# Could the use of saliva substitutes improve food oral processing in individuals with xerostomia? A systematic review

Sophie Piaton, Anne Duconseille, Valérie Roger-leroi, Martine Hennequin

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Sophie Piaton, Anne Duconseille, Valérie Roger-leroi, Martine Hennequin. Could the use of saliva substitutes improve food oral processing in individuals with xerostomia? A systematic review. Journal of Texture Studies, 2021, 52 (3), pp.278-293. 10.1111/jtxs.12591. hal-03285510

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1 Could the use of saliva substitutes improve food oral processing in individuals with

2 xerostomia? A systematic review

3

4 Short title : Saliva substitutes and FOP

5

6 Sophie Piaton¹,², Anne Duconseille¹, Valérie Roger-Leroi¹,², Martine Hennequin¹,²

7

8 ¹ Université Clermont Auvergne, CROC, F-63000 Clermont-Ferrand, France.

9 ² CHU de Clermont-Ferrand, Service d'Odontologie, F-63003 Clermont-Ferrand, France

10

11 Corresponding author

12 Prof Martine Hennequin

13 CROC EA4847 UFR d'Odontologie

14 2 rue de Braga

15 63000 Clermont-Ferrand

16 France

17 Email: martine.hennequin@uca.fr

18 Tel: 00 33 4 73 17 73 81

19

20

21

22
23 **ABSTRACT**

Xerostomia was associated with food avoidance and low nutritional assessment. This review seeks to document whether products called "saliva substitutes" or "artificial saliva" can really replace saliva in food oral processing. Pubmed and Science Direct were searched for articles using the keywords "saliva substitutes" and "artificial saliva". An advanced search was applied using the terms "xerostomia" and/or "food oral processing" and/or "eating" and/or "mastication" and/or "chewing" and/or "swallowing". The analysis methods and the inclusion criteria were documented in a protocol published in the International prospective register of systematic reviews (PROSPERO with the registration number CRD42019124585).

The search included 43 articles, published between 1979 and 2017. Among the included studies, 17 were observational studies, 5 were pilot studies, 21 were crossover studies and 14 of these studies were blinded. The Strobe score for the included articles varied from 7.5 to 20.

The possible effects of the use of saliva substitutes on the ingestion function were poorly investigated. No evidence was based on physiological studies. It is unknown whether using a saliva substitute has an effect on the composition and rheological properties of the food bolus, on the lubrication of the oral and laryngeal mucosa or on both phenomena. Moreover, saliva substitutes were not formulated to improve food oral processing and most of them are flavoured.

New saliva substitutes and artificial saliva should be designed and formulated to improve food oral processing.

42
43 **Keywords:** Xerostomia, Sjögren's syndrome, saliva substitutes, artificial saliva, Food oral
44 Processing, review

45
46
47
48

# 1 INTRODUCTION

Xerostomia is a subjective feeling of dryness in the mouth related to possible quantitative and qualitative changes in saliva composition (Fox, Busch, & Baum, 1987). It should be differenciated from hyposalivation which results from an objective assessment of a reduced salivary flow rate (Łysik, Niemirowicz-Laskowska, Bucki, Tokajuk, & Mystkowska, 2019). The causes of xerostomia are heterogenous, and may or may not be related to saliva production deficiencies. Among the origins of xerostomia, one can distinguish the consequences of salivary diseases (salivary gland trauma, and tumor, surgery or radiotherapies), from the effects of systemic chronic diseases (chronic, autoimmune, diabete mellitus, Sjogren's syndrome, lupus erythematosus and others autoimmune disorders), dehydration, mouth breathing or the adverse effects of drugs. More than 400 medicines are associated with xerostomia (Porter, Scully, & Hegarty, 2004). Determining the epidemiology of xerostomia is complex due to the unclear definitions of dry mouth being used and the different methods for measuring this condition (Ying Joanna & Thomson, 2015). A systematic review reported that the prevalence of xerostomia ranged from 8% to 42%, while the prevalence of hyposyalia varied from 12% to 47% (Hopcraft & Tan, 2010). Xerostomia prevalence is estimated to be approximately 20% in the general population, with an increased prevalence in women (up to 30%) and in elderly (up to 50%) (Furness, Worthington, Bryan, Birchenough, & McMillan, 2011). Overall, 54% of people complaining of xerostomia actually had objective evidence of hyposalivation after salivary flow measurements were taken (Longman et al., 1997).

Various treatments were proposed to patients with xerostomia. Saliva stimulants and saliva substitutes aim to alleviate the symptoms of xerostomia. Saliva stimulants activate the salivary gland function. Their composition is based either on pilocarpine, a nonselective muscarinic agonist, or on cemivaline, which has specific affinity for receptor subtypes. The indications of saliva stimulants are restricted to individuals suffering from hyposalivation. Saliva substitutes
73 have no effect on saliva production. They are indicated for all patients suffering from xerostomia, including those having hyposalivation. Artificial saliva products definitely are not 74 saliva. They were developed to imitate and act as saliva but they do not act as saliva for all of 75 its complex functions (antimicrobial, digestive/perceptive, teeth protection etc..). are indicated 76 for all patients suffering for xerostomia, including those having hyposalivation. 77

78 The effects of saliva substitutes have been reported in many studies measuring self-perception 79 of pain, comfort in mouth and quality of life related to oral health. However, it is not clear 80 whether saliva substitutes could improve eating capacities and the nutritional status. The 81 question is challenging, as saliva plays vital roles in maintaining oral health and in food oral 82 processing (FOP). Food oral processing covers all ingestive functions and includes sucking, 83 biting, chewing, manipulating the food with the tongue and swallowing. The dryness of the 84 mouth affects both the oral preparatory and oral phases of swallowing, and can lead to impaired 85 bolus formation and oropharyngeal bolus transport. This can cause chewing and swallowing 86 difficulty and may influence the quality and/or quantity of dietary intakes. 87

87 Previous research showed that a reduced salivary flow rate and/or subjective oral dryness were 88 associated with food avoidance and low nutritional assessment. It was shown that the use of a 89 mucin-containing saliva substitute three times a day before meals treats xerostomia and oral 90 mucosa disorder in elderlies (Blixt-Johansen, Sjöholm, Wiesel, & Ek, 1992). Moreover, meals 91 duration was longer after the treatment period than before. The consequences of xerostomia on 92 swallowing depend on the food type. For friable and non hydrophilic foods, the collection of 93 particles into a single bolus could be affected, as could its transportation towards the pharynx 94 (Liedberg, Ekberg, & Owall, 1991). Indeed, there is little information about the association 95 between hyposalivation and actual nutrient intake (Iwasaki et al., 2016). A systematic review 96 and meta-analysis identified a clear gap in knowledge on the influence of saliva incorporation 97 and oral lubrication on appetite ratings and food intake (Krop et al., 2018). The influence of the
lubrication parameters of food on appetite and food intake remains largely unquantified. This
review seeks to document whether the products called “saliva substitutes” or “artificial saliva”
can really replace saliva during food oral processing.

## 2 MATERIALS AND METHODS

A systematic review was conducted based on the Preferred Reporting Items for Systematic
reviews and Meta-analyses Protocol (PRISMA-P) statement (Moher et al., 2015). The analysis
methods and inclusion criteria were documented in a protocol published in the International
prospective register of systematic reviews (PROSPERO with the registration number
CRD42019124585).

