Benzydamine

Benzydamine

PEP Topic 
Mucositis
Description 

Benzydamine is a nonsteroidal antiinflammatory drug that has been used in an oral rinse. It has some local anesthetic and analgesic properties. Benzydamine has been evaluated in patients with cancer for the prevention and management of mucositis.

Likely to Be Effective

Research Evidence Summaries

Epstein, J.B., Epstein, J.D., Epstein, M.S., Oien, H., & Truelove, E.L. (2008). Doxepin rinse for management of mucositis pain in patients with cancer: One week follow-up of topical therapy. Special Care in Dentistry, 28(2), 73–77.

doi: 10.1111/j.1754-4505.2008.00015.x
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Study Purpose:

To determine the impact of repeated dosing with doxepin rinse over the course of one week in patients with oral mucositis

Intervention Characteristics/Basic Study Process:

Patients were instructed to rinse the oral cavity for 1 minute with 5 mL doxepin suspension (5 mg/mL) and then spit it out. Patients were to continue using the rinse as needed, 3–6 times per day, for the following week until their second visit and assessment. Standard of care for mucositis also was used during this time. Subjects used diaries to record analgesic use and mouth rinses.

Sample Characteristics:

  • The study reported on 9 patients, 3 women and 6 men, with a median age of 41 years.
  • Patients were receiving radiation therapy, chemotherapy, hematopoietic stem cell transplantation (HSCT), or a combination of these for head and neck cancer.
  • All patients had painful oral mucositis.

Setting:

The study was conducted at a single site, outpatient setting in Canada.

Study Design:

This was a nonrandomized, unblinded, uncontrolled, open-label study.

Measurement Instruments/Methods:

  • Data was compiled in Microsoft Excel. Statistical analysis was conducted using SAS 9.0 for Windows. Frequencies, medians, and ranges were used to report subject characteristics.
  • Oral pain was graded using a visual analog scale (VAS) (0 = no pain, 10 = worst pain). Oral pain when eating and without function was graded prior to oral rinse and at 5 minutes, 15 minutes, 1 hours, 2 hours, 3 hours, and 4 hours following doxepin rinse.
  • A VAS was used to report the taste of the rinse, discomfort, and fatigue.
  • An Oral Mucositis Assessment Scale (OMAS) was used.
  • Patients were asked to record in a diary estimates of their average pain up to four hours after using the rinse.

Results:

Statistically significant reductions in pain scores were reported for two hours following doxepin rinse during the initial visit (p < 0.05). Patients recalled that their pain significantly dropped within 5 minutes of rinsing over the week of repeated dosing (p < 0.05). At the follow-up visits, subjects reported statistically significant pain reduction 5 minutes after doxepin rinsing (p < 0.05). No changes were reported in systemic analgesics used during the study week despite the increasing severity of mucositis. No significant differences were found in mucositis scores over time.

Conclusions:

Doxepin rinsing in addition to usual oral care produced reduced intensity of pain levels but no apparent difference in mucositis severity. No firm conclusions can be drawn from this extremely small sample.

Limitations:

  • The sample size was small.
  • Risk of bias exists because this was not a randomized, controlled, blinded study
  • The standard care protocol, which also was used for oral care, was not described.

Nursing Implications:

The doxepin rinse was well tolerated, and the results warrant a larger, randomized, controlled clinical trial.

Epstein, J.B., Silverman, S., Paggiarino, D.A., Crockett, S., Schubert, M.M., Senzer, N.N., … Leveque, F.G. (2001). Benzydamine HCl for prophylaxis of radiation-induced oral mucositis: Results from a multicenter, randomized, double-blind, placebo-controlled clinical trial. Cancer, 92, 875–885.

doi: 10.1002/1097-0142(20010815)92:4<875::AID-CNCR1396>3.0.CO;2-1
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Intervention Characteristics/Basic Study Process:

Participants were randomized to receive either benzydamine HCl oral rinse, containing 0.15% benzydamine oral rinse (1.5 mg/ml benzydamine) or placebo, which identical in appearance and taste consisting of the vehicle only (approximately 10% alcohol by volume, menthol, peppermint oil, clove oil, and other flavoring agents).

