single dose. placebo 11 but one trial suggests it is effective in preventing randomized proof of concept trial in head and neck cancer. mouth ulcers and delaying the use of systemic analgesics patients receiving radiotherapy The study was conducted at. following radiation for head and neck cancer 12 The cur five oncology centers in Bulgaria The protocol and the state. rently available oromucosal benzydamine products have a ment of informed consent were approved in Bulgaria by an. short duration of effectiveness and need to be administered Independent Ethics Committee The trial was conducted in. every 1 5 to 3 h accordance with the Declaration of Helsinki and its revisions. The present report describes the development and pilot as well as with the valid local and national laws of Bulgaria. testing of a new formulation of benzydamine designed to with the International Conference on Harmonisation ICH. extend its analgesic effects for a sustained period The pilot Harmonised Tripartite Guideline for Good Clinical Practice. study described herein a randomized crossover trial in pa E6 issued in July 1996 and with the relevant European. tients with head and neck cancer had the unexpected result Commission Directives All patients gave written informed. that the formulation itself had a prolonged analgesic effect consent prior to enrollment. regardless of whether it contained benzydamine or was un Study participants were male or female patients at least. medicated Based on these and other data and by virtue of its 18 years of age undergoing outpatient radiation therapy for. mechanical mode of action the formulation CAM2028 con newly diagnosed head and neck cancer At screening all pa. trol episil Camurus has recently received FDA and EU tients had undergone radical or postoperative radiotherapy to a. approvals as a medical device for the management of pain in significant part of clinically visible oral and or pharyngeal. oral mucositis mucosa at two or more anatomic sites The trial began during. weeks 3 to 4 of radiotherapy and took place over a maximum. duration of 12 days After a screening period of up to 7 days. Development of investigational formulation treatment was randomly assigned at this point patients must. have received at least one third of the planned total dosage of. CAM2028 benzydamine was developed as a lipid based drug radiation At screening participants were required to exhibit. carrier system for local and extended delivery of benzydamine symptomatic oral mucositis WHO grade 2 or above Pain. in the oral cavity After application to the oral mucosa phos scores of at least 6 on a Likert scale of 0 to 10 were required at. pholipid and triglyceride lipid components of the formulation screening and before each treatment Clinically relevant ex. spread in the oral cavity and self assemble with a trace volume clusion criteria were pregnancy or breastfeeding known con. of aqueous fluid at the mucosal surface to form a bioadhesive traindications or hypersensitivity to the trial drug or other. liquid crystalline lining protecting the sore and inflamed NSAIDs immunocompromised hepatitis A or B infection. Support Care Cancer 2014 22 1557 1562 1559, Fig 1 Mechanism of action of CAM2028 After application to the oral mucosa phospholipid and triglyceride lipid components self assemble with a. trace volume of water saliva to form a bioadhesive and protective liquid crystalline lining of the oral mucosa. and prior chemotherapy immunotherapy or radiation to the analgesics anti inflammatories antimicrobials and muco. upper airways protective agents Also prohibited were systemic anti. inflammatories analgesics and drugs that may affect the. Study design and procedures process of oral mucositis including growth factors vitamins. and newly introduced steroids Immediate release paraceta. Eligibility was confirmed at the screening visit a maximum of mol opioids and opiates were permitted as rescue medica. 7 days before the first treatment visit Patients were treated tion Eating and drinking hot beverages was not allowed until. with randomized study medication on Treatment Days 1 and 3 h after drug administration. 3 and returned for a final follow up evaluation on Day 5 At. the first treatment visit each patient was randomly allocated to Evaluations. one of two sequences CAM2028 benzydamine Day 1, followed by CAM20208 control Day 3 or CAM2028 On each treatment day oromucosal pain was assessed by the. control followed by CAM2028 benzydamine Patients were patient using an 11 point Likert scale 0 no pain 10 worst. assigned a random number and received trial medication sent possible pain Patients recorded their pain scores before dos. from the study coordinating center with the corresponding ing and at 5 and 30 min and 1 2 3 6 and 8 h post dose After. number The list of random numbers was generated at the the initial 3 h assessment patients were allowed to leave the. coordinating center using the permuted bloc method based on hospital with a diary for recording pain scores at 6 and 8 h. SAS for Windows SAS Institute Inc Cary NC USA Adverse events were to be recorded throughout the study. Treatment allocation was concealed from the investigators period not just on treatment days Symptomatic changes were. staff at the trial sites trial monitors data analysts and