### 2.1 Search

The search was designed to find articles reporting the use of saliva substitutes in individuals
with xerostomia, in order to answer the question: Could the use of saliva substitutes improve
food oral processing?

### 2.2 Information sources

Pubmed and Science Direct were searched for articles using the keywords “saliva substitutes”
and “artificial saliva”. An advanced search was applied using the terms “xerostomia” and/or
“food oral processing” and/or “eating” and/or “mastication” and/or “chewing” and/or
“swallowing”. The PRISMA protocol was applied for article selection reviews (Moher et al.,
2015). Criteria for exclusion were: articles not written in English, animal studies, in vitro
studies, articles with off-topics and reviewed articles. The remaining records were assessed for
screening and abstracts were read. Any article reporting an evaluation of saliva substitute was
included in the eligibility phase. The remaining records were assessed for eligibility and full
texts were read. The Strobe Grade approach (Cuschieri, 2019) was use to grade the quality of
the evidence in the different studies. Three systematic reviews aimed at evaluating the efficacy
122 of interventions for management of dry mouth were excluded (Furness, Bryan, McMillan,
123 Birchenough, & Worthington, 2013; Furness et al., 2011; Hahnel, Behr, Handel, & Bürgers,
124 2009).

125 **2.3 Data extraction**

126 A Microsoft Excel® chart file was created and a pre-piloted form was tested for 10 articles by
127 two investigators. Any quantitative or qualitative variable was considered as one item and noted
128 as a column label while the articles included were listed in the arrows. Depending on the
129 articles, some items were either not described or not available. Finally, twenty eight items were
130 listed for data extraction: design trial; population description (number of subjects, number of
131 females, number of males, age, number of groups of individuals, number of treatment per
132 groups, aetiology of xerostomia, exclusion criteria, salivary flow); treatment (saliva substitute
133 name, form, composition, posology); study parameters (duration, measurement frequency,
134 control group, placebo, primary outcomes, secondary outcomes); objective and/or subjective
135 measurements; significant results for primary and secondary outcomes; subjects' preferences
136 for using a substitute; study grade. A last column was added to check whether saliva substitutes
137 had an effect on one or more FOP functions such as biting, chewing, manipulating food between
138 tongue, palate, teeth and cheek and/or swallowing.

139 **2.4 Strategy for data synthesis**

140 Qualitative results were written as a narrative review. The term “saliva substitute” was used to
141 refer to both “saliva substitute” and “artificial saliva”.

142

143

144
145 **3 RESULTS**

146 **3.1 Search results**

147 The flow chart for inclusions is presented in Figure 1. The search included 43 articles, published
148 between 1979 and 2017 (Aliko, Alushi, Tafaj, & Isufi, 2012; Alpöz et al., 2015, 2008; Alves,
149 Motta, Messina, & Migliari, 2004; Andersson et al., 1995; Apperley, Medlicott, Rich, Hanning,
150 & Huckabee, 2017; Blixt-Johansen et al., 1992; Bots et al., 2005; Dalodom et al., 2016; Davies
151 & Singer, 1994; Dirix, Nuyts, Vander Poorten, Delaere, & Van den Bogaert, 2007; Donath,
152 Tonner, Chavda, Gatignol, & Bouyrie, 2016; Duxbury, Thakker, & Wastell, 1989; Epstein,
153 Emerton, Le, & Stevenson-Moore, 1999; Epstein & Stevenson-Moore, 1992; Frost, Shirlaw,
154 Walter, & Challacombe, 2002; Furumoto, Barker, Carter-Hanson, & Barker, 1998; Gil-
155 Montoya, Subirá, Ramón, & González-Moles, 2008; Heydarirad, Rezaeizadeh, Choopani,
156 Mosavat, & Ameri, 2017; Jellema et al., 2001; Johansson, Andersson, Attström, Glantz, &
157 Larsson, 1994; Klestov et al., 1981; Matear & Barbaro, 2005; McMillan, Tsang, Wong, & Kam,
158 2006; Momm, Volegova-Neher, Schulte-Mönting, & Guttenberger, 2005; Morales-Bozo et al.,
159 2017; Mouly, Orler, et al., 2007; Mouly, Salom, et al., 2007; Nakamoto, 1979; Oh, Lee, Kim,
160 & Kho, 2008; Regelink, Vissink, Reintsema, & Nauta, 1998; Rogus-Pulia, Gangnon, Kind,
161 Connor, & Asthana, 2018; Salom et al., 2015; Shahdad, Taylor, Barclay, Steen, & Preshaw,
162 2005; Silvestre, Minguez, & Suñe-Negre, 2009; Skrinjar et al., 2015; Stewart et al., 1998;
163 Sweeney, Bagg, Baxter, & Aitchison, 1997; Temmel, Quint, Schickinger-Fischer, & Hummel,
164 2005; van der Reijden, van der Kwaak, Vissink, Veerman, & Amerongen, 1996; Visch,
165 Gravenmade, Schaub, Van Putten, & Vissink, 1986; Vissink et al., 1983)

166 Among the included studies, 17 were observational studies, 5 were pilot studies, 21 were cross-
167 over studies and 14 of these studies were blinded. The Strobe score for the included articles
168 varied from 7.5 to 20. Xerostomia aetiologies and methods used to assess Food Oral Processing
169 in included studies are reported in Table 1.
170 **3.2 Review**

171 There are few objective and direct evaluations of the impact of the use of saliva substitutes on
172 Food Oral Processing. Overall, 30 studies used visual analogue scales and/or Likert scales to
173 evaluate the self-perception of subjects for the level of dryness of their mouth or throat,
174 swallowing, chewing and speaking difficulties, level of thirst, taste disturbance, or denture
175 retention (Aliko et al., 2012; Alpöz et al., 2015, 2008; Dalodom et al., 2016; Davies, Daniels,
176 Pugh, & Sharma, 1998; Davies & Singer, 1994; Dirix et al., 2007; Donath et al., 2016; Epstein
177 et al., 1999; Frost et al., 2002; Johansson et al., 1994; Matear & Barbaro, 2005; Nakamoto,
178 1979; Regelink et al., 1998; Temmel et al., 2005; Visch et al., 1986; Vissink, Burlage,
179 Spijkervet, Veerman, & Nieuw Amerongen, 2004). Four studies asked subjects to report on the
180 improvement in dryness related to the use of saliva substitutes (Salom et al., 2015; Silvestre et
181 al., 2009; Stewart et al., 1998; van der Reijden et al., 1996). Six studies reported the impact of
182 xerostomia on Quality of life (GOHAI (McMillan et al., 2006), OHIP 14 (Gil-Montoya et al.,
183 2008; Skrinjar et al., 2015), EORTC - QLQ + H&35 (Heydarirad et al., 2017; Jellema et al.,
184 2001), QoL (Dirix et al., 2007)). In one observation report, the staff of an establishment for
185 elderlies measured meal duration, reported the residents' pain complaints and subjectively
186 assessed their ability to speak, eat and swallow (Blixt-Johansen et al., 1992). Sixteen studies
187 globally measured the impact of xerostomia using validated (Apperley et al., 2017; Bots et al.,
188 2005; McMillan et al., 2006; Morales-Bozo et al., 2017), or non validated (Alves et al., 2004;
189 Andersson et al., 1995; Frost et al., 2002; Furumoto et al., 1998; Gil-Montoya et al., 2008;
190 Klestov et al., 1981; Momm et al., 2005; Mouly, Orler, et al., 2007; Mouly, Salom, et al., 2007;
191 Oh et al., 2008; Shahdad et al., 2005; Sweeney et al., 1997) comprehensive questionnaires.