Patients were to rinse with 15 ml of solution for two minutes, 4–8 times daily, before and during radiation therapy (RT) and for two weeks after completion of RT. If burning or stinging occurred, dilution of the rinse with water at 1:1 or 1:2 was allowed.  

Patients were evaluated before RT, twice weekly during RT, at the end of RT, and 2–3 weeks after RT.

Sample Characteristics:

  • The sample consisted of 172 patients, with 84 receiving benzydamine and 88 receiving placebo.
  • Patients ranged in age from 18–80 years old.
  • Patients had been diagnosed with head and neck cancer and were scheduled to receive at least 5000 cGy RT via megavoltage treatment. Patients were eligible if at least two oral sites were included in RT.
  • Patients were excluded if they had Karnofsky performance status of less than 80%, known hypersensitivity to benzydamine or typical nonsterioidal anti-inflammatory drugs, had residual oral or pharyngeal mucositis from previous RT or chemotherapy, or were already on RT and had taken experimental drugs within 30 days of study start.

Setting:

The study was conducted at 16 centers in North America (15 in the United States and 1 in Canada).

Measurement Instruments/Methods:

  • Mucositis assessment involved evaluating 14 anatomic areas for erythema, pseudomembrane, and ulceration using a 4-point scale ranging from 0–3.
  • Pain in the mouth or throat and pain during meals was assessed on a 7-point categorical self-rating scale ranging from 0–6.

Results:

Benzydamine produced a 26.3% reduction in mean mucositis area under the curve (AUC) compared with placebo for overall 0–5000 cGy (p = 0.009).

Pain also decreased as evidenced by a delay in use of concomitant systemic analgesics. Mouth pain showed a 25.8% reduction in AUC (p = 0.064) versus placebo, and throat pain showed a 22.5% reduction in AUC (p = 0.064).

Pain during meals was not effectively reduced.

Conclusions:

Benzydamine was not effective in reducing more severe mucositis in patients receiving high, single, daily RT regimens of 220 cGy per day or more.

Limitations:

  • The study is limited because of the small sample size.
  • The intervention is not approved by the U.S. Food and Drug Administration.
  • The decrease in pain was not statistically significant.

Erdem, O., & Gungormus, Z. (2014). The effect of royal jelly on oral mucositis in patients undergoing radiotherapy and chemotherapy. Holistic Nursing Practice, 28, 242–246. 

doi: 10.1097/HNP.0000000000000033
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Study Purpose:

To determine the efficacy of royal jelly on oral mucositis in patients receiving chemotherapy and radiation

Intervention Characteristics/Basic Study Process:

Patients were divided into two groups. All patients received benzydamine hydrochloride and nystatin rinses. In the experimental group, royal jelly was swished orally for 30 seconds and then swallowed twice per day for a total of 1 g per day. Patients could not eat or drink within 30 minutes of using the royal jelly. Both groups used the mouthwash protocol or mouthwash protocol plus royal jelly until mucositis was resolved. All participants and assessors were blinded to group. Oral mucosa was divided into five sites—labial mucosa, buccal mucosa, gingivae, tongue, and soft and hard palates—and the mucositis score was determined daily by a trained researcher for each site until no further evidence of mucositis existed.

Sample Characteristics:

  • N = 103  
  • AGE = 52.25 years
  • MALES: 47%, FEMALES: 53%
  • KEY DISEASE CHARACTERISTICS: Multiple types of cancer
  • OTHER KEY SAMPLE CHARACTERISTICS: Multiple stages of cancer, chemotherapy types, and chemotherapy cycles

Setting:

  • SITE: Single site    
  • SETTING TYPE: Outpatient    
  • LOCATION: Turkey

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Active antitumor treatment

Study Design:

  • Prospective, randomized clinical trial

Measurement Instruments/Methods:

  • World Health Organization criteria for mucositis

Results:

No statistical difference was seen in mucositis severity at the beginning of the study between the two groups. For grade 1 mucositis, the mean number of days to healing in the royal jelly group was 1.1 days, and in the control group it was 2.7 days (U = 64; p = 0.0001). For grade 2 mucositis, the mean number of days to healing in the control group was 5.8 days, and in the experimental group it was 3 days (U = 77; p = 0.0001). For grade 3 mucositis, those in the experimental group had a faster healing time than those in the control group (U = 59; p = 0.005).