man elicited from the patient in a non leading manner at each visit. agers and patients Clinically relevant laboratory values or pathological changes. Patients were administered the trial medication after under as determined by the investigator were also to be recorded as. going radiotherapy The investigational medication consisted adverse events Investigators were to record information on an. of the oromucosal solution CAM2028 containing Adverse Event Report Form including severity grading res. benzydamine 28 2 mg mL The comparison treatment was olution and relationship to study medication as determined by. CAM2028 control One milliliter of either the study med the investigator An adverse event was defined as treatment. ications was applied to the oral mucosa using a syringe emergent if it had onset or worsened after the first use of study. and patients were instructed to swirl the medication medication and no more than 1 day after the last use. around in the mouth for approximately 15 s and then spit. out any residual medication The procedure was repeated Statistical methods. after 5 min, Concomitant use of any oromucosal medication was not A total of 38 patients were enrolled with the aim of a final. permitted from 3 days before dosing on Day 1 until the final sample of 32 evaluable patients As this was a pilot study. evaluation on Day 5 This prohibition included oromucosal sample size was determined empirically The primary efficacy. 1560 Support Care Cancer 2014 22 1557 1562, endpoint was the pain intensity difference PID calculated as Treatment efficacy. the change in the Likert pain scale from baseline to 6 h after. administration of study medication Secondary outcome mea We present results of the analysis of treatment efficacy for the. sures were the PID at other time intervals peak pain maxi per protocol data set results in the full patient population did. mum Likert score on each treatment day and the area not differ The mean pain intensity difference at 6 h was 2 5 for. under the curve AUC of the PID The last observation CAM2028 benzydamine and 2 2 for CAM2028 control i e. carried forth LOCF method was used to replace miss patients experienced an average 2 plus point decline in pain. ing pain score data from the same day The primary intensity from baseline to 6 h after treatment Mean pain. efficacy endpoint was evaluated using the mixed effects intensity ratings decreased by about 40 from a baseline. analysis of covariance ANCOVA model on ranks The of 6 5 CAM2028 benzydamine or 6 4 CAM2028 control. model included effects for treatment center sequence to 4 6 both treatments already within 5 min of study medi. period patient and baseline Likert pain score cation application and remained at this level or lower through. Secondary endpoints were analyzed in the same manner out the 8 h of observation Table 1 Fig 2 At no time did. Analyses were planned on the safety data set patients mean pain ratings or PID differ statistically between the two. who received at least one dose of study medication the treatments. full data set patients who provided data on the primary The mean AUC of pain intensity over time did not differ. efficacy variable for both treatments and the per between the two treatments The mean peak PID was 2 8 for. protocol data set patients who completed the trial with CAM2028 benzydamine and 2 7 for CAM2028 control All. no protocol deviations Analyses were conducted using of the analyses of pain intensity outcomes showed a statisti. SAS release 8 2 cally significant clinical center effect with one center. reporting larger PID values than others The data do not. suggest any explanation for this difference,Safety and tolerability. Patient characteristics and disposition, Four patients experienced seven treatment emergent adverse. Thirty eight patients were randomly assigned to treatment events None were considered severe and none were judged. and all completed the trial Twenty patients were assigned to to be related to study medication Two patients experienced. receive CAM2028 benzydamine on Day 1 and CAM2028 nausea or vomiting on CAM2028 benzydamine one on. control on Day 3 and 18 patients received the treatments in CAM2028 control and one on both treatments Upper respi. the opposite order All were included in the safety population ratory tract infection and hemoptysis each occurred in 1 pa. and the full data set Three patients were not included in the tient who received the CAM2028 benzydamine. per protocol set because they had a baseline pain score lower Regarding rescue medication only paracetamol was used. than 6 on the second treatment visit when all three were in a total of 8 patients 21 during the course of the. scheduled to receive CAM2028 benzydamine and three treatment period None of the patients used opioids as rescue. others had minor protocol violations in recording their pain medication. scores The per protocol set consisted of 19 patients who. received the CAM2028 benzydamine first and 13 who re. Table 1 Patient evaluations of pain intensity on an 11 point Likert scale. ceived CAM2028 control first All patients took all doses of before and at selected time points after administration of CAM2028. study medication benzydamine or CAM2028 control per protocol population n 32. Demographic characteristics did not differ between the two. Before 5 min 1h 6h 8h, treatment groups with the exception that women were over. represented in the group receiving placebo first 5 versus 1. Patients were a median age of 52 years range 32 to 73 32 CAM2028 benzydamine. patients 84 2 were male and all were of Caucasian Mean SD 6 5 0 80 4 6 1 60 4 1 1 98 4 0 2 06 4 2 2 03. ethnicity Mean body mass index was 21 5 kg m2 Nearly half Median 6 0 4 5 4 0 4 0 4 0. of the participants were sporadic consumers of alcohol Range 6 8 2 8 1 8 1 8 1 8. 