192 Xerostomia was described in different conditions of gender, age and medical condition. The
193 age range was from 18 to 94 and gender was not a criterion for inclusion. The medical
194 conditions observed were: radiotherapy and/or chemotherapy after head and neck cancers
(Andersson et al., 1995; Apperley et al., 2017; Dirix et al., 2007; Epstein & Stevenson-Moore, 1992; Epstein et al., 1999; Jellema et al., 2001; Momm & Guttenberger, 2002; Nakamoto, 1979; Regelink et al., 1998; Shahdad et al., 2005), systemic auto immune disease (Aliko et al., 2012; Alpöz et al., 2008; Alves et al., 2004; Klestov et al., 1981; van der Reijden et al., 1996); drug consumption (Donath et al., 2016; Mouly, Orler, et al., 2007; Skrinjar et al., 2015); elderlies (Mouly, Salom, et al., 2007; Rogus-Pulia et al., 2018); final stage renal disease on haemodialysis (Bots et al., 2005). Regardless of the aetiology of xerostomia, controlling the effect of saliva substitutes on the production of a swallowable food bolus is of importance.

The possible effects of saliva substitutes on FOP were reported in 14-13 articles for swallowing only (Blixt-Johansen et al., 1992; Davies et al., 1998; Davies & Singer, 1994; Dirix et al., 2007; Donath et al., 2016; Epstein et al., 1999; Jellema et al., 2001; Klestov et al., 1981; Matear & Barbaro, 2005; Morales-Bozo et al., 2017; Nakamoto, 1979; Rogus-Pulia et al., 2018; van der Reijden et al., 1996) and in one article for mastication with objective measurements (Apperley et al., 2017). Evaluation of difficulties/easiness to swallow, to chew, to eat and/or to sip liquids were reported in 22 studies. Positive effects on FOP based on statistical analysis were assessed in 14 studies (Aliko et al., 2012; Alpöz et al., 2008; Alves et al., 2004; Andersson et al., 1995; Frost et al., 2002; Heydarirad et al., 2017; McMillan et al., 2006; Momm et al., 2005; Morales-Bozo et al., 2017; Mouly, Orler, et al., 2007; Mouly, Salom, et al., 2007; Rogus-Pulia et al., 2018; Salom et al., 2015; Shahdad et al., 2005). Only one clinical trial measured xerostomia with a validated questionnaire and compared the effects of three different saliva substitutes on the chewing kinematics during ingestion of crackers (Apperley et al., 2017). The Test of Mastication and Swallowing Solids (TOMASS) required ingestion of a cracker as quickly and as comfortably as possible (Hägglund, Blom, Thoden, & Karlsson, 2020; Huckabee et al., 2018). During mastication, the number of cycles, chewing time, and swallows per bite were measured. It was found that the use of saliva substitutes slightly improved xerostomia but had
no effect on chewing kinematic parameters during the cracker eating. The authors suggested
that TOMASS test was not appropriate to evaluate mastication in subjects with xerostomia.

# 4 DISCUSSION

This review demonstrated showed that the possible effects of the use of saliva substitutes on the ingestion function were poorly investigated. No evidence is-was based on physiological studies. Saliva participates in food bolus constitution, affects its rheological properties and initiates digestion. Food bolus rheology has a dominant influence on mastication and swallowing (Chen, 2007). During FOP, saliva gradually fills the gap between food particles and increases their viscous cohesion. The swallowing threshold is defined as the moment when the food bolus reaches the maximum cohesive force (Prinz & Lucas, 1997). It is unknown whether the use of a saliva substitute has an effect on the composition and the rheological properties of the food bolus, on the lubrication of the oral and laryngeal mucosa or on both these phenomena.

Moreover, it is clear that saliva substitutes are not developed to improve FOP. For example, most of the saliva substitute listed in Table 1 have mint, grapefruit, lemon or sweet flavouring.
A flavoured saliva substitute could affect the perception of food and could limit the use of the saliva substitute during meals. Spontaneous food consumption could be altered for individuals using a saliva substitute, independently of the consequences of xerostomia.

Natural saliva is a non-Newtonian fluid. This characteristic ensures bolus aggregation and the lubrication of the oral and laryngeal mucosa during FOP. It could be suggested that a saliva substitute should be a non-Newtonian fluid. However, among the saliva substitutes used within the 14 studies reporting a possible positive effect of saliva substitutes on FOP, seven were based on mucine and/or xanthan gum and could be considered as natural saliva simulators (NSS), six were Newtonian fluids based on carboxymethyl cellulose or glycerol and two were
uncategorized (Table 12). In most cases, non-Newtonian saliva substitutes contain substances of natural origin (salivary macromolecules such as mucins, lysozyme, lactoferrin) that provide high biocompatibility. However, mucines have pig or cow origins, which can affect the uses of the corresponding saliva substitute in some individuals for cultural reasons. The challenges of treating xerostomia are to mimic all properties of natural saliva definitely in order to improve oral comfort between and during meals.

The selection criteria of this review excluded the “saliva stimulant” keyword. Saliva stimulants are parasympathomimetics such as Pilocarpine or Cevimeline. These substances are indicated to improve the production of saliva compared with a placebo (LeVeque et al., 1993). The use of chewing gum was also described to increase saliva production. However, chewing a gum can be indicated only for persons whose salivary glands respond to stimulation. Saliva stimulant cannot meet the needs of all patients with xerostomia, contrary to saliva substitutes. It can be difficult to determine the amount of saliva that is indicative of the dysfunction of the salivary glands. The measurement of the salivary flow is the basis for the diagnosis of xerostomia/hyposalivation. Among the included studies, 28 reported a measure of saliva flow (Aliko et al., 2012; Alpöz et al., 2015, 2008; Andersson et al., 1995; Bots et al., 2005; Dalodom et al., 2016; Donath et al., 2016; Duxbury et al., 1989; Epstein et al., 1999; Epstein & Stevenson-Moore, 1992; Frost et al., 2002; Furumoto et al., 1998; McMillan et al., 2006; Morales-Bozo et al., 2017; Mouly, Orler, et al., 2007; Mouly, Salom, et al., 2007; Oh et al., 2008; Regelink et al., 1998; Silvestre et al., 2009; Skrinjar et al., 2015; Stewart et al., 1998; Sweeney et al., 1997; van der Reijden et al., 1996). Overall, hyposalivation was observed when salivary flow rate at rest falls below 0.1 mL per minute and stimulated saliva (Sreebny, 2000) below 0.5–0.7 mL per minute; (Navazesh, Christensen, & Brightman, 1992; Ship, DeCarli, Friedland, & Baum, 1990). However, the sialometric techniques used to measure the salivary flow varied a lot, the spitting method being the most often reported. Moreover, the salivary flow rate threshold as an
269 inclusion/exclusion criterion was set at different levels in different studies. Overall, the saliva
270 flow was measured in 22 studies, while only seven studies considered the value of the saliva
271 flow as an inclusion criterion (Table 23).