Conclusions:

The addition of royal jelly to a mouthwash protocol with benzydamine and nystatin rinses significantly decreased the healing time for grade 1, 2, and 3 oral mucositis.

Limitations:

  • Risk of bias (no random assignment)
  • Other limitations/explanation: Random assignment was not described in the study

Nursing Implications:

Royal jelly should be considered as an additional intervention to promote the healing of oral mucositis caused by chemotherapy and radiation. Royal jelly, in addition to a mouthwash protocol consisting of a benzydamine and nystatin rinse, effectively reduced the number of days to complete healing of oral mucositis. The sample in this study included a wide variety of cancer types as well as a wide range of types of chemotherapy and number of chemotherapy cycles.

Hadjieva, T., Cavallin-Stahl, E., Linden, M., & Tiberg, F. (2014). Treatment of oral mucositis pain following radiation therapy for head-and-neck cancer using a bioadhesive barrier-forming lipid solution. Supportive Care in Cancer, 22, 1557–1562. 

doi: 10.1007/s00520-014-2117-3
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Study Purpose:

To test the analgesic effect of CAM2028 with benzydamine compared with CAM2028 without benzydamine (the FDA-approved prescription formula of episil) over an eight-hour period. During treatment with CAM2028, phospholipid and triglceride lipid components self-assemble with a volume of water (saliva) to form a bioadhesive and protective liquid crystalline lining of the oral mucosa. Additional objective of the study was to assess the safety and tolerability of a single-dose of the combined formulation.

Intervention Characteristics/Basic Study Process:

  1. All patients were receiving radical or postoperative radiotherapy to a significant part of clinically visible oral and/or pharyngeal mucosa at two or more anatomic sites.
  2. Trial began during weeks 3 to 4 of radiotherapy and took place over a maximum duration of 12 days.
  3. Treatment randomly was assigned after a radiotherapy treatment period of seven days.
  4. Patients must have received at least one third of the planned total dosage of radiation.
  5. At screening, participants were required to exhibit symptomatic oral mucositis (WHO grade 2 or above). 
  6. Likert score of at least 6 was required at screening and before each treatment.
  7. Patients were treated with randomized study medication on treatment days 1 and 3 and returned for a final follow-up evaluation on day 5.
  8. At the first treatment visit, each patient was randomly allocated to one of two sequences: CAM2028-benzydamine on day 1 followed by CAM20208-control on day 3 or CAM2028-control followed by CAM2028-benzydamine.
  9. Patients were assigned a random number and received trial medication sent from the study coordinating center with the corresponding number.
  10. List of random numbers was generated at the coordinating center using the permuted bloc method.
  11. Treatment allocation was concealed from the investigators, staff at the trial sites, trial monitors, data analysts, managers, and the patients.
  12. Patients were given the trial medication after undergoing radiotherapy.
  13. One milliliter of the medication was applied to the oral mucosa using a syringe, and patients were instructed to swirl the medication around in the mouth for approximately 15 seconds and then spit. Procedure was repeated after five minutes.
  14. On each treatment day, oromucosal pain was assessed by the patient using the Likert scale, done before dosing and at 5 and 30 minutes, and one, two, three, six, and eight hours post dose.

Sample Characteristics:

  • N = 38 participated (All completed the trial, and no patients discontinued.)
  • MEDIAN AGE = 52 years (range = 2–72 years)
  • MALES: 84.2%, FEMALES: 15.8%
  • KEY DISEASE CHARACTERISTICS: Newly diagnosed head and neck cancer

Setting:

  • SITE: Five oncology centers
  • LOCATION: Bulgaria

Phase of Care and Clinical Applications:

  • PHASE OF CARE: Treatment
  • APPLICATIONS: Mucositis

Study Design:

Crossover, double-blind, placebo-controlled, single-dose, randomized, proof of concept trial

Measurement Instruments/Methods:

  • World Health Organization (WHO) 5 grade toxicity scale for oral mucositis
  • Likert scale of 0 to 10 for pain

Results:

All patients completed the trial. With both treatments, patients experienced a mean 40% decrease in pain intensity at six hours. Both treatments resulted in significant pain relief within five minutes of application that was evident during the entire eight-hour assessment period. At no time did mean pain ratings or pain intensity difference differ statistically between the two treatments. The mean AUC of pain intensity over time did not differ between the two treatments. All of the analyses of pain intensity outcomes showed a statistically significant clinical center effect, with one center reporting larger pain intensity difference values than others. No reason was offered for this difference.