47 4 rather than non drinkers 26 3 or regular drinkers CAM2028 control. 26 3 Most were current smokers 42 1 or ex smokers Mean SD 6 4 0 72 4 6 1 54 3 9 2 0 4 3 2 23 4 4 2 09. 42 1 Patients were screened for study participation at a Median 6 4 4 4 4. median of about 6 weeks following the diagnosis of head and Range 6 8 1 8 0 8 0 9 0 9. neck cancer range 9 days to 17 weeks,Support Care Cancer 2014 22 1557 1562 1561. CAM2028 benzydamine doses of CAM2028 with and without benzydamine suggest. CAM2028 control, 7 that the observed analgesic effect is mainly due to the effective. Mean Pain Intensity, mechanical protection of the oral mucosal surfaces provided. by the in situ barrier forming lipid solution This lipid barrier. 5 covers and isolates the sore mucosa and exposed nerve end. ings from external irritation Thus CAM2028 offers a unique. approach for treating local pain associated with oral mucositis. 3 that does not interfere with the use of other therapies and that. additional experience suggests may be used with additive. 0 1 2 3 4 5 6 7 8 effects In a preliminary study in patients undergoing high. Time hours dose chemotherapy for autologous stem cell transplantation. Fig 2 Patient evaluations pain intensity 11 point Likert scale versus. CAM2028 combined with cryotherapy resulted in fewer and. time after application of study medication at time 0 per protocol set less severe occurrences of oral mucositis compared with cryo. N 32 therapy alone 14 Unlike cryotherapy alone CAM2028 also. spared patients the need for total parenteral nutrition and for. opioids for pain relief, At present there are few other effective treatments for pain. Discussion associated with oral mucositis The most widely prescribed. topical therapy is a pharmacist compounded mouthwash gen. This randomized trial set out to compare the effects erally called magic or miracle mouthwash 15 16 There. CAM2028 benzydamine and CAM2028 control in patients is no standard formulation for this mouthwash but the most. who experienced oral pain while undergoing radiation therapy popular formulation consists of viscous lidocaine diphenhy. for head and neck cancers Both study medications had an dramine and an antacid Although its widespread use suggests. immediate and clinically significant pain relieving effect with clinicians perceive it to be effective there is no clinical trial. in 5 min of application and that analgesic effect was main evidence supporting the efficacy of compounded mouthwash. tained for up to 8 h We found that the two treatments had in relieving pain associated with oral mucositis 11 and one. similar effects in reducing pain due to the efficacy of the trial found it no more effective than salt and soda 17. bioadhesive and physically protective mechanical barrier Because lidocaine containing products can cause numbness. which we had not predicted The two treatments did not differ patients are advised to avoid eating or performing oral hygiene. on the main outcome measure PID from baseline or on any measures after using these products to avoid accidental trauma. other measure of pain to oral tissues 9 Lidocaine can also dampen the gag reflex. Based on subsequent experience administration of the placing the patient at risk for aspiration The diphenhydramine. currently approved CAM2028 product episil Camurus component of the mouthwash formulation can exacerbate the. differs from that described in this study A phase 2 clinical xerostomia that patients with oral mucositis frequently. trial showed that upon application the formulation takes less experience. than 1 min to form a bioadhesive and protective lining and that Based on the results of this study in 38 cancer patients with. a smaller quantity of CAM2028 is sufficient to provide effec oral mucositis while undergoing radiation treatment for head. tive coverage of oromucosal surfaces rather than the 1 mL and neck cancer it is concluded that CAM2028 resulted in. used in the present study where patients were informed to spit immediate and significant pain relief with a duration that was. out excess solution 13 The current product episil label maintained for up to 8 h The reduction of pain was similar. ing instructs patients to spray a 0 15 mL metered dose of the between both CAM2028 treatments suggesting that. liquid into the oral cavity 1 to 3 times delivering a quantity benzydamine did not contribute additionally to the reduction. ranging from 0 15 to 0 45 mL and to allow 5 min for the of oral mucositis pain compared with the CAM2028 control. bioadhesive barrier to form They are then able to eat or drink Both CAM2028 treatments were found to be safe and well. immediately rather than waiting several hours tolerated in this group of patients. The similar treatment effects of CAM2028 with or without. Acknowledgments