Compounding opportunities: Oral Mucositis

Marina Holt
BPharm Dip Quality Auditing Cert IV TAE MPS MACP
Training & Education Manager
PCCA

Learning objectives

1. Identify common risk factors for mucositis.
2. Describe the WHO grading system for oral mucositis.
3. Discuss some of the most common active pharmaceutical ingredients which may be incorporated into an oral mucositis mouth rinse.

Competency Standards: 1.4, 1.5, 2.1, 2.2, 2.3, 3.1, 3.2, 3.3, 3.4, 3.6

Accreditation number: A1902ITK1
Accreditation expiry: 1 February 2021

This activity has been accredited for 1.0 hour of Group One CPD (or 1.0 CPD credit) suitable for inclusion in an individual pharmacist’s CPD plan which can be converted to 1.0 hour of Group Two CPD (or 2.0 CPD credits) upon successful completion of relevant assessment activities.

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Introduction

Oral mucositis (OM) is the inflammation and ulceration of the oral mucosa observed in patients being treated for cancer with chemotherapy and/or radiation therapy. The mucositis initially results in painful sores. If left untreated, the pain and ulceration can lead to dysphagia, compromised nutrition and oral hygiene, as well as increased risk of local and systemic infection. Mucositis can also affect other areas of the alimentary tract and is therefore potentially a treatment-limiting complication of cancer therapy.

Although a well-recognised condition, there is no one specific treatment available for OM.

Compounding pharmacists are often called upon to prepare supportive treatments for patients in distress when other non-pharmacological treatments have proven ineffective.

By having a greater awareness of the condition, including an understanding of the epidemiology and classification of the different stages of mucositis, together with a knowledge of available active pharmaceutical ingredients that can play a role in the treatment of the condition, compounding pharmacists are in a unique position to provide treatment options which may significantly improve positive outcomes of treatment cycles.

Incidence and risk factors

The incidence of OM varies but is most common with drugs which affect DNA synthesis: fluororuracil, cytarabine and methotrexate.

It is estimated that 75% of all patients undergoing bone marrow transplants (HCT hematopoietic cell transplantation) and 80% to 100% of patients receiving radiation therapy for head and neck cancers will develop severe OM.1,2

40% of patients receiving standard-dose chemotherapy are expected to develop some degree of OM.3

Some of the newer monoclonal antibody (mAb) treatments appear to have a lower incidence of OM. Trastuzumab (Herceptin®), which is commonly used for treatment of breast cancer, is not associated with some of the commonly observed side effects of chemotherapy, such as alopecia and mucositis.4

There are also a number of patient-related risk factors which may act as predictors for OM. These risk factors include:

• Caucasian ethnicity5
• paediatric and elderly
• female
• low body mass index (BMI < 20 for males or <19 for females)6
• poor oral care/oral pathology, including dental caries or periodontal disease
• xerostomia (dry mouth)
• low baseline count of neutrophil cells
• prior history of OM and/or gastritis.7

In addition, other co-morbidities such as diabetes mellitus or impaired renal function may have an impact on mucositis risk. The impact of predisposing genetic factors should also not be underestimated.8

Classification

Standardised grading classifications, such as the World Health Organisation’s Mucositis Grading Scale, allow for a patient’s degree of mucositis to be assessed based on both objective and subjective variables, such as the degree of oral ulceration and the patient’s ability to eat.

Low level, Grade 1 mucositis is characterised by redness, mild soreness or low-grade ulceration, often without pain. By contrast, Grade IV oral mucositis is considered life-threatening, with patients requiring total parenteral or enteral nutrition.9

GRADE	DESCRIPTION
Grade 0           No mucositis	No mucositis present
Grade I            Mild oral mucositis	Irritation of oral mucosa, with pain; no overt ulceration; patient able to eat normal diet
Grade II           Moderate oral mucositis	Sores evident in oral mucosa; patient still able to swallow solid food
Grade III         Severe oral mucositis	Patient experiences extreme sensitivity when swallowing solid food; liquid diet necessary
Grade IV          Life-threatening	Patient unable to swallow; total parenteral nutrition or tube feeding necessary

Table 1: The WHO grading system for oral mucositis

Pathophysiology

The pathogenesis of mucositis currently follows a five-stage model, based on evidence and recent studies which indicate that the fundamental mechanisms involved are more complex than simply direct damage to the epithelium. It is believed that the mechanisms for both radiation-induced and chemotherapy-induced mucositis are similar.10

Phase 1: Initiation of tissue injury

Radiation and/or chemotherapy induces cellular damage which results in death of basal epithelial cells and generates reactive oxygen species (ROS) which cause further significant cell damage of the mucosa.

