Sucralfate

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

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

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

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.

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

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

To investigate, critically appraise, and rate the evidence regarding agents used for the prevention of mucositis in children

Databases searched included CINAHL, Cochrane library, Ovid MEDLINE, PubMed, BioMed Central, and other internet-based sources. A total of 19 databases were searched.

Search keywords were mucositis, stomatitis, oral inflammation, mouth mucosal inflammation, prophylaxis, management, and prevent; in addition to keywords to identify children and all types of cancer therapy.

Studies were included in the search if they

• Involved English-speaking children.
• Were clinical trials conducted on the prevention of oral mucositis during cancer therapy.

Studies were excluded if they

• Were not in English
• Did not involve children
• Involved only gastrointestinal mucositis.
• Involved treatment of mucositis rather than prevention.
• Were case studies or pilot studies.
• Were commentaries or letters to the editor.
• Involved sample sizes of less than 20 patients.

• The total number of references retrieved was 16,471.
• The authors evaluated the references using the Canadian Task Force on Preventive Health Care evidence-based guidelines.

• The final number of studies was 27. The sample range across studies was not reported.
• Other than inclusion of pediatric cases, no other characteristics were described.

• Patients were undergoing the active antitumor treatment phase of care.
• The study has clinical applicability for pediatrics.

• The studies involved the following interventions.
  • Oral care protocols (n = 5)
  • Chlorhexidine mouthwash (n = 7) 
  • Benzydamine mouthwash (n = 1)
  • Iseganan mouthwash (n = 1),
  • Granulocyte macrophage-colony stimulating factor (GM-CSF) mouthwash (n = 2)
  • Oral glutamine (n = 2)
  • Enteral glutamine (n = 1)
  • Oral propantheline and cryotherapy (n = 1)
  • Oral cryotherapy (n = 1)
  • Oral sucralfate suspension (n = 1)
  • Prostaglandin E2 tablets (n = 1)
  • Chewing gum (n = 1)
  • Laser therapy (n = 3). 
• Good evidential support was found for the use of oral care protocols. Fair support was found for the use of chlorhexidine with some mixed results.
• Only one article was found that studied benzydamine, CSF, and iseganan. The evidence was deemed insufficient to make a recommendation. 
• Good evidential support was found against the use of sucralfate and prostaglandin E2 tablets.
• Evidence regarding laser use and oral and enteral glutamine were mixed.

The authors concluded that oral care protocols should be used; oral sucralfate suspension, prostaglandin E2, and GM-CSF mouthwash should not be considered based on current evidence; and chlorhexidine (without use as part of an oral care protocol), laser therapy, and glutamine should not be considered because of conflicting evidence.

• No disease or treatment factors were reported or considered in the analysis. 
• Some interventions were evaluated in only one study.
• The quality of the evidence in general was highly variable.
• No information was provided on how the outcome for mucositis was measured in the included studies.
• The authors recommendations suggest no use of a specific intervention if findings were conflicting, which assumes that insufficient evidence of effectiveness is equivalent to ineffectiveness.

Findings provide further support for use of oral care protocols. Results provided no other useful recommendations for preventive therapies but identified the need for further research in this area.

STUDY PURPOSE: To develop clinical practice guidelines on the use of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the prevention and management of oral mucositis

TYPE OF STUDY: Systematic review

DATABASES USED: Ovid, MEDLINE

KEYWORDS: Acyclovir, amitriptyline, adhesive, amphotericin B, analgesic, analgesia, antacid, antibiotic, anti-infective, alfentanil, aqua oral, benzocaine, coating agent, clarithromycin, diclosan, doxepin, fentanyl, film, fluconazole, gabapentin, IB-367, hydromorphone, iseganan, kaopectate, ketamine, kefir, lidocaine, local anesthetic, “magic” or “miracle” mouthwash, mouth rinse or mouthwash, mucoadhesive, methadone, morphine, nystatin, patient controlled, polymyxin, povidone-iodine, polyvinylpyrrolidone, protegrin, sucralfate, tetracaine, tetracycline, tobramycin, topical, zilactin, xylocaine. In addition, the brand names of commercial products in these categories also were searched, including Gelclair^®, MuGard^®, and UlcerEase.