Conclusions:

The similar treatment effects of CAM2028 with or without benzydamine suggest that benzydamine did not contribute additionally to the reduction of oral mucositis pain compared with the unmedicated CAM2028 control. CAM2028 resulted in immediate and significant pain relief with a duration that was maintained for up to eight hours.

Limitations:

  • Small sample (< 100), split between five centers, and no mention of how many at each center
  • No mention of how the outcome assessor was trained to do the assessments of the mucositis, or who did the assessment
  • Women were over-represented in the group receiving placebo first.
  • One center reported larger pain intensity difference than the others. No reason was offered for this difference.

Nursing Implications:

  • Results differences between centers needed further evaluation.
  • No patients received chemotherapy in this study, so only applicable to radiotherapy treatment.
  • No mention of whether radiation techniques were different between the centers.
  • Study does not tell us who monitored the application of the medications.
  • CAM2028 may not be a suitable vehicle with which to combine benzydamine.
  • Other formulations for extended delivery of benzydamine need to be investigated and studied.

Kazemian, A., Kamian, S., Aghili, M., Hashemi, F. A., & Haddad, P. (2009). Benzydamine for prophylaxis of radiation-induced oral mucositis in head and neck cancers: A double-blind placebo-controlled randomized clinical trial. European Journal of Cancer Care, 18(2), 174–178.

doi: 10.1111/j.1365-2354.2008.00943.x
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Study Purpose:

To evaluate the efficacy of benzydamine oral rinse for prevention of radiation-induced mucositis

Intervention Characteristics/Basic Study Process:

Patients rinsed for 2 minutes four times a day with 15 mL study medication (0.15% benzydamine oral rinse) or identical placebo (in appearance and taste) from the first day of radiation therapy (RT) to the end of treatment. Patients were encouraged to brush their teeth at least twice daily and rinse as necessary with normal saline or sodium bicarbonate. Commercial mouthwashes were prohibited.

Sample Characteristics:

  • The study reported on a sample of 81 patients with a mean age 56.
  • There were 54 females and 27 males.
  • All patients had been diagnosed with head and neck cancer and were scheduled to receive a total external beam RT dose of at least 50 Gy in standard fractions and at least 2 oral or oropharyngeal sites were included in the planned RT treatment volume.

Setting:

The study was conducted at the Radiation Oncology Department of the Cancer Institute at Tehran University of Medical Sciences in 2004-2005.

Study Design:

This was a double-blind, randomized, placebo-controlled trial.

Measurement Instruments/Methods:

  • Patients oral hygiene before and during RT (number of tooth brushing per day) was recorded.
  • The Radiation Therapy Oncology Group (RTOG) grading system was used.
  • Patients were visited once.

Results:

  • The statistical analysis revealed that three variables significantly affected the grade of mucositis at the end of the treatment: smoking before and during RT (p = 0.008), chemoradiation (p = 0.002), and receiving benzydamine (p = 0.001).
  • Benzydamine produced a statistically significant reduction in mucositis during RT (p < 0.001).
  • An increase in the grade of mucositis in the first three weeks of treatment was found in both groups, but, after that time, a remarkable difference was found in this parameter in the two groups. Overall, mucositis scores increased rapidly in severity between the third and seventh week of treatment, with a plateau occurring near the end of RT in the placebo group. In the benzydamine group, the plateau appeared from the third week to the end of therapy.

Conclusions:

Benzydamine 0.15% oral rinse was safe and well tolerated. It significantly reduced RT-induced mucositis, which also decreased the interruption of treatment.