272 To conclude, this review underscores the need to develop new saliva substitutes to improve the
273 rheological properties of the bolus and the lubrication of the laryngeal mucosa. Flavours should
274 be excluded from their composition.

275
276 ETHICAL STATEMENT
277
278 Declarations of interest: The authors declare that they do not have any conflict of interest

279
280
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398 https://doi.org/10.1016/s0030-4220(81)80008-4

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407 Liedberg, B., Ekberg, O., & Owall, B. (1991). Chewing and the dimension of the pharyngoesophageal segment. *Dysphagia*, *6*(4), 214-218.

409 https://doi.org/10.1007/bf02493530

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430 Momm, F., Volegova-Neher, N. J., Schulte-Mönting, J., & Guttenberger, R. (2005). Different saliva substitutes for treatment of xerostomia following radiotherapy. A prospective crossover study. *Strahlentherapie Und Onkologie, 181*(4), 231-236. https://doi.org/10.1007/s00066-005-1333-7

434 Morales-Bozo, I., Ortega-Pinto, A., Rojas Alcayaga, G., Aitken Saavedra, J. P., Salinas Flores, O., Lefimil Puente, C., ... Urzúa Orellana, B. (2017). Evaluation of the effectiveness of a chamomile (Matricaria chamomilla) and linseed (Linum usitatissimum) saliva substitute in the relief of xerostomia in elders. *Gerodontology, 34*(1), 42-48. https://doi.org/10.1111/ger.12220

439 Mouly, S., Orler, J.-B., Tillet, Y., Coudert, A.-C., Oberli, F., Preshaw, P., & Bergmann, J.-F. (2007). Efficacy of a new oral lubricant solution in the management of psychotropic
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447 Nakamoto, R. Y. (1979). Use of a saliva substitute in postradiation xerostomia. *The Journal of Prosthetic Dentistry*, 42(5), 539-542. https://doi.org/10.1016/0022-3913(79)90249-x

449 Navazesh, M., Christensen, C., & Brightman, V. (1992). Clinical criteria for the diagnosis of salivary gland hypofunction. *Journal of Dental Research*, 71(7), 1363-1369. https://doi.org/10.1177/00220345920710070301

452 Oh, D. J., Lee, J. Y., Kim, Y. K., & Kho, H. S. (2008). Effects of carboxymethylcellulose (CMC)-based artificial saliva in patients with xerostomia. *International Journal of Oral and Maxillofacial Surgery*, 37(11), 1027-1031. https://doi.org/10.1016/j.ijom.2008.06.006

456 Porter, S. R., Scully, C., & Hegarty, A. M. (2004). An update of the etiology and management of xerostomia. *Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics*, 97(1), 28-46. https://doi.org/10.1016/j.tripleo.2003.07.010

459 Prinz, J. F., & Lucas, P. W. (1997). An optimization model for mastication and swallowing in mammals. *Proceedings. Biological Sciences*, 264(1389), 1715-1721. https://doi.org/10.1098/rspb.1997.0238

462 Regelink, G., Vissink, A., Reintsema, H., & Nauta, J. M. (1998). Efficacy of a synthetic polymer saliva substitute in reducing oral complaints of patients suffering from irradiation-induced xerostomia. *Quintessence International*, 29(6), 383-388.
465 Rogus-Pulia, N. M., Gangnon, R., Kind, A., Connor, N. P., & Asthana, S. (2018). A Pilot Study of Perceived Mouth Dryness, Perceived Swallowing Effort, and Saliva Substitute Effects in Healthy Adults Across the Age Range. *Dysphagia*, 33(2), 200–205.
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469 Salom, M., Hachulla, E., Bertolus, C., Deschaumes, C., Simoneau, G., & Mouly, S. (2015). Efficacy and safety of a new oral saliva equivalent in the management of xerostomia: A national, multicenter, randomized study. *Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology*, 119(3), 301–309. https://doi.org/10.1016/j.oooo.2014.12.005

473 Shahdad, S. A., Taylor, C., Barclay, S. C., Steen, I. N., & Preshaw, P. M. (2005). A double-blind, crossover study of Biotène Oralbalance and BioXtra systems as salivary substitutes in patients with post-radiotherapy xerostomia. *European Journal of Cancer Care*, 14(4), 319–326. https://doi.org/10.1111/j.1365-2354.2005.00587.x

477 Ship, J. A., DeCarli, C., Friedland, R. P., & Baum, B. J. (1990). Diminished submandibular salivary flow in dementia of the Alzheimer type. *Journal of Gerontology*, 45(2), M61-66.

480 Silvestre, F. J., Minguez, M. P., & Suñe-Negre, J. M. (2009). Clinical evaluation of a new artificial saliva in spray form for patients with dry mouth. *Medicina Oral, Patologia Oral Y Cirugia Bucal*, 14(1), E8–E11.

483 Skrinjar, I., Vucicevic Boras, V., Bakale, I., Andabak Rogulj, A., Brailo, V., Vidovic Juras, D., ... Vrdoljak, D. V. (2015). Comparison between three different saliva substitutes in patients with hyposalivation. *Clinical Oral Investigations*, 19(3), 753–757.
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487 Sreebny, L. M. (2000). Saliva in health and disease: An appraisal and update. *International Dental Journal*, 50(3), 140–161. https://doi.org/10.1111/j.1875-595x.2000.tb00554.x
489 Stewart, C. M., Jones, A. C., Bates, R. E., Sandow, P., Pink, F., & Stillwell, J. (1998).
490 Comparison between saliva stimulants and a saliva substitute in patients with
491 xerostomia and hyposalivation. *Special Care in Dentistry*, 18(4), 142–148.
492 https://doi.org/10.1111/j.1754-4505.1998.tb01136.x

493 Sweeney, M. P., Bagg, J., Baxter, W. P., & Aitchison, T. C. (1997). Clinical trial of a mucin-
494 containing oral spray for treatment of xerostomia in hospice patients. *Palliative
495 Medicine*, 11(3), 225–232. https://doi.org/10.1177/026921639701100307

496 Temmel, A. F. P., Quint, C., Schickinger-Fischer, B., & Hummel, T. (2005). Taste function in
497 xerostomia before and after treatment with a saliva substitute containing
498 carboxymethylcellulose. *The Journal of Otolaryngology*, 34(2), 116–120.
499 https://doi.org/10.2310/7070.2005.04008

500 van der Reijden, W. A., van der Kwaak, H., Vissink, A., Veerman, E. C., & Amerongen, A. V.
501 (1996). Treatment of xerostomia with polymer-based saliva substitutes in patients with
502 Sjögren's syndrome. *Arthritis and Rheumatism*, 39(1), 57–63.
503 https://doi.org/10.1002/art.1780390108

504 Visch, L. L., Gravenmade, E. J., Schaub, R. M., Van Putten, W. L., & Vissink, A. (1986). A
double-blind crossover trial of CMC- and mucin-containing saliva substitutes.
505 *International Journal of Oral and Maxillofacial Surgery*, 15(4), 395–400.
506
507 https://doi.org/10.1016/s0300-9785(86)80027-8