INCLUSION CRITERIA: Studies that focused on the use of antimicrobials, coating agents, anesthetics, and analgesics; English studies; published in MEDLINE on or before December 31, 2010; all age groups; and published in a peer-reviewed journal

EXCLUSION CRITERIA: Articles that did not report on effects of an intervention on mucositis, animal or in vitro studies, literature reviews, non-English papers

TOTAL REFERENCES RETRIEVED: 1,384

EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Only articles that reported on the effects of an antimicrobial, mucosal coating agent, anesthetic, or analgesic on oral mucositis that met the inclusion criteria described were included in the review. Also, articles did not have any major or minor flaws per Hadorn and levels of evidence were based on the Somerfield criteria. The results were sorted into three classifications: recommendation, suggestion, and no guidelines possible.

FINAL NUMBER STUDIES INCLUDED = 62

SAMPLE RANGE ACROSS STUDIES, TOTAL PATIENTS INCLUDED IN REVIEW: Not discussed in the review

KEY SAMPLE CHARACTERISTICS: Included patients actively being treated for head and neck cancers, hematologic cancers, and solid tumors with radiotherapy, chemotherapy, chemoradiotherapy, and high-dose total body irradiation for hematopoietic stem cell transplant

PHASE OF CARE: Active treatment

Recommendations were made against the use of topical antimicrobial agents for the prevention of mucositis, including recommendations against the use of iseganan for mucositis prevention in hematopoietic stem cell transplantation (HSCT) and head and neck radiation therapy (RT) and antimicrobial lozenges for mucositis prevention in head and neck RT. Recommendations were made against the use of sucralfate for the prevention and treatment of oral mucositis due to chemotherapy or RT. Recommendations were made for the use of patient-controlled analgesia with morphine in HSCT, transdermal fentanyl in HSCT and standard-dose chemotherapy treatment, and morphine and doxepin mouth rinse in patients with head and neck cancer undergoing RT. No guidelines were recommended for any of the other agents reviewed due to insufficient or conflicting evidence.

Additional well-designed RCT studies are needed on the prevention and management of oral mucositis. Studies that look at systemic dosing and absorption may be helpful.

Lack of high-level of evidence prevented the development of guidelines in many of the agents reviewed, such as topical anesthetics, antimicrobial agents, and mucosal coating agents.

The recommendations for use in clinical practice were made for the use of patient-controlled analgesia with morphine in patients undergoing HSCT and for transdermal fentanyl in HSCT and standard-dose chemotherapy treatment, and morphine and doxepin mouth rinse in patients with head and neck cancer undergoing RT. Any use of the other agents in this study were not recommended for use in the prevention or treatment of oral mucositis and should be used with caution.

To determine the efficacy of sucralfate mouthwash in the prevention of oral mucositis (OM) in patients receiving fluorouracil (5-FU) chemotherapy

Patients 18 years and older receiving chemotherapy containing 5-FU and calcium folinate were randomized into two groups through a computer-generated list of random numbers. One group received sucralfate suspension mouthwash and the other group received a placebo. Both groups received 10 ml of either sucralfate or placebo mouthwash every six hours for 10 days after the last dose of chemotherapy. Patients were instructed to rinse their mouth with the suspension for at least five minutes and spit it out 30 minutes after meals to ensure prolonged exposure of the mouthwash to the mucosal membranes.

