Likely to Be Effective

Benzydamine for Radiation-Related Mucositis

for Mucositis

Benzydamine is a nonsteroidal anti-inflammatory 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.

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.

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.

Print

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.

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.

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Research Evidence Summaries

Chitapanarux, I., Tungkasamit, T., Petsuksiri, J., Kannarunimit, D., Katanyoo, K., Chakkabat, C., . . . Traisathit, P. (2018). Randomized control trial of benzydamine HCl versus sodium bicarbonate for prophylaxis of concurrent chemoradiation-induced oral mucositis. Supportive Care in Cancer, 26, 879–886.

Study Purpose

To compare the efficacy of benzydamine HCl with sodium bicarbonate in the prevention of concurrent chemo rt-induced OM in patients with head and neck cancer.

Intervention Characteristics/Basic Study Process

Sixty locally advanced patients with head and neck cancer treated with high-dose RT concurrently with platinum-based chemotherapy were randomly assigned to receive either benzydamine HCl or sodium bicarbonate from the first day of treatment to two weeks after completion of treatment.

Sample Characteristics

  • N: 60   
  • AGE: 18-70 years
  • MALES (%): 24 and 23  
  • FEMALES (%): 6 and 7
  • CURRENT TREATMENT: Radiation 
  • KEY DISEASE CHARACTERISTICS: Patients with locally advanced head and neck cancer with high-dose radiotherapy and platinum-based chemotherapy 
  • OTHER KEY SAMPLE CHARACTERISTICS: Starting similar chemRT regimens; matched

Setting

  • SITE: Multi-site   
  • SETTING TYPE: Outpatient    
  • LOCATION: Chiang Mai UH (CMUH), King Chulalongkom Memorial H (KCMH), Siriraj H (SH) and Udonthani Cancer H (UCH)

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active anti-tumor treatment
  • APPLICATIONS:  Elder care, palliative care

Study Design

RCT with two intervention groups

Measurement Instruments/Methods

Patients were evaluated by the radiation oncologists at baseline before CCRT, weekly during CCRT, at the end of CCRT, and at four weeks after CCRT. The Oral Mucositis Assessment Scale (OMAS) was used to assess severity of mucositis. Ulceration score was 0 for no lesion, 1 for lesion less than 1 cm2, 2 for lesion 1–3 cm2, and 3 for lesion more than 3 cm2. Erythema score was 0 for no lesion, 1 for mild to moderate erythema, and 3 for severe erythema. Pain score (0–10), all prescribed medications including analgesic, artificial saliva supplement, and anti-infection medications, the need for hospitalization, treatment interruption, and the addition of nutritional support or feeding tube were also recorded. Oral candidiasis assessment was based on the physical examination of pseudomembranous lesions or angular cheilitis in centers except at CMUH center where confirmation by microscopic identification of Candida was used.