Phase 2: Signalling-upregulation of inflammation

Both radiation and/or chemotherapy continue to cause direct cell death, and free radicals (ROS) activate secondary messengers which transmit signals from receptors on the cell surface to the inside of the cell. This process induces apoptosis and up-regulates pro-inflammatory cytokines, tissue injury and cell death.

Phase 3: Amplification

Injury to mucosal cells continues due to further upregulation of pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-α). Molecular pathways which further amplify mucosal injury are also amplified.

Phase 4: Ulceration and inflammation

This is the most clinically significant phase. As ulceration develops, the associated bacteria are free to further colonise the submucosa. Continued production of pro-inflammatory cytokines leads to secondary infection. This phase of OM is ultimately responsible for the pain and loss of function which accompany the condition.

Phase 5: Healing

The integrity of the epithelium is restored as cells migrate to form an intact wound surface. Tissue and cell differentiation continue until the thickness of the mucosa returns to normal and the ulcer heals.

Physical changes

Initially, OM will present as erythema of the oral mucosa, which then continues as the mucosa atrophies. As the mucosa continues to breakdown, ulcers begin to form. These ulcers are typically covered by a white fibrinous pseudomembrane. Ulcers usually range in size from 0.5 cm up to 4 cm.

OM may be extremely painful and bleeding may also occur. As a result of the pain, patients may experience trouble eating, speaking or even opening their mouth.

Altered taste perception is also common, particularly in patients undergoing head and neck radiation therapy. Although the altered taste sensation may be a temporary condition, complaints that food tastes too sweet or too bitter, or has a metallic taste, may significantly impact the patients desire to eat.11

If the pain and discomfort is too severe, it may lead to the inability to chew and swallow, ultimately leading to dehydration, malnutrition, anorexia and cachexia (syndrome of extreme weight loss and/or muscle wasting).

Levels of saliva may be significantly diminished, which in itself may lead to more pain and mouth ulcers, since saliva generally has a cleansing effect and helps to keep bacteria in check.

As the symptoms grow worse, and patients find it more difficult to eat, weight loss may occur.

Poor nutrition leads to increased susceptibility of infection and approximately half of all patients receiving chemotherapy will develop such severe mucositis that treatment will need to be ceased or modified.

Chemotherapy-induced vs radiation-induced mucositis

While there are similarities in the cellular events of both chemotherapy- and radiation-induced mucositis, the biological pathways may be different, which will impact on the overall treatment of patients.

Chemotherapy is administered systematically, over a set period of time, whereas radiation therapy affects a specific body area.

Chemotherapy which is delivered over a short period of time may give rise to acute injury to mucosal tissue. Therefore, chemotherapy-induced oral mucositis usually develops within a four-to-seven-day period after initiation of treatment and peaks within 10–14 days, followed by improvement over the course of a few weeks.

Conversely, with radiation-induced mucositis, the clinical course may be more gradual. Typically, the mucositis will begin to develop after ten days of cumulative dosing, and may last for weeks, or even months.

For the compounding pharmacist, it is important to understand that the overall peak process occurs within a relatively short time frame, giving the compounder a huge opportunity to provide timely access to supportive treatments, which may have a significant positive impact on overall treatment outcomes.

Sites of mucositis

While, for the most part, oral mucositis is considered the most notable site of mucosal involvement, particularly during chemotherapy, it is important to note that mucositis may involve the full length of the alimentary tract, including the oesophagus, stomach, colon and rectal mucosa.12

In the case of targeted radiation therapy, pharmacists should be aware of the impact of treatment to those specific areas. For example, local treatment of ovarian cancer will impact the vaginal mucosa, treatment of prostate cancer will impact the rectal area and treatment of nasopharyngeal cancers will require support of the nasal mucosa.