• N = 51   
• AGE = Older than 18 years
• MALES: 15 (sucrafate group), 20 (placebo group); FEMALES: 10 (sucralfate group), 6 (placebo group)
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Gastrointestinal cancer (e.g., esophageal, colon, rectal, gastric)

• SITE: Single site   
• SETTING TYPE: Inpatient    
• LOCATION: Imam Khomeini Educational Hospital, Sari, Iran

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Pediatrics, elder care, palliative care 

• Double-blind, randomized controlled study

• World Health Organization (WHO) grading system for mucositis
• Visual analog scale (VAS) to grade pain intensity

A statistically significant difference in the severity of mucositis was shown between the sucrafate group and placebo group on both day 5 and day 10 (p = 0.005, p < 0.001), respectively. The severity of mucositis in the sucrafate group on day 5 and 10 was grade 0. The majority of patients in the placebo group had a mucositis severity grade 2 on day 5 and day 10. A statistically significant reduction in pain intensity was shown in the sucrafate group versus the placebo group on both day 5 and day 10 (p = 0.004, p = 0.001), respectively.

Sucralfate mouthwash may be more effective than placebo in the prophylaxis of 5-FU–induced OM. A correlation between both the reduction of pain intensity and mucositis severity was shown with the use of the sucralfate mouthwash suspension, further confirming the role of sucralfate in the prophylaxis of OM in patients receiving 5-FU chemotherapy.

• Small sample (< 100)

Sucralfate mouthwash may be effective in reducing the severity and pain intensity of OM in patients receiving 5-FU.

To compare placebo to sucralfate for prevention of mucositis in high-dose chemotherapy and bone marrow transplant (BMT)

Treatment was started one day before the regimen. Patients received one 2 g dose pack every three hours during the day and once during the night if awakened for a maximum of 7 per 24 hours until bone marrow (BM) recovery or end of mucositis.

The study reported on 102 patients hospitalized for allogeneic or autologous BMT.

The study was conducted between April 1991 and November 1993.

This was a prospective, randomized, double-blind study.

Patients were examined twice weekly by two physicians only, recorded prospectively, according to adapted Oral and Maxillofacial Surgeon (OMS) criteria for grafted patients.

• Slightly less patients in the sucralfate group (84%) experienced any grade mucositis compared to placebo (88%).
• Incidence of grade 3-4 mucositis was lower in the sucralfate group (29%) versus placebo (47%) (p = 0.07).
• The rate of severe mucositis was decreased possibly because of mechanical mouth rinses.
• When adjusted for total body irradiation (TBI), the p value for frequency of grade 3–4 mucositis in patients who received sucralfate versus placebo was 0.06.

• Long-term administration of sucralfate was not possible in this patient population because of nausea and vomiting.
• This study was conducted more than 20 years ago.
• The summary claims effectiveness for oral and intestinal mucositis; however, data does not support this claim.

Patients with head and neck cancer receiving radiation therapy (RT) were instructed to use the PRO_SELF Mouth Aware (PSMA) Program, an oral hygiene protocol, throughout RT. Those who developed RT-induced oral mucositis (OM) were randomized to either 1 gm carafate or normal saline (NS) mouthwash. Patients were instructed to rinse with the mouthwash four times per day. Nurses who were trained in the intervention, PSMA, and oral assessment phoned the patients twice weekly until one month after RT. One month after RT completion, oral assessment was done.

The study reported on 30 adult patients with head and neck cancer receiving RT with or without chemotherapy. The mean age of the sample was 55.2 years.

This was a randomized, double-blind, clinical trial.

The MacDibbs Mouth Assessment was used to measure the severity of OM. Patients also recorded pain when swallowing. Healing, weight loss, tube feeds, breaks in RT, hospital admissions, and Karnofsky Performance Status Scale scores were recorded. The investigators used t-tests and chi-square analysis.

No significant differences were found in the two groups in terms of average worst severity rating (p = 0.85), severe pain (p = 0.54), MacDibbs scores at the end of RT (p = 0.61), average pain at the end of RT (p = 0.51), MacDibbs scores at the follow-up visit (p = 0.24), pain at the follow-up visit (p = 0.41), or days to heal (p = 0.19).