508 Vissink, A., Burlage, F. R., Spijkervet, F. K., Veerman, E. C. I., & Nieuw Amerongen, A. V.
509 (2004). Prevention and treatment of salivary gland hypofunction related to head and
510 neck radiation therapy and chemotherapy. *Supportive Cancer Therapy*, 1(2), 111–118.
511 https://doi.org/10.3816/SCT.2004.n.004

512 Vissink, A., s-Gravenmade, E. J., Panders, A. K., Vermey, A., Petersen, J. K., Visch, L. L., &
513 Schaub, R. M. (1983). A clinical comparison between commercially available mucin-
514 and CMC-containing saliva substitutes. *International Journal of Oral Surgery*, 12(4),

515 232-238. https://doi.org/10.1016/s0300-9785(83)80048-9

516 Ying Joanna, N. D., & Thomson, W. M. (2015). Dry mouth—An overview. *Singapore Dental

517 *Journal*, 36, 12-17. https://doi.org/10.1016/j.sdj.2014.12.001

518

519
<table><caption>Table 1: Aetiologies for xerostomia and criteria for evaluation of FOP functions in included studies</caption><thead><tr><th>Studies</th><th>Xerostomia aetiology</th><th>FOP function targeted</th><th>Objectives measures</th><th>Subjectives measures</th></tr></thead><tbody><tr><td>(Aliko et al., 2012)</td><td>Sjögren's Syndrome</td><td>Mastication<br>Swallowing<br>Taste</td><td>Salivary flow<br>Quantity of SS' use</td><td>VAS</td></tr><tr><td>(Alpöz et al., 2008)</td><td>Sjögren's Syndrome</td><td>Taste<br>Mastication<br>Siping<br>Speech<br>Swallowing</td><td>Salivary flow</td><td>VAS</td></tr><tr><td>(Alpöz et al., 2015)</td><td>Mixed, unspecified</td><td>Chewing<br>Sipping<br>Swallowing<br>Taste</td><td>Salivary flow<br>Oral examination</td><td>Questionnaire</td></tr><tr><td>(Alves et al., 2004)</td><td>Sjögren's syndrome</td><td>Mastication<br>Swallowing</td><td>Salivary flow</td><td>Questionnaire</td></tr><tr><td>(Andersson et al., 1995)</td><td>Radiotherapy</td><td>Chewing<br>Swallowing<br>Taste</td><td>Oral examination<br>Salivary flow</td><td>Questionnaire</td></tr><tr><td>(Apperley et al., 2017)</td><td>Radiotherapy</td><td>Mastication<br>Swallowing</td><td>Chewing cycles<br>Chewing time<br>Swallows/bite<br>(TOMASS)</td><td>Questionnaire</td></tr><tr><td>(Blixt-Johansen et al., 1992)</td><td>Drugs<br>Other unspecified</td><td>Eating<br>Swallowing</td><td>Oral examination</td><td>Reports of frequency<br>by Staff</td></tr><tr><td>(Bots et al., 2005)</td><td>Kidney failure</td><td>ND</td><td>Salivary flow</td><td>Questionnaire</td></tr><tr><td>(Dalodom et al., 2016)</td><td>Mellitous diabetes<br>Hypertension</td><td>Chewing<br>Swallowing<br>Taste disturbance</td><td>Oral examination<br>Salivary flow</td><td>VAS</td></tr><tr><td>(Davies & Singer, 1994)</td><td>Radiotherapy</td><td>Dysphagia<br>Dysgeusia</td><td>ND</td><td>Questionnaire<br>VAS</td></tr><tr><td>(Davies et al., 1998)</td><td>Cancer</td><td>Dysphagia<br>Dysgeusia</td><td>ND</td><td>Questionnaire<br>VAS</td></tr><tr><td>(Dirix et al., 2007)</td><td>Radiotherapy</td><td>Swallowing<br>Taste</td><td>ND</td><td>Questionnaire<br>VAS</td></tr><tr><td>(Donath et al., 2016)</td><td>Drugs</td><td>Swallowing</td><td>Oral examination<br>Salivary flow</td><td>VAS</td></tr><tr><td>(Duxbury et al., 1989)</td><td>Drugs<br>Diabetes<br>Radiotherapy<br>Sjögren's syndrome<br>Smoking</td><td>Eating<br>Taste</td><td>Frequency of SS' use<br>Salivary flow</td><td>VAS</td></tr><tr><td>(Epstein & Stevenson-Moore, 1992)</td><td>Radiotherapy</td><td>ND</td><td>Frequency of SS' use<br>Salivary flow</td><td>Questionnaire</td></tr><tr><td>(Epstein et al., 1999)</td><td>Radiotherapy</td><td>Swallowing<br>Taste</td><td>Salivary flow</td><td>VAS</td></tr><tr><td>(Frost et al., 2002)</td><td>Buccal respiration<br>Drugs<br>Sjögren's syndrome<br>Other</td><td>Chewing<br>Swallowing</td><td>Oral examination<br>Salivary flow</td><td>Questionnaire</td></tr><tr><td>(Furumoto et al., 1998)</td><td>Mixed, unspecified</td><td>Eating</td><td>Salivary flow</td><td>Questionnaire</td></tr></tbody></table>
<table><tr><td>(Gil-Montoya et al., 2008)</td><td>Aging</td><td>Swallowing<br>Biting<br>Chewing<br>Eating<br>Swallowing</td><td>ND</td><td>Questionnaire</td></tr><tr><td>(Heydarirad et al., 2017)</td><td>Radiotherapy</td><td>Eating<br>Swallowing<br>Taste</td><td>ND</td><td>Questionnaire</td></tr><tr><td>(Jellema et al., 2001)</td><td>Radiotherapy</td><td>Swallowing</td><td>Frequency of SS' use</td><td>Questionnaires</td></tr><tr><td>(Johansson et al., 1994)</td><td>Drugs<br>Radiotherapy<br>Sjögren's Syndrome</td><td>Mastication<br>Swallowing<br>Taste</td><td>Oral examination</td><td>Questionnaire</td></tr><tr><td>(Klestov et al., 1981)</td><td>Sjögren's syndrome</td><td>Chewing<br>Drinking<br>Swallowing</td><td>ND</td><td>Questionnaire</td></tr><tr><td>(Matear & Barbaro, 2005)</td><td>Aging<br>Drugs<br>Systemic diseases</td><td>Swallowing</td><td>ND</td><td>Questionnaire</td></tr><tr><td>(McMillan et al., 2006)</td><td>Radiotherapy</td><td>Biting<br>Chewing<br>Eating<br>Swallowing</td><td>Salivary flow</td><td>Questionnaire</td></tr><tr><td>(Momm et al., 2005)</td><td>Radiotherapy</td><td>Chewing<br>Eating<br>Swallowing</td><td>ND</td><td>Questionnaire</td></tr><tr><td>(Morales-Bozo et al., 2017)</td><td>Various</td><td>Swallowing</td><td>Salivary flow</td><td>VAS</td></tr><tr><td>(Mouly, Orler, et al., 2007)</td><td>Aging</td><td>Chewing<br>Swallowing<br>Taste</td><td>Oral examination<br>Salivary flow</td><td>VAS</td></tr><tr><td>(Mouly, Salom, et al., 2007)</td><td>Drugs</td><td>Chewing<br>Swallowing<br>Taste</td><td>Frequency of SS' use<br>Oral examination<br>Salivary flow</td><td>Questionnaire<br>VAS</td></tr><tr><td>(Nakamoto, 1979)</td><td>Radiotherapy</td><td>Eating<br>Swallowing<br>Taste</td><td>ND</td><td>Questionnaire</td></tr><tr><td>(Oh et al., 2008)</td><td>Sjögren's syndrome<br>Autoimmune disorders<br>Radiotherapy</td><td>Chewing<br>Eating<br>Sipping<br>Swallowing</td><td>Salivary flow</td><td>Questionnaire</td></tr><tr><td>(Regelink et al., 1998)</td><td>Radiotherapy</td><td></td><td>Salivary flow</td><td>Questionnaire</td></tr><tr><td>(Rogus-Pulia et al., 2018)</td><td>Aging</td><td>Swallowing</td><td>ND</td><td>One single question</td></tr><tr><td>(Salom et al., 2015)</td><td>Autoimmune disorders<br>Drugs<br>Radiotherapy<br>Sjögren's syndrome<br>Other various medical conditions</td><td>Chewing<br>Swallowing<br>Taste</td><td>ND</td><td>Questionnaire<br>VAS</td></tr><tr><td>(Shahdad et al., 2005)</td><td>Radiotherapy</td><td>Chewing<br>Swallowing<br>Taste</td><td>ND</td><td>Questionnaire<br>VAS</td></tr><tr><td>(Silvestre et al., 2009)</td><td>Drugs<br>Radiotherapy</td><td>Eating<br>Swallowing</td><td>Frequency of SS' use<br>Salivary flow</td><td>VAS</td></tr><tr><td>(Skrinjar et al., 2015)</td><td>Drugs</td><td>Taste<br>Mastication</td><td>Salivary flow</td><td>Questionnaire<br>VAS</td></tr></table>
<table><tr><td>(Stewart et al., 1998)</td><td>Auto-immune disease<br>Drugs<br>Radiotherapy</td><td>Eating<br>Sipping<br>Swallowing<br>Taste</td><td>Salivary flow</td><td>Questionnaire<br>VAS</td></tr><tr><td>(Sweeney et al., 1997)</td><td>Motor neurone disease<br>cancer</td><td>Eating Taste</td><td>Salivary flow</td><td>VAS</td></tr><tr><td>(Temmel et al., 2005)</td><td>Sjögren's syndrome<br>Menopause</td><td>Taste</td><td>Frequency of SS' use<br>Oral examination</td><td>Questionnaire</td></tr><tr><td>(van der Reijden et al.,<br>1996)</td><td>Sjögren's syndrome<br>Autoimmune disorders</td><td>Eating<br>Swallowing<br>Taste</td><td>Salivary flow</td><td>Questionnaire</td></tr><tr><td>(Visch et al., 1986)</td><td>Radiotherapy<br>Sjögren's syndrome</td><td>Chewing<br>Swallowing</td><td>ND</td><td>Questionnaire</td></tr><tr><td>(Vissink et al., 1983)</td><td>Drugs<br>Radiotherapy<br>Sjögren's syndrome<br>Other unspecified</td><td>Mastication<br>Swallowing<br>Taste</td><td>Oral examination<br>Salivary presence</td><td>Questionnaire</td></tr></table>