Limitations:

  • The study was conducted at a single institution.
  • The sample size was small, with fewer than 100 patients.
  • The authors did not address who conducted the mucositis assessment, opening up the possibility for discrepancy between the evaluators.

Nursing Implications:

Nurses will need to know how to effectively teach patients to use the oral rinse. This study also highlights the importance of daily oral hygiene, which is another good teaching point.

Pettit, L., Sanghera, P., Glaholm, J., & Hartley, A. (2014). The use of MuGard™, Caphosol® and Episil® in patients undergoing chemoradiotherapy for squamous cell carcinoma of the head and neck. Journal of Radiotherapy in Practice, 13(2), 218–225.

doi: 10.1017/S1460396912000581
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Study Purpose:

To record mucositis and dysphagia toxicity and level of anesthesia for patients receiving MuGard, Caphosol, or Episil in comparison to standard care

Intervention Characteristics/Basic Study Process:

Patients undergoing concurrent radiotherapy and chemotherapy for locally advanced head and neck cancer were audited for eight weeks during treatment. Patients were sequentially given either the standard oral care regimen of aspirin, glycerin, and sucralfate and Gelclair® or one of the other products. Patients were assessed weekly during four weeks of radiotherapy and for four weeks after completion. All patients received the same protocol approach for analgesia.

Sample Characteristics:

  • N = 104  
  • AGE: Not reported
  • MALES: Not reported, FEMALES: Not reported
  • KEY DISEASE CHARACTERISTICS: All had squamous cell head and neck cancer, most were of the oropharynx. All were receiving concurrent carboplatin or cetuximab. Radiotherapy was 55 Gy in 20 fractions over 25 days.

Setting:

  • SITE: Single site 
  • SETTING TYPE: Outpatient 
  • LOCATION: United Kingdom

Phase of Care and Clinical Applications:

PHASE OF CARE: Active antitumor treatment

Study Design:

Observational

Measurement Instruments/Methods:

Common Terminology Criteria for Adverse Events v3

Results:

No differences were seen between groups in average grade of dysphagia or analgesia use. No differences were seen between those receiving radiotherapy with intensity-modulated radiation therapy or conformal radiotherapy.

Limitations:

  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Unintended interventions or applicable interventions not described that would influence results
  • A much larger group of patients was in the standard care group. No information is provided about general oral care, and frequency of use of any of the oral agents is not described. Adherence varied considerably across groups, with the largest adherence to the standard care regimen.

Nursing Implications:

This study had numerous design limitations and provides little supportive evidence for any of the approaches used for prevention and management of oral mucositis or associated pain.

Roopashri, G., Jayanthi, K., & Guruprasad, R. (2011). Efficacy of benzydamine hydrochloride, chlorhexidine, and povidone iodine in the treatment of oral mucositis among patients undergoing radiotherapy in head and neck malignancies: A drug trail. Contemporary Clinical Dentistry, 2, 8–12.

doi: 10.4103/0976-237X.79292
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Study Purpose:

To manage oral mucositis induced by radiotherapy and to reduce pain by using benzydamine hydrochloride, chlorhexidine, and povidone iodine

Intervention Characteristics/Basic Study Process:

Selected patients were divided into study and control groups. The study groups were further subdivided into group 1, group 2, and group 3. Each study group consisted of 25 patients, and the control group also consisted of 25 patients; the three study groups and the control group were given benzydamine hydrochloride, chlorhexidine, povidone iodine, and distilled water, respectively. These rinses were given after two weeks of radiation therapy (RT) at the onset of oral mucositis.

Patients in the study groups as well as the control group were instructed to rinse the oral cavity with 15 ml of their respective rinses for at least 30 seconds, 4 times a day at six-hour intervals. The mouth-rinsing regimen was performed under professional supervision. The samples of mouth rinses were given to the patients without dilution for one week use, one at a time, for convenience. Patients also were given measuring cups to measure the quantity of oral rinses. All patients were examined at the end of every week during the RT for about a six-week period.

Sample Characteristics:

  • Patients' age ranged from 30–70 years old.
  • Patients all had head and neck malignancies (no explanation offered).

Setting:

The study was conducted at the Radiotherapy Department of Kidwai Memorial Institute of Oncology in Bangalore, Karanataka, India.

