Stimulating the discussion on saliva substitutes: a clinical perspective

Authors


Address for correspondence:

Associate Professor Camile Farah

The University of Queensland Centre for Clinical Research

Building 71/918

RBWH Complex

Herston QLD 4029

Email: c.farah@uq.edu.au

Abstract

Xerostomia is a significant problem commonly faced by patients and oral health practitioners. There is no cure for this condition, which commonly manifests as a side effect of medications, head and neck irradiation and other systemic conditions, such as Sjögren's syndrome and type 2 diabetes. It may also arise idiopathically. Therefore, treatment is palliative and takes the form of oral lubricants and saliva substitutes which aim to reduce symptoms associated with xerostomia as well as prevent oral disease secondary to it. Recently there has been an expansion of the number and range of products available in Australia for the palliative management of xerostomia. It is imperative then that oral health professionals have a sound understanding of the advantages and disadvantages of using such products as patients tend to be well informed about new products which are commercially available. This article discusses some of the most commonly available products used for the symptomatic relief and preventive management of xerostomia. Amongst the plethora of products available to the patient suffering from xerostomia, no single product or product range adequately reproduces the properties of natural saliva and therefore consideration of patients' concerns, needs and oral health state should be taken into account when formulating a home care regime. With Australia's ageing population and its heavier reliance on medications and treatments which may induce xerostomia, oral health professionals are likely to encounter this condition more than ever before and therefore an understanding of xerostomia and its management is essential to patient care.

Abbreviations and acronyms
CMC

carboxylmethycellulose

CPP-ACP

casein phosphopeptide amorphous calcium phosphate

SGH

salivary gland hypofunction

SLS

sodium lauryl sulfate

Introduction

Saliva is essential for good oral and general health. While saliva is comprised mostly of water, providing lubrication and comfort to the oral mucosa, a small percentage is composed of other minerals and molecules which act as a natural defence system.[1, 2] Physical protection is provided to the oral mucosa and dental hard tissues through lubrication and formation of the salivary pellicle, a protective film which provides a physical barrier against chemical and bacterial irritants. Further protection of the dental hard tissues is provided by a range of antimicrobial agents which have been identified in human saliva, including antibodies and a range of bacteriostatic compounds. Being a pH neutral reservoir for calcium, phosphate and bicarbonate, saliva not only buffers exogenous and endogenous acids, but also promotes remineralization of enamel and dentine following acid attacks.[1] Where saliva is deficient, in either quantity or quality, oral health and as a result general health is negatively impacted.

Xerostomia is the chronic and subjective sensation of dry mouth.[3] The condition is in most cases the result of salivary gland hypofunction (SGH) of which there are many causes, the most common being medication induced, head and neck irradiation and some systemic conditions, including Sjögren's syndrome and type 2 diabetes.[1, 4] Alternatively, xerostomia may be experienced in the absence of SGH and reduced saliva flow.[3] Diagnosis is difficult and several tools have been devised to assess the level of oral dryness and discomfort, namely the Xerostomia Inventory.[5] While the Xerostomia Inventory is validated and is considered a useful tool for diagnosing and scaling the severity of xerostomia, it has been suggested that a number of the set of 11 questions are either unhelpful or inappropriate to judge oral dryness.[6] To date, no gold standard exists in diagnosing xerostomia.

While it is difficult to quantify the burden of disease of xerostomia, it is estimated that 30% of the general population suffers from this condition, which significantly impacts on quality of life.[1, 7] The most common complaints of patients suffering from xerostomia include generalized oral discomfort, difficulty speaking, dysphagia and dysgeusia.[8] Oral manifestations secondary to xerostomia in patients with SGH may include heightened rates of dental caries, periodontal disease, non-carious tooth loss and oral infection.[1, 8] Systemic effects of xerostomia, whether subjective or due to SGH, include nutritional deficiencies as a consequence of dysphagia and oral discomfort, particularly in more severe cases.