523

524

525
<table><caption>Table 2 Composition of saliva substitute used in the included studies (NSS: Natural saliva simulators: saliva substitutes containing mucin or mucin with xanthan or guar gum</caption><thead><tr><th>Name</th><th>Composition</th><th>NSS</th><th>Form</th><th>Aromas</th><th>Instructions for use</th><th>Placebo or Control</th><th>References</th></tr></thead><tbody><tr><td>Aequasyal®</td><td>94.4% triesters of glycerol; Oxidized fatty acids of vegetal origin (corn oil) Silicius dioxide Aspartame</td><td>No</td><td>Spray</td><td>Orange, Grapefruit, And mint Aspartam</td><td>2 spray (one by cheek then swill the product with the tongue until it had coated oral mucosa, after breakfast, and 15 min before a standard meal<br>At least 5 times/day<br>1 or 2 spray up to 4 times a day</td><td></td><td>(Donath et al., 2016)<br>(Mouly, Orler, et al., 2007)<br>(Mouly, Salom, et al., 2007)</td></tr><tr><td>Novasial®</td><td></td><td></td><td>Sticks<br>Spray</td><td></td><td>One stick 4 times a day<br>One spray four times a week</td><td>Aequasyal®<br>Biotène®</td><td>(Salom et al., 2015)</td></tr><tr><td>DC161- DP0293</td><td>Paraffin liquid, Cotton refine oil, Alphatopheryle acetate (oily solution)</td><td>No</td><td>Spray</td><td>Orange flavor</td><td>3 sprays (one by cheek, one on the tongue,) twice a day. One after breakfast, and one 15 min before a standard meal</td><td></td><td>(Donath et al., 2016)</td></tr><tr><td>DC161- DP0291</td><td>Glycerol, Polysorbate 80, Soja lecithin, Sodium hyaluronate, Xanthan gum, Potassium chloride, Xylitol, Anhydrous disodiumhydrogen phosphate, potassium dihydrogen, phosphate, sucralose, macrogolglycerol 40 hydroxystearate, benzylic, alcohol, Sodium benzoate, Cetylpyridinium chloride, alpha, tocopheryle</td><td>Yes</td><td>Spray</td><td>soft mint flavor</td><td>3 sprays (one by cheek, one on the tongue,) twice a day. One after breakfast, and one 15 min before a standard meal</td><td></td><td>(Donath et al., 2016)</td></tr></tbody></table>
<table><tr><td></td><td>acetate, Water. (Aqueous solution)</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>DC161- DP0292</td><td>Glycerol, Povidone K30, Copovidone, xanthan Gum, Potassium chloride, Xylitol, Marshmallow concentrated hydroglycerin extract, Anhydrous disodium hydrogen phosphate, potassium dihydrogen phosphate, Macrogolglycerol 40 hydroxystearate, Potassium sorbate, benzylic alcohol, Water</td><td>Yes</td><td>Spray</td><td>3 sprays (one by cheek, one on the tongue,) twice a day. One after breakfast, and one 15 min before a standard meal</td><td></td><td>(Donath et al., 2016)</td></tr><tr><td>Biotene Oral Balance®</td><td>Lactoperoxidase, Lysozyme Glucose oxidase, Lactoferrin, Hydrogenated starch, Polymethacrylate, Xylitol sweetening; Hydroxyethyl sweetening Cellulose, Potassium thiocyanate, Aloe vera.</td><td>No</td><td>Gel</td><td>Sweetening</td><td>1 cm of gel on tongue and oral mucosa</td><td>(Aliko et al., 2012; Frost et al., 2002; Regelink et al., 1998; Rogus-Pulia et al., 2018; Shahdad et al., 2005)</td></tr><tr><td>Biotene mouthwash® and Oral Balance gel®</td><td>Lactoperoxidase, Lysozyme, Glucose oxidase, Lactoferrin</td><td></td><td>Mouthwash</td><td>Slightly mentholed flavour and xylitol sweetening</td><td>Three times a day after brushing the teeth and/or dentures (12 ml) during 30 seconds</td><td>Carboxymethylen : 0.8% Triethanolamine Xylitol Nipagim : 0.3%</td></tr><tr><td></td><td></td><td></td><td>Gel</td><td></td><td>Following the mouthrinse, 1 cm of gel on tongue and oral mucosa</td><td>Aqueous solution with mint essence</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td>Cream of similar appearance and flavor was prepared using carboxymethyl cellulose</td></tr></table>
<table><tr><td>Oral Balance gel and Biotene toothpaste®</td><td>No</td><td>Gel Toothpaste</td><td></td><td></td><td>CMC gel and commercial toothpaste</td><td>(Epstein et al., 1999)</td></tr><tr><td>Oral Balance gel and Biotene toothpaste and Mounthwash®</td><td>No</td><td>Gel Toothpaste Mouthwash</td><td></td><td></td><td></td><td>(Matear & Barbaro 2005; Shahdad et al., 2005)</td></tr><tr><td>Device and Oral Balance gel</td><td>No</td><td>Gel</td><td></td><td>At night<br>Gel alone in the form of an oral bolus<br>Gel on demand via an intra-oral device(at least 4hours per day and remove it at night)</td><td></td><td>(Frost et al., 2002)<br>(McMillan et al., 2006)</td></tr><tr><td>Xialine®</td><td>Polysaccharide xanthan gum, sodium fluoride</td><td>Yes</td><td>Spray</td><td>Mint-taste<br>Mint-taste<br>Neutral taste</td><td>At least 6 times a day<br>At least 6 times/ day<br>At least 4 times a day</td><td>Water<br>Dilued tea<br>Xialine without Xanthan gum</td><td>(Alpöz et al., 2008)<br>(Bots et al., 2005)<br>(Jellema et al., 2001)</td></tr><tr><td>Xanthan gum high viscosity</td><td>KCl,NaCl,MgCl2,CaCl2, Methylhydroxybenzoate, Benzalkonium chloride, Keltrol KTL, Distilled water</td><td>Yes</td><td></td><td>Peppermint flavour</td><td></td><td></td><td>(van der Reijden et al., 1996)</td></tr><tr><td>Xanthan gum low viscosity</td><td>KCl,NaCl,MgCl2,CaCl2, Methylhydroxybenzoate, Benzalkonium chloride, Keltrol KTL, Distilled water</td><td>Yes</td><td></td><td>Peppermint flavour</td><td></td><td></td><td>(van der Reijden et al., 1996)</td></tr><tr><td>Polyacrylic acid</td><td>KCl,NaCl,MgCl2,CaCl2, Methylhydroxybenzoate, Benzalkonium chloride, Carbopol, Distilled water</td><td>No</td><td></td><td>Peppermint flavour</td><td></td><td></td><td>(van der Reijden et al., 1996)</td></tr><tr><td>Saliva Orthana®</td><td>Mucin, xylitol, Potassium chloride, sodium chloride,</td><td>Yes</td><td>Mouthwash</td><td>Neutral-tasting</td><td>Rince + swallow with 5ml 3 times/day before meal</td><td></td><td>(Blixt-Johansen et al., 1992)</td></tr></table>