Phase of Care and Clinical Applications:

Patients were undergoing the active treatment phase of care.

Study Design:

The study did not involve blinding.

Measurement Instruments/Methods:

  • The World Health Organization Grading scale for mucositis was used.
  • The Lindquist/Hickey scale was used to evaluate pain.

Conclusions:

This study was oorly designed, and the report was confusing and difficult to understand.

Limitations:

  • No explanation was given as to how the groups were divided into study and control.
  • The authors were unclear as to whether the groups were all given the same mouth rinses or different ones.
  • No blinding was involved.
  • This was a single institution study.
  • No randomization was noted in the report.
  • No mention was made of how compliance was tracked during the study.
  • No age breakdown was given.
  • The authors did not identify who conducted the oral assessments and what training they received to ensure consistency.
  • No mention was made of whether opioids were permitted during treatment for pain control.

Nursing Implications:

Several studies have pointed in the direction that benzydamine hydrochloride is effective in the management of oral mucositis. Further well-designed, randomized placebo controlled studies are needed for verification.

Systematic Review/Meta-Analysis

Kwong, K.K. (2004). Prevention and treatment of oropharyngeal mucositis following cancer therapy: Are there new approaches? Cancer Nursing, 27(3), 183–205.

doi: 10.1097/00002820-200405000-00003
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Search Strategy:

Database searched was MEDLINE (1993–2003) for randomized, controlled trials evaluating mucositis interventions.

Literature Evaluated:

A total of 50 randomized controlled trials were presented. Other trials and papers were referenced.

Sample Characteristics:

  • Sample sizes ranged from 10–222.
  • Patients were treated with chemotherapy, radiotherapy, and bone marrow transplantation.

Conclusions:

The author concluded that most agents require more study.

  • Evidence for cryotherapy and bolus 5-fluorouracil was strong.
  • Sucralfate studies produced conflicting results and included varying doses and administration frequencies, making comparisons difficult. Most studies indicated no difference in severity or duration. The validity and reliability of the data were questioned because of the measurement scales used.
  • Similarly, studies of cytokine-like agents used different doses, making comparisons difficult.
  • Moderate evidence suggested that benzydamine is effective in relieving mouth pain caused by radiation-induced mucositis in patients with head and neck cancer. The agent requires additional investigation and study for chemotherapy-induced mucositis.
  • Large studies of chlorhexidine mouthwashes have failed to show significant findings; however, the studies may have had inadequate sample sizes, as power analyses were not performed.
  • Povidone-iodine showed significant reduction in onset, incidence, total duration, and worst grade of mucositis for patients with head and neck cancer undergoing radiation with carboplatin in two studies. Both studies had sample sizes of 40. Given these sample sizes and specific populations, generalizability of the findings was restricted.
  • Oral hygiene protocols were shown to reduce the duration and severity of mucositis; however, the content of the protocols was not proven.

Limitations:

The author noted the problem of variation in study protocols, insufficient sample sizes, and a lack of consensus regarding the scoring system for mucositis.

Nursing Implications:

The author noted the need to include psychotherapeutic interventions and management and pointed out the lack of a quality-of-life tool for mucositis.

Shih, A., Miaskowski, C., Dodd, M. J., Stotts, N.A., & MacPhail, L. (2002). A research review of the current treatments for radiation-induced oral mucositis in patients with head and neck cancer. Oncology Nursing Forum, 29, 1063–1078.

doi: 10.1188/02.ONF.1063-1080
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Search Strategy:

Database searched was MEDLINE (1966–2001). Additional papers were found from reference lists.

Studies were included in the review if they were aimed at prevention, palliation, or reduction of radiation-induced oral mucositis in patients with head and neck cancer.

Studies were excluded if they were not in English.

Literature Evaluated:

More than 50 studies were included. Most were randomized, controlled trials; some were pilot or descriptive studies. 

Sample Characteristics:

Sample sizes ranged from 10 to more than 200.

