Characteristics of medication-induced xerostomia and effect of treatment

Kayoko Ito; Naoko Izumi; Saori Funayama; Kaname Nohno; Kouji Katsura; Noboru Kaneko; Makoto Inoue

doi:10.1371/journal.pone.0280224

. 2023 Jan 12;18(1):e0280224. doi: 10.1371/journal.pone.0280224

Characteristics of medication-induced xerostomia and effect of treatment

Kayoko Ito ^1,^*,^#, Naoko Izumi ^2,^#, Saori Funayama ^1,^#, Kaname Nohno ^3,^#, Kouji Katsura ^4,^#, Noboru Kaneko ^5,^#, Makoto Inoue ^1,^6,^#

Editor: Sompop Bencharit⁷

¹Oral Rehabilitation, Niigata University Medical and Dental Hospital, Niigata, Japan

²Medical Affairs, Internal Medicine, Pfizer Japan, Inc., Tokyo, Japan

³Division of Oral Science for Health Promotion, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan

⁴Department of Oral Radiology, Niigata University Medical and Dental Hospital, Niigata, Japan

⁵Division of Preventive Dentistry, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan

⁶Division of Dysphagia Rehabilitation, Faculty of Dentistry & Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan

⁷Medical University of South Carolina, UNITED STATES

Competing Interests: This study was funded by Pfizer Japan, Inc. Naoko Izumi, one of the co-authors, is an employee of Pfizer Japan Inc. and has contributed to preparation of the study design, data analysis, decision to publish and preparation of the manuscript. However, Pfizer Japan Inc. did not provided support in the form of salaries for authors other than NI. Pfizer is a marketing authorization holder of fesoterodine, an anti-cholinergic medicine for overactive bladder and pediatric neurogenic bladder. These do not alter our adherence to PLOS ONE policies on sharing data and materials.

^✉

* E-mail: k-ito@dent.niigata-u.ac.jp

Contributed equally.

Roles

Kayoko Ito: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

Naoko Izumi: Conceptualization, Formal analysis, Funding acquisition, Methodology, Resources, Writing – review & editing

Saori Funayama: Conceptualization, Data curation, Investigation, Writing – review & editing

Kaname Nohno: Conceptualization, Formal analysis, Investigation, Methodology, Validation, Writing – review & editing

Kouji Katsura: Conceptualization, Data curation, Investigation, Writing – review & editing

Noboru Kaneko: Conceptualization, Data curation, Formal analysis, Investigation, Writing – review & editing

Makoto Inoue: Conceptualization, Data curation, Supervision, Writing – review & editing

Sompop Bencharit: Editor

PMCID: PMC9836311 PMID: 36634078

Abstract

Objective

Side-effects of medications cause xerostomia. There have been cases where a medication has been discontinued owing to its severe side-effects. Therefore, the xerostomia must be treated to ensure that the primary disease is managed effectively. This study analyzed the actual status of patients with medication-induced xerostomia and investigates factors associated with its improvement.

Methods

This study assessed 490 patients diagnosed with medication-induced xerostomia who had an unstimulated salivary flow of ≤0.1 mL/min and received treatment for xerostomia at a xerostomia clinic. Patient age, sex, medical history, medications used, disease duration of xerostomia, and psychological disorders were recorded. The anticholinergic burden was assessed using the Anticholinergic Cognitive Burden scale. The unstimulated salivary flow was measured by the spitting method. According to their symptoms and diagnoses, the patients were introduced to oral lubricants, instructed on how to perform massage, and prescribed Japanese herbal medicines, and sialogogues. Factors associated with the subjective improvement of xerostomia and objective changes in the salivary flow rate were recorded at six months.

Results

Xerostomia improved in 338 patients (75.3%). The improvement rate was significantly lower in patients with psychiatric disorders (63.6%) (P = 0.009). The improvement rate decreased as more anticholinergics were used (P = 0.018). However, xerostomia improved in approximately 60% of patients receiving three or more anticholinergics. The unstimulated salivary flow increased significantly more in patients who reported an improvement of xerostomia (0.033±0.053 mL/min) than in those who reported no improvement (0.013±0.02 mL/min) (P = 0.025).

Conclusion

Xerostomia treatment improved oral dryness in 75.3% of patients receiving xerogenic medications in this study. If xerostomia due to side-effects of medications can be improved by treatment, it will greatly contribute to the quality of life of patients with xerogenic medications and may reduce the number of patients who discontinue medications.

Introduction

Xerostomia refers to the subjective feeling of dry mouth, while hyposalivation refers to a low salivary flow rate [1]. The overall estimated prevalence of dry mouth was 22.0% (95%CI 17.0–26.0%) [2]. The reported prevalence of hyposalivation among older adults is 17%-47%; it varies depending on the approach and definition of hyposalivation used in the studies [3]. Patients with hyposalivation complain of symptoms—such as difficulties in eating, swallowing, speaking, halitosis, a chronic burning sensation, and altered taste perception—that significantly diminish the patients’ quality of life (QOL) [4]. Furthermore, decreased salivary production can lead to oral mucosal Candida infection and increase the risk of dental caries [4]. Moreover, Ohara et al. reported an association between anorexia and hyposalivation [5]. Hyposalivation may also lead to malnutrition in older adults [6].