As the damage to salivary glands is often irreversible and in the instance of medication induced xerostomia, an inescapable side effect, management is mostly palliative and consists largely of topical therapies. Therefore, management is aimed at symptomatic relief through the use of oral lubricants and saliva substitutes. More complex saliva substitutes attempt to mimic the protective properties of saliva through the addition of remineralizing and antimicrobial agents. Where residual salivary gland function remains, saliva stimulants may also be considered. A recent Cochrane review concluded that there was no evidence to suggest that any commercial saliva substitute was effective in relieving symptoms associated with xerostomia and called for more rigorous clinical studies.[2] Lack of objective criteria to assess comfort, pain and relief of symptoms and comparing these variables across patients has resulted in limited significance of current studies.

Despite this, oral health professionals are routinely faced with patients requiring management of xerostomia who are more aware these days of the range of products available on the market. Therefore, it is essential that all oral health professionals have a good understanding of the range of products available and are able to discuss the advantages and disadvantages of these with their patients. In this paper we set out to outline the products available to oral health professionals in Australia and to discuss the features of each, in relation to clinical practice.

Oral lubricants

The purpose of oral lubricants is to alleviate the oral discomfort associated with xerostomia. A survey of Canadian cancer patients who experienced xerostomia following radiation treatment reported an average oral pain score of 5.5 on a 10-point numerical visual analogue scale.[9] A recent Australian study found that patients suffering from xerostomia were five times more likely to develop an oral lesion compared to a non-xerostomic patient.[8] These patients were also three times more likely to have difficulty eating and to require water when swallowing.

As a result, oral lubricants have been developed to substitute the need to frequently sip on water, to alleviate oral discomfort and to moisten the oral mucosa. Table 1 compares some of the qualities of home remedies and commercially available saliva substitutes and stimulants which should be considered prior to recommendation and use. Water is the most commonly used home remedy for the management of discomfort associated with xerostomia by providing some moisture to the oral mucosa and often aiding in speech and swallowing.[1] In mild cases of xerostomia, frequent sipping of water, along with avoidance of certain foods and chemicals, such as alcohol, caffeine and sodium lauryl sulfate (SLS) may alleviate xerostomia to an acceptable level.[2] Olive oil is another home remedy used to alleviate the symptoms of xerostomia, which not only has lubricating properties, but has also demonstrated anti-inflammatory and antimicrobial characteristics. A 2007 study stated that olive oil containing lubricants and hygiene products improve oral discomfort in patients suffering from medication induced xerostomia.[10]

Table 1. A summary of commonly used oral lubricants and commercially available saliva substitutes
ProductProduct rangeTherapeutic agentspHAvailabilityDuration of actionEfficacy
ToothpasteGelRinseGumLP3 SystemFluorideCalciumXylitolSLS freeAlcohol free
  1. †10% diluted solution in Milli-Q deionized water (Millipore Corporation).

  2. ‡Manufacturer's claims.

  3. §Toothpaste, ¶Mouthrinse, #Gel, ^Milk derivatives.

Water × × × × × × 6.7FreelyLimitedEffective in mild cases
Milk × × × × × × 6.7SupermarketLimitedEffective in mild cases, provides protective features
Olive Oil × × × × × × × SupermarketLimitedSome evidence to support alleviation in medication induced xerostomia
GC Dry Mouth Gel × × × × × × × 6.0Dentist4 hoursNo published data
Colgate Dry Mouth Relief Fluoride Mouthwash × × × × × × 5.8Pharmacy Twice daily use recommendedNo published data
Biotène § ×

4.7§

5.6#

4.6

Pharmacy6–8 hoursSubjective efficacy in symptom relief, limited antimicrobial activity, demineralizing properties, reported duration <2 hours
OralSeven § §

6.1#

4.8

Pharmacy7 hoursNo published data
BioXtra § ^ 6.8 Not currently available in AustraliaOvernightSubjective efficacy in symptom relief greater than Biotène, limited antimicrobial effects
Extra Professional Calcium Sugar Free × × × × × × Supermarket
Recaldent gum × × × × × Dentist or online
Spry Dental Defence System × × × × × × Dentist or online

Milk has also been suggested in the literature as a readily available oral lubricant, which not only provides lubrication to the oral tissues, but may also aid in buffering acids and promoting remineralization of dental hard tissues due to the high calcium and phosphate content.[11] While milk may be contraindicated in patients with dietary constraints, and its duration of action may be limited, it demonstrates many of the qualities ideal for therapy of xerostomia.