Conclusions:

Based on the findings of studies conducted to date, no conclusions regarding the agents and their ability to decrease the severity of radiation-induced oral mucositis were possible. Results were inconsistent. The most effective measure to treat radiation-induced mucositis was frequent oral rinsing with a bland mouthwash such as saline or sodium bicarbonate. Consistent oral care, dental care, oral assessment, and standardized oral hygiene were the suggested approaches to managing oral mucositis. Sodium bicarbonate reduces the acidity of the oral fluids immediately; it also dilutes accumulating mucus and discourages yeast colonization.

Findings related to benzydamine were inconsistent. In a trial of chlorhexidine versus benzydamine, patients reported more discomfort with benzydamine and were more likely to discontinue participation in the trial. Chlorhexidine was not effective in reducing the severity of mucositis in three double-blind, placebo-controlled trials. Two trials that examined antimicrobial activity failed to show any significant effects on the suppression of any type of oral flora using chlorhexidine.

Dose variations in granulocyte macrophage colony-stimulating factor (subcutaneous) trials make it impossible to determine whether this agent has a role in the radiation setting.

Four studies investigated the effectiveness of using topical antibiotics with a more specific spectrum for gram-negative bacteria and yeast. Two placebo-controlled, randomized clinical trials, both with fewer than 100 patients, and one case-controlled study investigated the efficacy of amphotericin B (polymyxis E, tobramycin, and amphotericin B [PTA] lozenge) to reduce the severity of radiation-induced mucositis. One study examined tetracaine and antibiotics. Additional work is warranted to determine the effects of the PTA lozenge on mucositis severity, pain severity, and dysphagia. Results for the trial were promising; however, conclusions cannot be drawn because only one study examined tetracaine.

Nursing Implications:

Additional investigation of immunoglobulin and povidone-iodine are recommended.

Guideline/Expert Opinion

Nicolatou-Galitis, O., Sarri, T., Bowen, J., Di Palma, M., Kouloulias, V.E., Niscola, P., . . . Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). (2013). Systematic review of anti-inflammatory agents for the management of oral mucositis in cancer patients. Supportive Care in Cancer , 21(11), 3179–3189.

doi: 10.1007/s00520-013-1847-y
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Purpose & Patient Population:

PURPOSE: Systematically review literature and define updated clinical practice guidelines regarding use of anti-inflammatory agents

TYPES OF PATIENTS ADDRESSED: Patients receiving chemotherapy or radiation therapy

Type of Resource/Evidence-Based Process:

RESOURCE TYPE: Evidence-based guideline

PROCESS OF DEVELOPMENT: Studies evaluated using Hadorn criteria and assigned levels of evidence on Somerfield criteria by independent reviewers. Findings were integrated into guidelines based on overall level of evidence for each intervention.

DATABASES USED: MEDLINE (1966–December 31, 2010)

KEYWORDS: aminosalicylic acid, amifostine, amlexanox, anti-inflammatory, anti-TNF, anti-tumor necrosis factor, aspirin, Benadryl®, benzydamine, betamethasone, celecoxib, corticosteroid, dexamethasone, diphenhydramine, Ethyol®, flurbiprofen, histamine, hydrocortisone, ibuprofen, indomethacin, infliximab, irsogladine, lactoferrin, mesalazine, misoprostol, N-acetylcysteine, non-steroidal anti-inflammatory agents, NSAIDS, orgotein, prednisone, prostaglandin, RK-02-02, salicylic acid, steroid, thalidomide, TNF antibody, TNF inhibitor, and tumor necrosis factor/TNF

INCLUSION CRITERIA: Articles involving anti-inflammatory agents for prevention or treatment of oral mucositis

Phase of Care and Clinical Applications:

PHASE OF CARE: Active antitumor treatment

Results Provided in the Reference:

Forty-one studies were included in the review involving use of multiple anti-inflammatory agents.

Guidelines & Recommendations:

  • Benzydamine mouthwash is recommended for prevention in patients with head and neck cancer receiving moderate-dose radiation therapy without concomitant chemotherapy.
  • Misoprostol is not recommended for use of prevention of radiation-induced oral mucositis.
  • For all other anti-inflammatory agents, no guidelines were deemed possible due to insufficient evidence.