Impact of oral mucositis

The overall impact of oral mucositis should never be underplayed.

Initial physical changes, such as oral ulceration seen in a Stage 1 mucositis (see table 1), may appear reasonably manageable, but recent studies have investigated the impact of oral mucositis in cancer patients who developed chemotherapy- and/or radiotherapy-induced oral mucositis.

One 2015 study considered seven parameters of impact:

• functional limitation
• physical pain
• psychological discomfort
• physical deficiency
• psychological deficiency
• social incapacity13

While physical pain is still the most significant factor in patients suffering from OM, almost 30 percent of patients reported social limitation as part of their condition. There was a greater impact on male patients.

Other studies have assessed anxiety and depression in OM patients,14 particularly on those patients who already suffer from anxiety or depressive disorders before commencing treatment. In many of these patients, side effects are more intense due to the fact that many antidepressants themselves cause side effects, such as hyposalivation, which impacts oral health.

The role of the compounding pharmacist in the initial interaction with OM patients can be critical in contributing to positive treatment outcomes.

As part of the regular risk assessment which forms part of the required professional practice guidelines for compounding,15 pharmacists should take particular note of any co-morbidities in patients when they present with compounded prescriptions for OM, and counsel patients accordingly.

Mental health first aid should be a high priority with all patients undergoing cancer treatments and pharmacists are encouraged to take an active role in engaging with patients regularly and referring them to appropriate support services if and when the need is identified.

Goals of therapy

Although the development of OM may be a foregone conclusion, there are three main goals that pharmacists should aim for in the treatment of OM. These are:

1. Control oral pain and discomfort.
2. Decrease the incidence of ulcerations.
3. Reduce the duration and severity of lesions which develop.

The role of the pharmacist

Prevention and treatment

There is no one effective approach to the treatment of oral mucositis. For the compounding pharmacist, this therefore represents a significant area of unmet need, one where their expertise in formulation may provide valuable supportive care for sufferers.

Prevention and treatment can be divided broadly into two groups: non-pharmacological and pharmacological.

Non-pharmacological interventions include:

• reviewing dental hygiene prior to commencement of treatment, and ongoing regular oral support. Patients should be advised to visit the dentist and clean their mouth every four hours or so, and always after eating.16
• using artificial saliva substitutes, saline or sodium bicarbonate rinses. Several commercial products are currently available in Australia and are usually recommended by cancer treatment centres as part of their regular protocols.17
• drinking plenty of water, avoiding alcohol and soft drinks
• avoiding citrus and strongly acidic foods, as well as spicy foods
• avoiding/discontinuing smoking
• sucking on ice cubes to cool the mouth.

In their regular interactions with patients, pharmacists have the opportunity to remind patients of these straightforward interventions and discuss any increased development of lesions.

Compounding pharmacists, often already preparing tailored nutritional compounds for other patient groups, are well placed to adopt a holistic approach to treatment of OM.

Knowing that increased ulceration will lead to reduced nutritional status, there is an opportunity for pharmacists to work with allied health professionals, such as dietitians, together with family caregivers, to provide liquid diet supplements which may be better tolerated during acute phases of OM. Supplements, such as zinc and alpha lipoic acid, have been shown to be helpful.18,19

Preparing compounded mouthwashes: The compounder’s domain

Compounding pharmacists are in a unique position to prepare tailor-made mouthwashes and oral suspensions for individual patients whose needs may vary depending on the treatment they are undergoing.

Compounded mouthwashes, often generically described as ‘magic’ mouthwashes, are known by a variety of names, each with its own combination of actives. However, compounders have the opportunity to vary the combinations and strengths of the active ingredients as required by the patient.20

Some of the names of specific mouthwashes include, but are not limited to:

• Miracle mouthwash: Dexamethasone, Tetracycline, Nystatin, Diphenhydramine
• Stanford mouthwash: Tetracycline, Nystatin, 2-Deoxy-D-Glucose, Chlorpheniramine
• Duke’s magic mouthwash: Nystatin, Hydrocortisone, Diphenhydramine
• Kaiser’s mouthwash: Hydrocortisone, Tetracycline, Nystatin

Directions for these preparations are generally to ‘swish, gargle and spit’, or swallow 5–10 ml every six hours as required.