Commercial oral lubricants use chemicals of high viscosity to mimic the physical properties of natural saliva and one of the most frequently used is carboxymethylcellulose (CMC), a water soluble polymer used commonly in pharmaceuticals as a suspension matrix.[12] In the case of oral lubricants, its ability to increase the viscosity of liquids is taken advantage of. Due to the water soluble nature of CMC, duration of action tends to be limited and frequent reapplication of the lubricant is required to maintain moisture. CMC has been shown to significantly improve subjective symptoms associated with xerostomia, the greatest benefit particularly amongst patients suffering from more severe cases.[1, 13]

GC Dry Mouth Gel (GC Corporation) utilizes a CMC base in its range of pH neutral flavoured gels for the alleviation of symptoms associated with xerostomia. While no clinical trials have been conducted to evaluate GC Dry Mouth Gel as an oral lubricant, one author claims effectiveness in general oncology patients following radiation treatment.[14] Being alcohol, SLS and sugar free, no adverse effects have been associated with the use of GC Dry Mouth Gel. While the gel only provides topical lubrication, combined use with GC Toothmousse or GC Toothmousse Plus is recommended by the manufacturer where indicated for remineralization and caries prevention secondary to xerostomia.[15]

Colgate Dry Mouth Relief Fluoride Mouthwash (Colgate-Palmolive Company) is a recently developed oral lubricant which claims symptom relief, enhanced patient tolerance and cariostatic properties.[16] Oral comfort is delivered through the addition of CMC as the primary lubricant and supplemented by carbomer and xanthan gum, the latter of which has physical properties comparable to natural saliva and has demonstrated slight improvements in symptom relief.[17] Cariostatic properties of Colgate Dry Mouth Relief Fluoride Mouthwash are provided through the inclusion of fluoride and cetylpyridinium chloride, the latter of which has been shown to inhibit plaque formation and prevent gingivitis.[18, 19] Being a relatively new product on the Australian market, no clinical studies have yet been conducted assessing the efficacy of Colgate Dry Mouth Relief Fluoride Mouthwash as an oral lubricant or cariostatic agent. However, internal testing by Colgate-Palmolive has reported that this rinse was favoured over the equivalent Biotène product in a patient preference study.[16]

Patient preference and acceptability is a significant factor when considering treatment for patients suffering from xerostomia. Being a chronic condition, which requires lifelong reliance on saliva substitutes, patient acceptability reflects the likelihood of patient compliance, and while Colgate Dry Mouth Relief Fluoride Mouthwash and GC Dry Mouth Gel both feature mild flavours which may be well tolerated by patients, there is no published evidence to suggest either of these products provide effective relief of symptoms. Furthermore, oral lubricants provide limited prevention against the oral manifestations associated with xerostomia and require coupling with other products, reducing patient compliance. Therefore, more complete products which provide oral lubrication and protective and preventive properties should be favoured.

Antimicrobial saliva substitutes

The variety of oral manifestations which may develop as a consequence of xerostomia has led to the development of saliva substitutes which attempt to mimic the protective properties of natural human saliva. Saliva substitutes which incorporate antimicrobial agents and have some remineralization and buffering capabilities should be favoured over oral lubricants which provide only symptomatic relief and offer little or no preventive properties. The combination of lactoferrin, lysozyme and lactoperoxidase has been utilized by various commercial saliva substitutes with varying degrees of success.[1] This combination, dubbed the LP3 protein enzyme system, incorporates antimicrobials found naturally in human saliva; lactoferrin binds iron, rendering it inaccessible to cariogenic bacteria for growth and hence functions as a bacteriostatic agent; lysozyme, a naturally occurring antibacterial, interferes with bacterial cell walls, resulting in cell death; and lactoperoxidase further controls bacterial levels by stimulating the production of hypothiocyanite, an effective antimicrobial naturally found in human saliva.[1] This LP3 protein enzyme system has been utilized by Biotène (GlaxoSmithKline), OralSeven (Pharma777 Ltd) and BioXtra (Bio-X Healthcare).