Limitations:

  • Most evidence reported was from studies of patients with head and neck cancer.
  • Very few studies per individual agent were reviewed, and the level of evidence was low for all but benzydamine.

Nursing Implications:

Two new guidelines were identified by this systemic review. The panel suggests that misoprostol mouthwash should not be used for the prevention of radiation-induced oral mucositis in patients with head and neck cancer. The other new guideline the panel recommends is benzydamine mouthwash for the prevention of oral mucositis in patients with head and neck cancer receiving moderate-dose radiation therapy (up to 50 Gy) without concomitant chemotherapy. In addition to this, the lack of clear evidence supporting the use of any anti-inflammatory agent other than benzydamine, the use of anti-inflammatory agents continues to be a promising strategy for the prevention and treatment of oral mucositis. More well-designed studies are needed to examine the use of anti-inflammatory agents for oral mucositis in various cancer care settings.

Peterson, D.E., Bensadoun, R.J., Roila, F., & ESMO Guidelines Working Group. (2010). Management of oral and gastrointestinal mucositis: ESMO Clinical Practice Guidelines. Annals of Oncology, 21(Suppl. 5), v261–v265.

doi: 10.1093/annonc/mdq197
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Purpose & Patient Population:

To summarize the evidence around the use of radiotherapy, standard-dose chemotherapy, and high-dose chemotherapy with or without total body irradiation plus hematopoietic stem cell transplantation (HSCT) for the management of mucositis

Type of Resource/Evidence-Based Process:

  • Databases searched were the Multinational Association of Supportive Care in Cancer (MASCC)/International Society of Oral Oncology (ISOO).
  • Evidence was evaluated based on the American Society of Clinical Oncology (ASCO) Levels of Evidence (I-V) and Grades of Recommendation (A-D). Statements without grading were considered justified standard clinical practice by the expert authors and the European Society for Medical Oncology (ESMO) faculty.

Guidelines & Recommendations:

  • Institutions should develop oral care protocols based on clinical practice and interdisciplinary involvement. Staff and patient education are essential. Basic oral care should include saline mouth rinses 4–6 times per day and use of a soft toothbrush replaced on a regular basis. 
  • Patient-controlled analgesic (PCA) with morphine is recommended for the treatment of pain in patients with oral mucositis undergoing HSCT.
  • Regular oral pain assessment and topical anesthetics can provide short-term pain relief. 
  • Benzydamine oral rinse is recommended for prevention of mucositis in patients with head and neck cancer receiving radiotherapy.
  • For prevention of mucositis in patients receiving standard-dose chemotherapy,
    • Oral cryotherapy for 30 minutes is recommended in patients receiving fluorouracil (5-FU).
    • Keratinocyte growth factor-1 (palifermin) 40 mcg/kg per day for three days may be useful in patients receiving bolus 5-FU plus leucovorin.
  • For prevention of mucositis in patients receiving high-dose chemotherapy with or without total body irradiation plus HSCT, the following are recommended.
    • Palifermin 60 mcg/kg per day for three days prior to transplant and three days post-transplant
    • Cryotherapy in high-dose melphalan
    • Low-level laser therapy (LLLT) before HSCT

Limitations:

The primary author was the principal investigator on the National Institutes of Health (NIH) R13 Conference Grant that provided partial support for the symposium “Oral Complications of Emerging Cancer Therapies,” 14-15 April 2009, Bethesda, MD, USA. Production of a Journal of the National Cancer Institute (JNCI) Monograph for conference publications was supported by an unrestricted educational grant form Biovirum, which owned palifermin at the time of the publication. Peterson also is a member of the Scientific Advisory Board and a paid consultant for the GI Co., Inc, which is responsible for the development of recombinant intestinal trefoil factor, for which the phase II study is cited in the references.

Nursing Implications:

The mucositis guidelines reported contain few changes from the previous two versions of the ESMO Clinical Practice Guidelines. With the 2009 MASCC/ISCO Mucositis Study Group in June 2009, it was decided that no new guidelines were warranted based on the current published literature. Progress has been made in the understanding of molecular basis of mucositis. Evidence-based, cancer-specific identification of risk factors and management of mucositis depend on clinical research so that approval of new drugs and devices will be possible.


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