Results

Prophylaxis rinsing with benzydamine HCl can be more effective in reducing severity of OM induced by CCRT, when compared to basic care with sodium bicarbonate mouthwash. Median of OMAS scores at weekly assessment during CCRT was lower in benzydamine HCl group compared to control. In both groups, maximum of third quartile of OMAS scores around fifth to seventh week of CCRT. Scores decreased at four weeks after CCRT. Statistically, median for OMAS scores was significantly lower in study group at every week between second and eighth week of CCRT. The corresponding p values for those weeks in chronological order were 0.003, < 0.001, < 0.001, < 0.001, < 0.001, 0.01, and 0.04. Maximum of third quartile of OMAS scores to be around fifth to sixth week in both groups. Maximum OMAS score across whole period of CCRT in benzydamine HCl group was 25, lower than maximum of 37 in sodium bicarbonate group. No significant difference in median of pain scores between two groups during CCRT and at follow-up. Corresponding p values from second to eighth week were 0.88, 0.59, 0.96, 0.73, 0.63, 0.92, and 0.15 and p value at follow-up after CCRT was 0.8. Maximum of third quartile of pain scores at seventh week of CCRT in study group and eighth week in control group. Maximum pain score across period of CCRT was 10 in both groups. Four weeks after CCRT, median of pain score decreased to 2 in both groups. Poor compliance was defined as patients in postoperative CCRT group and in definitive CCRT group who received weekly chemotherapy less than 3 cycles and 4 cycles, respectively. More patients with poor compliance in control group than in study group (i.e., 13 patients versus 10 patients). No differences were found between the two groups. Most patients in both groups need analgesic drugs; 89% in control group and 90% in study group, p value = 1. The most common analgesic drugs used were opioids (syrup morphine/morphine sulfate tablet; MST/morphine sulfate sustain released; kapanol®), prescribed usage rates were 48% in control group and 33% in study group. For antifungal agents, none in benzydamine HCl group needed them, whereas 19% of patients in sodium bicarbonate group required nystatin oral suspension or clotrimazole tablet. Rate of feeding tube placement was same in both groups during CCRT (i.e., 24 and 22% in the study group and the control group, respectively). Oral retention and compliance for mouthwash products were better in sodium bicarbonate arm than in benzydamine HCl arm. Four patients (6.75%) in study arm could not tolerate full dose of benzydamine HCl due to burning and stinging sensation. For these patients, mouthwash was diluted at 1:1 with water.

Conclusions

Prophylaxis oral rinsing with benzydamine HCl for patients undergoing high-dose radiotherapy concurrently with platinum-based chemotherapy was superior to sodium bicarbonate mouthwash in terms of alleviating the severity of oral mucositis and encouraging trend for reducing the need of oral antifungal agents use.

Limitations

  • Small sample (< 100)
  • Other limitations/explanation: Small study with limitations in descriptive measurement.

Nursing Implications

Review prophylaxis and acute treatment protocol practices.

Print

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.

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.
Print

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. 

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.
Print

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.

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.

Print

Rastogi, M., Khurana, R., Revannasiddaiah, S., Jaiswal, I., Nanda, S.S., Gupta, P., . . . Bhatt, M.L. (2016). Role of benzydamine hydrochloride in the prevention of oral mucositis in head and neck cancer patients treated with radiotherapy (> 50 Gy) with or without chemotherapy. Supportive Care in Cancer. Advance online publication. 

Study Purpose

To evaluate the role of benzydamine in the prevention of mucositis in patients receiving more than 50 Gy of radiation therapy

Intervention Characteristics/Basic Study Process

Patients were stratified according to receiving radiotherapy or radiotherapy and chemotherapy, and then randomly assigned to control or treatment with benzydamine. All patients were advised to use saline mouth rinses, and those in the treatment group also used 0.15% benzydamine hydrochloride rinse. Both groups were to rinse and gargle with the mixture four to six times daily. Patients were examined weekly until four weeks after completion of the treatment.

Sample Characteristics

  • N = 120   
  • AGE RANGE = 19–90 years
  • MALES: 87.5%, FEMALES: 12.5%
  • CURRENT TREATMENT: Radiation, combination radiation and chemotherapy
  • KEY DISEASE CHARACTERISTICS: All had head and neck cancer.
  • OTHER KEY SAMPLE CHARACTERISTICS: Radiotherapy dosages ranged from 56–70 Gy.

Setting

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

Phase of Care and Clinical Applications

PHASE OF CARE: Active antitumor treatment

Study Design

Randomized, controlled trial

Measurement Instruments/Methods

  • Common Terminology Criteria for Adverse Events (CTCAE) toxicity, version 4
  • World Health Organization (WHO) mucositis grading scales

Results

Patients receiving radiotherapy alone who used benzydamine had a lower prevalence of grade 3 mucositis compared to controls (p = 0.038); however, control patients receiving only radiotherapy also had a longer duration of radiation treatment (p = 0.042, 56 versus 44 days). No significant difference in mucositis outcomes occurred among those receiving both chemotherapy and radiation. Control patients in this group had a longer duration of radiation therapy.