<table><tr><td></td><td>magnésium, calcium, dipotassium hydorgenophosphate, Methagine, Benzalconchloride, Sodium-EDTA</td><td></td><td></td><td>Peppermint flavor</td><td>Ad libitum</td><td>KCl, NaCl, MgCl2, CaCl2, methylhydroxybenzoate, benzilkonium chloride, distilled water</td><td>(van der Reijden et al., 1996)</td></tr><tr><td></td><td></td><td></td><td></td><td>Peppermint flavor</td><td>Ad libitum</td><td></td><td>(Visch et al., 1986)</td></tr><tr><td></td><td></td><td></td><td></td><td>Peppermint flavor</td><td>Ad libitum</td><td></td><td>(Vissink et al., 1983)</td></tr><tr><td></td><td></td><td></td><td>Spray</td><td>Peppermint flavor</td><td>2-3 sprays when required</td><td>Saliva Orthana® its no-mucin base<br>Flavored distilled water</td><td>(Duxbury et al., 1989)</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td>At least twice per day</td><td>Saliva Orthana® its no-mucin base</td><td>(Davies et al., 1998; Davies & Singer, 1994; Sweeney et al., 1997)</td></tr><tr><td>BioXtra®</td><td>Hydroxyethylcellulose, Polyglycerylmethacrylate, Lactoperoxidase, Glucose oxidase, Lactoferrin, lysozyme and Monofluorophosphate and Xylitol (=oralbalance gel)+ peptides and Immunoglobulins</td><td>No</td><td>System: toothpaste mouthwash gel</td><td>Sweetening (less than OB)</td><td>Apply to your tongue and gums with your fingertip or a cotton swab Ad libitum</td><td></td><td>(Dirix et al., 2007; Shahdad et al., 2005)</td></tr><tr><td>HCC Spray Hydroxyethylcellulose citric acid spray</td><td></td><td>No</td><td>spray</td><td></td><td>Ad libitum</td><td></td><td>(Furumoto et al., 1998)</td></tr><tr><td>Hydroxyethylcellulose gel</td><td></td><td>No</td><td>gel</td><td></td><td>Ad libitum</td><td></td><td></td></tr><tr><td>Salinum®</td><td>Linseed mucilage: 54% Protein: 9%</td><td></td><td>Mouthwash</td><td></td><td>Dosage of 2 ml of fluid Ad libitum</td><td></td><td>(Andersson et al., 1995; Johansson et al., 1994)</td></tr></table>
<table><tr><td>Plant mucilage</td><td>Matricaria chamomilla Linseed (linum usitatissimum)</td><td>Mouthwash</td><td>2ml 4 times a day</td><td>(Morales-Bozo et al., 2017)</td></tr><tr><td rowspan="6">Carboxymethyl Cellulose (Original preparations: CMC, MAS-84, CMC-NZ, CMC Spray)</td><td rowspan="6">Sodium carboxymethylcellulose</td><td rowspan="6">No</td><td>Plastic bottle 2 ml portion</td><td>(Andersson et al., 1995; Apperley et al., 2017)</td></tr><tr><td>2ml 4 times a day</td><td>(Morales-Bozo et al., 2017; Temmel et al., 2005)</td></tr><tr><td>Ad libitum</td><td>(Visch et al., 1986)</td></tr><tr><td>Ad libitum</td><td>(Furumoto et al., 1998)</td></tr><tr><td>Ad libitum</td><td>(Vissink et al., 1983)</td></tr><tr><td>2ml Ad libitum</td><td>(Oh et al., 2008)</td></tr><tr><td rowspan="3">VA-Oralube®</td><td>Carboxymethycellulose</td><td rowspan="3">No</td><td>Ad libitum</td><td>(Epstein & Stevenson-Moore, 1992)</td></tr><tr><td>Water</td><td>Ad libitum</td><td>(Vissink et al., 1983)</td></tr><tr><td>Sorbitol</td><td>Ad libitum</td><td>(Nakamoto, 1979)</td></tr><tr><td></td><td>Preservative Fluorure, Ions</td><td rowspan="2">Squeeze bottle</td><td>Peppermint flavor</td><td></td></tr><tr><td></td><td>Dry concentrate</td><td>Peppermint flavor</td><td>Ad libitum</td></tr><tr><td>Salivart</td><td>Carboxymethylcellulose</td><td>No</td><td>Spray</td><td>Ad libitum</td><td>(Epstein & Stevenson-Moore, 1992)</td></tr><tr><td>Moistir</td><td>Carboxymethycellulose</td><td>No</td><td>Spray</td><td>Ad libitum</td><td>(Epstein & Stevenson-Moore, 1992)</td></tr><tr><td>Polyox</td><td>Polyethylene oxide 1% Water</td><td>No</td><td>Glassbottle</td><td>Ad libitum</td><td>(Epstein & Stevenson-Moore, 1992)</td></tr><tr><td>New oily formulation</td><td>Rice bran oil (RBO Alfa One®): 30% w/w</td><td>No</td><td>Spray</td><td>Flavoring</td><td>At least 4 times a day Distilled water (Apperley et al., 2017)</td></tr></table>
<table><tr><td>OMJ® (Oral Moisturizing Jelly)</td><td>Soy lecithin 30% w/w<br>Propylene glycol<br>Water: 40% w/w</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>New preparation saliva substitute</td><td>Water-releasing (jelly)</td><td>Gel</td><td>Strawberry flavour or lime mint flavour</td><td>10 ml (spoon) 5 times/day</td><td></td><td>(Dalodom et al., 2016)</td></tr><tr><td>AldiaMed® gel</td><td>Distilled water<br>Methylcellulose<br>Spirit of chloroform KCl, NaF, CaCl.</td><td>Mouthwash 5ml</td><td>Essence of lemon</td><td>Ad libitum</td><td>Glycerine mouthwash<br>Distilled water<br>Spirit of chloroform</td><td>(Klestov et al., 1981)</td></tr><tr><td>Glandosane® spray</td><td>Aloe vera gel</td><td>No</td><td></td><td>Ad libitum</td><td></td><td>(Momm et al., 2005)</td></tr><tr><td>Rape spray</td><td>Carboxymethylcellulose</td><td>No</td><td></td><td>Ad libitum</td><td></td><td>(Momm et al., 2005)</td></tr><tr><td>Margarine</td><td>Liquid margarine</td><td></td><td></td><td>Ad libitum</td><td></td><td>(Momm et al., 2005)</td></tr><tr><td>Saliva Medac® spray</td><td>containing mucin extracted from pig stomach</td><td>Yes</td><td>Spray</td><td>Ad libitum</td><td></td><td>(Furumoto et al., 1998)</td></tr><tr><td>Salivèze®</td><td>aqueous electrolyte-containing solution calcium chloride 0.15 mg/mL, magnesium chloride 0.05 mg/mL, sodium chloride 0.05 mg/mL, potassium chloride 1.2 mg/Ml, sodium phosphate 0.28 mg/mL and sorbitol 30 mg/mL in purified water</td><td></td><td>Spray</td><td>At least 5 times/day<br>1 or 2 spray up to 4 times a day</td><td></td><td>(Momm et al., 2005)<br>(Mouly, Orler, et al., 2007; Mouly, Salom, et al., 2007)</td></tr><tr><td>New artificial saliva formulation</td><td>aqueous solution of potassium thiocyanate, potassium chloride, sodium chloride, calcium chloride, magnesium chloride, potassium dihydrogen phosphate, xylitol and citric acid</td><td></td><td>Spray</td><td>Flavor</td><td>At least 2 times / day</td><td>(Silvestre et al., 2009)</td></tr></table>
<table><tr><td>Buccotherm®</td><td>Thermal spring water</td><td></td><td>Spray</td><td>4 times daily</td><td></td><td>(Skrinjar et al., 2015)</td></tr><tr><td></td><td></td><td></td><td></td><td>6 times daily</td><td>1/10 diluted black tea(plain water and Lipton tea)</td><td>(Alpöz et al., 2015)</td></tr><tr><td>Xeros®</td><td>Betaine, Sodium fluoride, Hydroxyethylcellulose</td><td>No</td><td>Mouthwash</td><td>4 times daily</td><td></td><td>(Skrinjar et al., 2015)</td></tr><tr><td>Marshmallow root</td><td>Infusion of marshmallow root into 2 dcl of cold water</td><td></td><td>Mouthwash</td><td>Rinsing with one large spoon 4 h after preparation</td><td></td><td>(Skrinjar et al., 2015)</td></tr><tr><td>Mouth-Kote®</td><td>Yerba santa (Eriodictyon californicum), Xylitol</td><td></td><td>Spray</td><td>Ad libitum</td><td></td><td>(Stewart et al., 1998)</td></tr><tr><td>TPM (Traditional Persian Medecine)</td><td>Sachet 4 g of mixed powder of A. digitata and M. Sylvestris (in a proportion of 1:1), in a glass of boiled water (250 mL) as one dose. After 10 min, when the herbal infusion somewhat cooled, the patients were to sip the entire</td><td></td><td>Sip/Drink</td><td></td><td>Hypozalix spray (sodium carboxymethyl cellulose)</td><td>(Heydarirad et al., 2017)</td></tr></table>