Quite often, when initiated in a hospital setting, patients are prescribed the ‘Pink Lady’ formula, traditionally prepared from a combination of commercial products. The pink colour appears from the dilution of the white Mylanta with the red colour of the viscous lignocaine and diphenhydramine elixir.

Traditional ‘Pink Lady’ formula

• 80 ml viscous lidocaine (lignocaine) 2%
• 80 ml Mylanta
• 80 ml diphenhydramine 12.5 mg per 5 ml elixir
• 80 ml nystatin 100,000 U suspension
• 80 ml prednisolone 15 mg per 5 ml suspension
• 80 ml purified water

Depending on the patient’s needs, individual ingredients may be excluded, to the point where only the Mylanta and Viscous Lidocaine 2% are combined.

Common ingredients in compounded mouthwashes

Antihistamines	Diphenhydramine, chlorpheniramine
Antifungals	Nystatin
Antibiotics	Tetracycline
Corticosteroids	Hydrocortisone, dexamethasone
Local anaesthetics	Lidocaine (lignocaine) Dyclonine
Magnesium hydroxide/Aluminium hydroxide	Mylanta, sucralfate (Aluminium complex)

Table 2: Common Ingredients Included in compounded mucositis mouthwash formulas

Antihistamines: Diphenhydramine, Chlorpheniramine

Diphenhydramine hydrochloride is an ethanolamine derivative antihistamine. It has a relatively short duration of action but pronounced sedative properties. Some clinical studies have considered its effectiveness as a local anaesthetic and analgesic.21,22

In Australia, it is available in an oral liquid for cough and oral capsules as a short-term sleeping aid. Typically, diphenhydramine would be incorporated into a mouthwash at 1.25 mg/ml.

Antifungals: Nystatin

Nystatin is an antifungal antibiotic that is used most commonly for treatment of oral thrush. Although nystatin is commonly included in ‘magic’ mouthwash formulations, there is limited evidence with regard to its specific efficacy in the treatment of oral mucositis. However, recent research has considered its inclusion in solid dosage forms for the treatment of mucositis in combination with lidocaine.23

There may be some benefit in its inclusion if the patient is prone to oral candidiasis or has an active infection. Nystatin, which is dosed in International Units (IU), is generally incorporated in strengths ranging from 12,500 IU/ml to 35,000 IU/ml.

Antibiotics: Tetracyclines

Tetracyclines are antimicrobials derived from Streptomyces aureofaciens. Formerly widely used, tetracycline use has been declining due to increased bacterial resistance.

There are several potential problems which may arise when tetracycline is included in these mouthwashes:

1. Tetracyclines themselves may cause oral or vaginal thrush and therefore should either be avoided in those patients, or it may be wise to consider the inclusion of nystatin to counteract this situation.
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2. Stability of tetracyclines in an aqueous base is questionable. Some studies report that tetracycline hydrochloride exhibits as much as 10% loss in seven days even when refrigerated.24 Tetracyclines degrade quickly in the presence of hydroxides. It has been suggested that use of the tetracycline base may be more appropriate for stability purposes.
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3. Interactions between tetracyclines and antacids are well documented and may be cause for consideration when preparing formulations. Tetracycline is chelated by aluminium or magnesium, commonly found in antacids included in OM preparations. Sucralfate, also studied for inclusion in OM preparations, is sucrose-sulphate aluminium complex.25 Less well documented but still recognised, is the potential for an interaction between hydrocortisone and tetracycline.
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4. Tetracyclines should not be added to paediatric mouthwashes for patients under eight years old because they are known to cause permanent discolouration of teeth, enamel hypoplasia and can interfere with bone growth.

Corticosteroids: Hydrocortisone, Dexamethasone

Hydrocortisone and dexamethasone are the two most common corticosteroids which are included in OM mouthwashes for their anti-inflammatory action.

Corticosteroids are cost effective and have a well-documented history in the treatment of other oral inflammatory conditions such as oral dermatitis. T

he protective effect of dexamethasone in 5-Fluoruracil-induced OM has been recently studied and shows beneficial effects.26

Hydrocortisone is usually incorporated at a strength of 0.05%.