Conclusions

Benzydamine prophylaxis appears to be effective to reduce the severity of oral mucositis among patients receiving radiotherapy alone for head and neck cancer. Effects for patients receiving both chemotherapy and radiation therapy were not seen.

Limitations

  • Baseline sample/group differences of import
  • Risk of bias (no blinding)
  • Measurement/methods not well described
  • Exact measure used in analysis and timing of measurement used not stated
  • In both treatment types, patients in the control group had a significantly longer duration of radiation therapy.

Nursing Implications

Oral rinses with benzydamine were helpful to reduce the prevalence of severe mucositis among patients receiving radiation therapy for head and neck cancer. It is unclear if benzydamine can also be helpful for patients receiving combination chemotherapy and radiation therapy.

Print

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.

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.

Print

Sheibani, K.M., Mafi, A.R., Moghaddam, S., Taslimi, F., Amiran, A., & Ameri, A. (2015). Efficacy of benzydamine oral rinse in prevention and management of radiation-induced oral mucositis: A double-blind placebo-controlled randomized clinical trial. Asia-Pacific Journal of Clinical Oncology, 11, 22–27.

Study Purpose

To assess the efficacy of prophylactic benzydamine in an oral solution for reducing the signs and symptoms of oral mucositis in patients receiving radiation therapy (RT) with or without chemotherapy for head and neck cancers

Intervention Characteristics/Basic Study Process

A 0.15% benzydamine or placebo oral rinse of 15 ml was used for two minutes four to eight times daily starting the day before RT and continuing till two weeks RT completion.

Sample Characteristics

  • N = 51  
  • MEAN AGE = 52.65 years
  • MALES: 60.8%, FEMALES: 39.2%
  • KEY DISEASE CHARACTERISTICS: Head and neck cancer
  • OTHER KEY SAMPLE CHARACTERISTICS: Adults receiving at least 5,000 cGy RT via megavoltage treatment with either cobalt 60 or a linear accelerator to at least two oral mucosal sites with a Karnofsky Performance Status (KPS) > 60

Setting

  • SITE: Single site    
  • SETTING TYPE: Not specified    
  • LOCATION: Jorjani Cancer Center at the Shahid Beheshti University of Medical Sciences in Tehran, Iran (2009–2012)

Phase of Care and Clinical Applications

  • PHASE OF CARE: Active antitumor treatment

Study Design

Randomized, double-blinded, placebo-controlled trial stratified according to KPS and treatment schedule (once- or twice-daily fraction) and then randomized

Measurement Instruments/Methods

  • The oral cavity was divided into 14 anatomical sites.  
  • A complete oral examination was done weekly after the initiation of treatment, and a four-point scale was used to score each oral site.  
  • At each weekly visit, an overall mean score was calculated based on at-risk areas.

Results

No difference in the severity of mucositis was found during weeks 1–3. By week 4, the placebo arm had significantly more mucositis than the treatment arm (p = 0.01), and this trend continued until the end of treatment. The difference in the mean score at one and two weeks after treatment continued to show lower scores in the treatment group, but this was nonsignificant.

Conclusions

An oral rinse of benzydamine 0.15% was safe and well-tolerated with no noticeable side effects reported by patients. It reduced the incidence and severity of radiation-induced oral mucositis.

Limitations

  • Small sample (< 100)
  • Risk of bias(sample characteristics)
  • Unintended interventions or applicable interventions not described that would influence results
  • Measurement validity/reliability questionable
  • Other limitations/explanation: Single site; unable to analyze data regarding analgesic consumption because of noncompliance; unclear who did the oral examination and training to ensure interrater reliability

Nursing Implications

Benzydamine was well-tolerated, easy to administer, and may be an appropriate prophylactic treatment for oral mucositis in patients receiving RT for head and neck cancer.

Print

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.

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.

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