The Biotène product range, which includes a toothpaste, mouthrinse, gel, liquid, spray and chewing gum, has been the most well known and recommended in Australia. In addition to the LP3 enzyme protein system, further antimicrobial activity is achieved through the addition of fluoride and xylitol (a cariostatic sugar alcohol) to selected products.[20, 21] Furthermore, being both alcohol and SLS free, mucosal irritation is reduced, enhancing patient acceptance.[20] With a pH reportedly ranging between 5.2 to 6.5,[22] concerns have arisen over the demineralizing properties of the product range and Biotène has hence been contraindicated in dentate patients by some authors.[23, 24] Nevertheless, the Biotène formulation has shown some efficacy in reducing symptoms associated with xerostomia.

A study of 19 patients diagnosed with secondary Sjögren's syndrome reported significant improvements in subjective symptoms of dry mouth following four weeks use of Oral Balance Gel.[25] However, patient acceptance proved a problem, with three patients reporting a dissatisfying taste and one patient dropping out of the study due to unpleasant taste. Evaluation of Biotène Dry Mouth Fluoride Toothpaste, which contains xylitol, found patients approved of the flavour, with 80% satisfied with the taste.[22] In the same cohort, seven of the 20 patients found Biotène Dry Mouth Mouthwash too strong, 25% reporting that following the trial, they would discontinue use of the mouthrinse. However, following twice daily use of both the Biotène toothpaste and mouthrinse for four weeks, 16 patients reported slight to good relief of symptoms. While studies have shown Biotène to be effective, the lack of a control group, small sample numbers and subjective test outcomes severely limit the validity of these results.[1] A double blind crossover trial funded in part by the manufacturers of Biotène, compared Biotène Oral Balance Gel and toothpaste against a placebo and found a significant improvement of several subjective criteria of xerostomia.[26] Small sample size and no objective test outcomes limit generalizability of these results.

In relation to the antimicrobial characteristics of Biotène products, evidence would suggest very limited efficacy against the most common cariogenic bacteria outside of in vitro studies.[22, 26, 27] While most studies cite no effect of Biotène products on Candida albicans, one in vitro study claims inhibitory effects of Biotène Oral Balance Gel.[28]

Biotène products have shown some efficacy in reducing symptoms associated with xerostomia. However, the design of clinical trials, small sample size and lack of controls put into question the validity of these results. Furthermore, it is difficult to establish whether any of these products work in isolation, or if the entire Biotène system is required to observe a true effect. Adverse effects, including a pH below the critical level for enamel and dentine as well as poor taste contraindicate Biotène for many patients, unless other preventive measures are taken. Given that the range produces little antimicrobial effect, it may be prudent to advise dentate patients against using Biotène.

An alternative may be the OralSeven range of toothpaste, mouthrinse and gel, which have formulations similar to that of Biotène yet claim to maintain a neutral pH. OralSeven markets its range not only for patients suffering from xerostomia, but also to patients with a healthy saliva flow.[29] The product range is both SLS and alcohol free, which renders it suitable for dry mouths. Furthermore, some caries and calculus prevention is claimed through the addition of fluoride and calcium lactate,[30] which may justify OralSeven's marketing to healthy patients as a routine toothpaste. OralSeven also boasts the inclusion of aloe vera, which has demonstrated some ability to prevent mucositis following radiation therapy.[31] While the OralSeven range seems promising in alleviating symptoms associated with xerostomia and perhaps preventing dental disease secondary to xerostomia, rigorous clinical trials are required before OralSeven can be confidently recommended to patients.

BioXtra, a saliva substitute based on similar active ingredients to Biotène and OralSeven, is currently available in parts of Europe, Asia and Canada with a view to be made available to oral health professionals and patients in Australia. BioXtra claims superior antimicrobial properties compared to Biotène through the inclusion of immunoglobulins which mimic those of natural saliva, milk and colostrum extracts.[32] The range includes toothpaste, mouthrinse, gel, mouth spray, chewing gum and lozenges.

BioXtra has shown some efficacy against the most common cariogenic bacteria in vitro, however these results have not been replicated in clinical trials and more research is required in this area.[27] In relation to its efficacy as an oral lubricant, studies suggest significant improvement in oral comfort.[33] Superior levels of alleviation of oral discomfort have also been reported of BioXtra compared to Biotène; direct comparison of both systems (toothpaste, mouthrinse and gel) found that while both improved subjective symptoms of xerostomia, BioXtra produced significantly greater results.[34] BioXtra was also preferred by patients, with study participants reporting a better taste than Biotène.