We thank the following study investigators. benzydamine suggest that benzydamine did not contribute Vaselina Parvanova MD PhD Marianna Yaneva MD PhD Raumen. additionally to the reduction of oral mucositis pain compared Gabrovski MD PhD and Petio Chilingirov MD PhD for their contri. with the unmedicated CAM2028 control Although no further butions to the study We also thank Jackie Turner at Premier Research plc. for performing biostatistical analysis, effects were seen with benzydamine it cannot be excluded. that benzydamine has a role in the management of oral mu. Conflict of interest This study was funded by Camurus AB Lund. cositis but this would require further investigation in repeat Sweden Two of the authors ML and FT are employees and principals of. dose studies However the present results obtained with single Camurus The others have no financial relationships to disclose. 1562 Support Care Cancer 2014 22 1557 1562, The authors have full control of all primary data and have agreed to allow Evaluating the supportive care costs of severe radiochemotherapy. the journal to review the data if requested induced mucositis and pharyngitis results from a Northwestern. University Costs of Cancer Program pilot study with head and neck. Open Access This article is distributed under the terms of the Creative and nonsmall cell lung cancer patients who received care at a county. Commons Attribution Noncommercial License which permits any non hospital a Veterans Administration hospital or a comprehensive. commercial use distribution and reproduction in any medium provided cancer care center Cancer 113 6 1446 1452. the original author s and the source are credited 9 Bensinger W Schubert M Ang KK et al 2008 NCCN Task Force. Report Prevention and management of mucositis in cancer care J. Natl Compr Cancer Netw 6 Suppl 1 S1 S21 quiz S22 24. References 10 Keefe DM Schubert MM Elting LS et al 2007 Mucositis study. section of the multinational association of supportive care in cancer. international society for oral oncology Updated clinical practice. 1 Peterson DE Bensadoun RJ Roila F ESMO Guidelines Working guidelines for the prevention and treatment of mucositis Cancer. Group 2008 Management of oral and gastrointestinal mucositis 109 5 820 831 doi 10 1002 cncr 22484. ESMO clinical recommendations Ann Oncol 19 Suppl 2 122 125 11 Clarkson JE Worthington HV Furness S McCabe M Khalid T. doi 10 1093 annonc mdn109 Meyer S 2010 Interventions for treating oral mucositis for patients. 2 Elting LS Cooksley CD Chambers MS Garden AS 2007 Risk with cancer receiving treatment Cochrane Database Syst Rev 8. outcomes and costs of radiation induced oral mucositis among pa CD001973 doi 10 1002 14651858 CD001973 pub4. tients with head and neck malignancies Int J Radiat Oncol Biol Phys 12 Epstein JB Silverman S Jr Paggiarino DA Crockett S Schubert. 68 4 1110 1120 MM Senzer NN Lockhart PB Gallagher MJ Peterson DE Leveque. 3 Elting LS Keefe DM Sonis ST Garden AS Spijkervet FK Barasch FG 2001 Benzydamine HCl for prophylaxis of radiation induced. A Tishler RB Canty TP Kudrimoti MK Vera Llonch M Burden of oral mucositis results from a multicenter randomized double blind. Illness Head and Neck Writing Committee 2008 Patient reported placebo controlled clinical trial Cancer 92 4 875 885. measurements of oral mucositis in head and neck cancer patients 13 Barauskas J Christerson L Wads ter M Lindstr m F Lindqvist AK. treated with radiotherapy with or without chemotherapy demonstra Tiberg F 2014 Bioadhesive lipid compositions self assembly. tion of increased frequency severity resistance to palliation and structures functionality and medical applications Mol Pharm. impact on quality of life Cancer 113 10 2704 2713 doi 10 1021 mp400552u. 4 Russo G Haddad R Posner M Machtay M 2008 Radiation treat 14 Svanberg A Birgeg rd G hrn K 2010 A new preventive strategy. ment breaks and ulcerative mucositis in head and neck cancer using a bioadhesive oral mucosal lipid solution and oral cryotherapy to. Oncologist 13 8 886 898 doi 10 1634 theoncologist 2008 0024 protect the oral cavity and reduce the need for total parenteral nutrition. 5 Rosenthal DI 2007 Consequences of mucositis induced treatment TPN for patients undergoing autologous stem cell transplantation. breaks and dose reductions on head and neck cancer treatment Abstract no 08 076 Support Care Cancer 18 Suppl 3 S114 S115. outcomes J Support Oncol 5 9 Suppl 4 23 31 15 Tom WC 2007 Magic mouthwash an update Pharm Lett Prescr. 6 Murphy BA 2007 Clinical and economic consequences of mucosi Lett 23 1 5. tis induced by chemotherapy and or radiation therapy J Support 16 Sonis S 2011 The quest for effective treatments of mucositis J. Oncol 5 9 Suppl 4 13 21 Support Oncol 9 5 170 171 doi 10 1016 j suponc 2011 07 001. 7 Silverman S Jr 2007 Diagnosis and management of oral mucositis J 17 Dodd MJ Dibble SL Miaskowski C MacPhail L Greenspan D Paul. Support Oncol 5 2 Suppl 1 13 21 SM et al 2000 Randomized clinical trial of the effectiveness of 3. 8 Nonzee NJ Dandade NA Patel U Markossian T Agulnik M Argiris commonly used mouthwashes to treat chemotherapy induced muco. A Patel JD Kern RC Munshi HG Calhoun EA Bennett CL 2008 sitis Oral Surg Oral Med Oral Pathol Oral Radiol Endod 90 1 39 47.
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