Local Anaesthetics: Lidocaine (Lignocaine), Dyclonine

Traditionally, formulas such as the Pink Lady formula have relied on the viscous nature of commercial lidocaine formulas to help improve the adhesive nature of the local anaesthetic, particularly for patients who have oesophageal involvement and benefit from swallowing the medication.

Xylocaine Viscous® is a 2% preparation which is often further diluted. Overall, the typical strength requested would be 0.5% to 2%.

Dyclonine, a local anaesthetic which has seen more use overseas than in Australia, is generally used more in dental medicine as a rinse to anesthetise gingival and palatal tissue, and helps to numb the gag reflex.

Although not included very often, it provides a local anaesthetic alternative for patients who are allergic to ‘-caine’ anaesthetics.

Dyclonine is generally used in concentrations of 0.5% or 1%.

General formulation considerations

Having taken a thorough patient history, compounding pharmacists should regularly liaise with relevant prescribers and members of the oncology treatment team to adjust formulations if required.

Most of the drugs mentioned are vile tasting and, in combination, will require significant improvement of flavour in order to aid patient compliance.

The compounding pharmacist is able to add natural sweeteners, such as steviol glycosides, and flavours which will make the regular use of these mouthwashes more pleasant and tolerable. Peppermint oil, for example, is a salicylate-based oil, and while consumers generally consider the ‘freshness’ of a minty taste appropriate when using regular toothpastes and mouthwashes, the burning nature of this oil is likely to be inappropriate during treatment of OM.

It is important for the pharmacist to be aware that sugar-based vehicles, such as ‘SYRUP’ or ‘SYRUP BP’, are largely unsuitable for these preparations. Locally, the sugar will increase the incidence of dental caries, as well as feed any fungal conditions. The sugar content may also affect any diabetic patients.

Sorbitol-based preparations may be more beneficial, particularly in ‘rinse-and-spit’ formulations, as they will not increase dental caries. However, in preparations which are to be swallowed, sorbitol preparations are likely to cause unwanted diarrhoea due to their laxative nature.

In recent years, there has been an increase in the availability of mucoadhesive preparations designed to form protective layers over the oral mucosa.[xvii] Not all of these products are currently available in Australia.

Some oral mucoadhesive products, currently available to compounders in Australia, may have the benefit of being able to act as a base for the other active ingredients to be incorporated into, providing both increased moisturisation to the mucosa as well as improved contact time, which may improve treatment outcomes.

If bleeding occurs from severe ulceration, compounders should also discuss the use of a compounded tranexamic acid mouth rinse as adjunct therapy.[xviii] Tranexamic acid is readily soluble in water and is generally prepared as a 4.8% or 5% oral rinse.

Counselling

Pharmacists are trained to counsel patients about their medications as a regular part of medication management. However, this process can often prove challenging for a compounding pharmacist who is providing a compounded mouth rinse for which no commercial Consumer Medicines Information (CMI) is readily available.

Due to the nature of the treatment involved, it is critical for the compounding pharmacist to ensure the utmost privacy when counselling oncology patients.

It is understandable that patients undergoing chemotherapy or radiotherapy may be distressed about their condition and treatment, even before the impact of the ensuing mucositis is taken into account. The patient may be distracted at the time of collecting their medication, or in fact it may be collected by a family member or friend.

The compounding pharmacist should be aware of these possible scenarios and make the time to follow up with the patient to make sure they are confident about how to use the compounded preparation.

Provision of a patient information leaflet, which clearly identifies the name of the compounding pharmacy and gives reinforced information about how to correctly use and store the medication, together with possible side effects, would be a valuable counselling tool.

Information, such as how often to use the medication, including clear instructions about volumes to be taken, and whether the medication should be spat out or swallowed, should be reinforced during counselling, in order to avoid unnecessary side effects.

All compounded medications should also carry ‘This product has been compounded by the pharmacist’ together with appropriate ‘Refrigerate’ and ‘Shake the bottle’ labels.