While currently unavailable in Australia, it seems that of the most common CMC based oral lubricants which incorporate salivary proteins and enzymes, BioXtra appears the most effective in relation to reducing symptoms and patient acceptability.

Saliva stimulants

Saliva stimulants are an effective way of promoting salivation in patients with residual salivary gland function. As no commercial saliva substitute has yet been developed which accurately replicates all essential qualities of natural saliva, attempts should be made to increase the natural flow of saliva as much as possible. Saliva stimulation may be via local action, through physical stimulation, or systemically via the parasympathetic nervous system through the use of medication.[1] Local saliva stimulants take the form of sugar free chewing gum and lozenges, with a recent Cochrane review concluding that chewing gum aids in increasing salivary flow.[2] A range of sugar free gums exist and many of these are supplemented with remineralizing or bacteriostatic agents. For the xerostomic patient, who is deficient in these qualities, supplemented gums should be favoured over standard sugar free gums.

Wrigley's range of Extra Sugar Free gums (Mars Incorporated) are perhaps the most well known by patients and the most widely accessible. A recent addition to the range is Extra Professional Calcium Sugar Free, which releases 40 mg of calcium per piece of gum within 20 minutes.[35] Recaldent Gum (GC Corporation) supplements the saliva's natural ability to remineralize hard tissue through the release of both calcium and phosphate in the form of casein phosphopeptide amorphous calcium phosphate (CPP-ACP).[36] Saliva stimulants with antimicrobial properties may also be utilized by patients. The Spry Dental Defence System (Xlear Australia Pty Ltd) chewing gums incorporate xylitol, a sugar substitute with sweetness comparable to that of sucrose. Long-term regular use of xylitol has shown to reduce Streptococcus mutans numbers and in turn reduce the long-term incidence of caries.[21] Biotène and BioXtra also include chewing gums in their range and these incorporate the protein enzyme system included in their other oral hygiene and oral lubrication products.

While chewing gum may increase salivation and in some cases supplement the saliva with cariostatic and remineralizing agents, gums are limited in altering the composition of saliva. Systemic saliva stimulants in the form of medication may be considered in cases of severe xerostomia. The most commonly used medication is pilocarpine, which acts on the parasympathetic nervous system to increase secretion of bodily fluids.[1, 37] As a result, patients often experience heightened levels of saliva production as well as excessive sweating and more frequent urination, which are the most common side effects associated with the use of pilocarpine. While pilocarpine has been shown to benefit patients suffering from xerostomia as a consequence of head and neck irradiation, Sjögren's syndrome and graft versus host disease, duration of action is limited to two to three hours, which may limit patient acceptability.[1, 37] The use of pilocarpine is contraindicated in patients suffering from significant cardiovascular and pulmonary disease and therefore should not be prescribed by a general oral health professional. Consultation with the patients' general medical practitioner and an oral medicine specialist is indicated in such circumstances.

Conclusions

Saliva is a unique natural secretion essential for oral and general health. While several oral lubricants and saliva substitutes are currently available or soon to be on the Australian market, no single product or product range has effectively replicated natural saliva to alleviate symptoms and prevent oral diseases associated with xerostomia. Therapy requires an in-depth risk assessment of the patient, their concerns, and requirements to maintain good oral health in the absence of natural saliva. Avoidance of mainstream oral hygiene products, which often contain SLS and alcohol, should be recommended to most, if not all xerostomic patients, as these chemicals can worsen oral discomfort levels.

Inclusion of commercial saliva substitutes in xerostomia management should be tailored to the individual patient's concerns, preferences and oral health needs. Symptom relief, which is a priority for patients, is difficult to readily address as many of the newer products have not been scientifically or clinically tested, and studies which do exist suffer from a high level of bias. Consideration of the patient's current oral health status and hygiene regime and general attitude to compliance should be taken into account when constructing an oral maintenance plan for patients suffering from xerostomia.

Ancillary