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<table><caption>Table 3: Values of saliva flow rate in the set of seven studies considering saliva flow rate as inclusion criteria</caption><thead><tr><th>REFERENCES</th><th>Unstimulated saliva method</th><th>flow rate</th></tr></thead><tbody><tr><td>(Alpöz et al., 2008)</td><td>Spitting method 5 min</td><td>&lt;0.3mL/min</td></tr><tr><td>(Andersson et al., 1995)</td><td>Spitting method 15 min</td><td>&lt;1.5mL</td></tr><tr><td>(Donath et al., 2016)</td><td>Swab/test of saliva weight absorbed 5 min</td><td>≤0.5g</td></tr><tr><td>(Furumoto et al., 1998)</td><td>Spitting method 5 min</td><td>&lt;0.2 mL/min</td></tr><tr><td>(Mouly, Orler, et al., 2007; Mouly, Salom, et al., 2007)</td><td>Swab/test of saliva weight absorbed 5 min</td><td>≤0.5g</td></tr><tr><td></td><td>Spitting method</td><td>≤0.16 mL/min</td></tr><tr><th></th><th>Stimulated saliva method</th><th>flow rate</th></tr><tr><td>(Alpöz et al., 2008)</td><td>Drops of acid citric spitting method</td><td>&lt;1mL/min</td></tr><tr><td>(Alves et al., 2004)</td><td>Acid citric on cotton swab 5 min test spitting</td><td>&lt;0.5mL/min</td></tr><tr><td>(Andersson et al., 1995)</td><td>Paraffin chewing 5 min</td><td>&lt;3.5mL</td></tr><tr><td>(Gil-Montoya et al., 2008)</td><td>Chewing paraffin 5 min</td><td>≤0.7mL/min</td></tr><tr><td>(Mouly, Orler, et al., 2007; Mouly, Salom, et al., 2007)</td><td>Chewing paraffin Spitting method</td><td>≤0.5mL/min</td></tr></tbody></table>