No significant differences were found for any of the other variables as well (e.g., weight loss, tube feeds, breaks in RT).

• The study sample was small.
• The study lacks statistical power.
• Some patients had oral lesions prior to the study.
• Adherence to the mouthwash protocol was modest.

Patient were randomized to receive sucralfate or placebo, delivered in an oral suspension with identical appearance, taste, and consistency. Patients received six 1-gram doses daily at regular intervals beginning on day one of radiation therapy (RT) and throughout RT, including weekends.

• The study reported on 44 patients with head and neck cancer; 23 received sucralfate and 21 received placebo.
• Mean age of the sample was 55 years with a range of 34–72 years.
• Patients were receiving RT covering at least one-third of the oral mucosa to a minimum dose of 60 Gy.
• Patients were not receiving chemotherapy.

The study was conducted between December 1996 and December 1997.

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

• Patients received baseline oral examinations and questionnaires with drug- and oral mucositis-related questions.
• The Vander Schueren et al. scoring system was used to assess for mucositis.
• World Health Organization (WHO) criteria for oral and topical analgesics were used.
• Patients underwent biopsy on the 20th day of RT.

• Compliance in the sucralfate group ranged from 3–6 times per day with a median of 5. Patients in the placebo group had a 4–6 times per day compliance rate with a median of 5 (p = 0.21).
• Mean mucositis scores on the 20th day of RT were 2 in the sucralfate group versus 4 in the placebo group (p = 0.0002).
• Pain and dysphagia were reported less frequently in the sucralfate group, but the difference was not significant.
• Patients in the sucralfate group had decreased altered vascular calibration, altered vascular permeability, and leukocyte emigration.

Sucralfate is low in cost, is easily administered, and had a similar compliance rate.

• The sample size was small.
• Compliance rates raise questions.

To evaluate the effectiveness of sucralfate mouthwash in preventing 5-fluorouacil (5-FU) -induced oral mucositis (OM)

Patients were block randomized to receive sucralfate or an identical-appearing placebo. They were instructed to swish 10 ml of mouthwash for 2 minutes and then swallow it. The mouthwash was to be used four times per day starting on day 1 of radiation therapy (RT) and continuing until day 15.

Patients received throat swabs at the beginning of treatment to exclude infection. All patients used cryotherapy and the same salvage treatment (xylocaine topical, acetaminophen/codeine, then morphine sulfate if needed).

Patients were given 1 liter of study drug, and compliance was assessed by the volume left over after day 15. Research nurses contacted each patient by telephone after one week to assess compliance with the mouthwash and complete questionnaires.

• The study reported on 81 patients with colorectal cancer receiving 5-FU and leucovorin for one cycle; 42 patients were in the sucralfate group and 40 were in the placebo group.)
• The median age of patients was 61 years.

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

Patients graded the severity of mucositis at the same time each day (in the evening) for 15 days using a 0–4 rating scale developed by the North Central Cancer Treatment Group. In addition, 1–6 analgesic diaries, the McGill Pain Questionnaire, and a 0–10 quality of life measurement tool were used on follow-up visits.

No significant differences were found between the two groups in terms of the following measures.

• Sum of daily mucositis score (p = 0.86)
• Daily pain score (p = 0.90)
• Eating difficulty (p = 1.00)
• QOL (p = 0.57)
• Duration of mucositis (p = 0.74)
• Number of analgesics (p = 0.19)

More women experienced mucositis than men.

The patient and medical assessments differed, and the authors stated that patient reporting is believed to be more sensitive.

The study did not conclude that sucralfate was an effective solution for the prevention of oral mucositis in this study population.

• The trial was closed early because the placebo expired.
• The trial did not meet patient accrual numbers.
• Medical staff underestimated mucositis incidence.
• The study lacked statistical power.
• No daily assessment was done.
• The placebo mouthwash was not described.