Other agents and new opportunities

Many agents have been studied as possible suitable therapies for treatment of OM. Some, such as allopurinol, traditionally used for treatment of gout by reducing high uric acid levels, have been investigated for the treatment of fluorouracil-induced mucositis with poor results.29

Low level laser therapy (LLLT) is suggested to reduce incidence of OM and its associated pain in patients before head and neck radiation and may become useful for management of OM at treatment centres which have access to this technology.

Palifermin is a human keratinocyte growth factor that enhances epithelial cell proliferation, differentiation and migration. It has been assessed in some patients having chemotherapy and radiation before stem cell transplantation for haematological malignancies.30

Treatment is given via daily intravenous injection consecutively for three days before, and three days after chemotherapy and/or radiotherapy.31

Glutamine – L-Glutamine is an essential amino acid found in muscle and plays an essential role in intestinal health and support of the immune system. Stressors, such as major surgery, burns and injury, may reduce levels of this naturally occurring amino acid, which will require supplementation. It has been investigated in both children and adults and appears to be a simple and useful measure to increase the comfort of many patients at high risk of developing mouth sores as a consequence of intensive cancer chemotherapy.32

N-acetyl cysteine (NAC) is a potent antioxidant and has been suggested for the prevention of OM in hematopoietic SCT (stem cell transplantation). A 2014 double-blind, randomised, placebo-controlled trial of leukaemia patients found that parenteral NAC is effective in reducing the incidence of severe cases and the total duration of OM.33

Melatonin is a hormone synthesised from tryptophan and is produced in the human body in the pineal gland. It is a potent antioxidant which is generally used to promote sleep and shorten the duration of jet lag.

Recent findings have demonstrated that melatonin reduces irradiation toxicity and prevents treatment-induced mucositis, indicating that preparation of a 3% melatonin gel may provide an innovative, adjuvant strategy in the treatment of cancer.34

This appears to be one of the most exciting developments which may be able to be prepared by compounding pharmacists and represents an example of the need for pharmacists to stay abreast of new novel therapies available for supportive treatment of OM.

Conclusion

Oral Mucositis (OM) is a predictable condition affecting a large proportion of patients undergoing chemotherapy and/or radiation therapy. Severe OM may lead to cessation of treatment and reduced quality of life. Symptoms include oral pain and ulceration and are associated with increased infection, both local and systemic.

The pathobiology of the condition is multifactorial and there is no one recognised treatment which is appropriate in all conditions. However, OM plays a significant role in the treatment outcomes of patients.

Compounding pharmacists are in a unique position to be able to offer early intervention and support by providing tailor-made compounded preparations to minimise patients’ symptoms and improve treatment outcomes. Pharmacists have access to a range of therapeutic agents which may be used alone or in combination to provide relief of symptoms for treatment of patients suffering from this potentially life-threatening complication of treatment. Nutritional support for patients suffering from OM should also form part of pharmacist counselling.

Investigations continue to explore new options for treatment, with newer bases expanding the formulation capabilities of pharmacists. It is important for the compounding pharmacist to understand the range of options and continue to review available therapies.

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Submit your answers to earn CPD credits

Answers can be submitted through GuildEd at guilded.guild.org.au.

Australian College of Pharmacy members can submit answers online at acp.edu.au in the CPD Library.

Assessment questions

1. Predictors for oral mucositis include:

a. patients undergoing bone marrow transplantation.
b. prior history of oral mucositis.
c. poor oral hygiene.
d. genetic factors.
e. All of the above

2. A patient who has reached Stage III Mucositis as per the World Health Organisation’s Mucositis Grading Scale, is very likely to:

a. have low grade ulceration in their mouth.
b. be unable to swallow.
c. have trouble swallowing and require a liquid diet.
d. still be able to swallow food.

3. A common ingredient which would be included in a compounded oral mucositis mouthwash is:

a. Amoxycillin.
b. Diphenhydramine.
c. Ranitidine.
d. Amitriptyline.
e. All of the above

4. The ‘Pink Lady’ formula contains all of the following ingredients except for:

a. Diphenhydramine.
b. Mylanta.
c. Tetracycline.
d. Lidocaine.
e. Prednisolone.

5.Which one of the following hormones may show promise when it comes to treatment of oral mucositis?

a. Estriol
b. Melatonin
c. Testosterone
d. Progesterone
e. Estradiol

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References available on request.