Hyposalivation may develop as a side-effect of using certain medications or may be caused by Sjögren’s syndrome, psychological conditions, irradiation, and/or physiological changes [7, 8]. Up to 21% of patients seeking treatment at specialized xerostomia outpatient clinics have medication-induced hyposalivation [9]. In residential aged care, more than 95% of the population burden of dry mouth arises as a result of medication use [10]. It is well-known that the use of anticholinergics results in hyposalivation as saliva secretion is triggered via the stimulation of muscarinic receptors by acetylcholine [1]. Anticholinergics administered to treat overactive bladder cause xerostomia at a rate of 16.9%-53.7% [11–13]. Moreover, xerostomia accounts for about 40% of the reasons for discontinuation of anticholinergics due to adverse events in overactive bladder patients [14, 15]. Therefore, medication-induced xerostomia may reduce drug compliance and interfere with treatments for primary diseases.

The treatment of xerostomia includes drug therapy with sialogogues (such as pilocarpine hydrochloride and cevimeline hydrochloride hydrate), Japanese herbal medicines, oral lubricants, stimulation with gum or tablets, and changes or dose reductions of xerogenic medications [16–19]. While several studies have described therapeutic interventions for xerostomia caused by Sjögren’s syndrome [20, 21] or radiotherapy for the head and neck region [22, 23], there have been few reports on medication-induced xerostomia [18, 24].

If xerostomia due to side-effects of medications can be improved by treatment, it will greatly contribute to the QOL of patients with xerogenic medications and may reduce the number of patients who discontinue medications. Accordingly, this study aimed to analyze the characteristics of patients with medication-induced xerostomia and the effect of treatment of xerostomia.

Methods

This was a case series analysis of a large clinical convenience sample for which there was an intervention.

Participants

Among 1,378 patients who visited the Xerostomia and Taste Disorder Clinic at Niigata University Medical and Dental Hospital with a chief complaint of xerostomia between August 2003 and December 2019, medication-induced xerostomia patients who had an unstimulated salivary flow rate of ≤0.1 mL/min and received treatment for xerostomia were included in this retrospective study. Medication-induced xerostomia was diagnosed in patients treated with xerogenic medications with package inserts warning of hyposalivation or xerostomia as a side-effect. Patients with missing data regarding medical history or medications were excluded from the study. The requirement for informed consent was waived because of the retrospective study design. An opt-out period was provided for eligible patients, and those who did not consent to participate in this study were also excluded. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was approved by the Niigata University Ethics Committee (2020–0306).

Patient data

Patient age, sex, medical history, medications used, and disease duration of xerostomia were extracted from medical records. Polypharmacy was defined as the use of six or more medications. Anticholinergic drugs were identified with reference to past Japanese study, taking into account four anticholinergic scales and drugs approved in Japan [25]. The Anticholinergic Cognitive Burden (ACB) scale was used to classify patients according to the degree of anticholinergic burden [26, 27]. The number of xerogenic medications was also counted for each patient.

The presence of psychological disorders was investigated using the Japanese version of the 30-item General Health Questionnaire (GHQ-30) [28]. The maximum score was 30; patients scoring seven or more points were regarded as having psychiatric symptoms [29].

Measurement of the unstimulated saliva

The unstimulated salivary flow was measured via the 15-minute spitting method. Patients were instructed to spit out their saliva into a cup. The weight of the saliva was measured, and 1 g was considered to be equivalent to 1 mL [30]. Patients were categorized into three groups: having severe hyposalivation (<0.033 mL/min), moderate hyposalivation (0.033–0.066 mL/min), and mild hyposalivation (0.067–0.1 mL/min).

Classification of xerostomia

Although we collected the patients diagnosed as medication-induced xerostomia, coexisting causes of the xerostomia were identified according to the Diagnosis Chart for Xerostomia [31]. Patients with a GHQ-30 score ≥7 points or those who simultaneously experienced psychological stress events and onset of xerostomia were diagnosed with psychological stress-induced xerostomia. Patients meeting the diagnostic criteria for Sjögren’s syndrome were diagnosed as having xerostomia caused by Sjögren’s syndrome. Patients with a history of radiotherapy for the head and neck regions were diagnosed as having radiation-induced xerostomia. Patients who reported mouth breathing were diagnosed as having evaporation-induced xerostomia. Patients with metabolic diseases such as diabetes mellitus were diagnosed as having systemic disease-induced xerostomia.

Treatment methods

All patients were administered over-the-counter oral lubricants [32] and instructed salivary gland massage [33]. Parotid gland massage was performed by placing the palm on the anteroinferior area of the auricle and gently moving the palm in a circle. Submandibular and sublingual gland massage was performed by gently pushing the inner edges of the mandibles upward with the thumbs.

Pilocarpine hydrochloride or cevimeline hydrochloride hydrate were prescribed to patients with Sjögren’s syndrome or radiation-induced xerostomia. Japanese herbal medicines, for example Byakkokaninjinto, Ninjinyoeitou were also prescribed according to the patients’ symptoms [17]. When changes in medications or dose reduction were preferable to improve xerostomia, we asked the prescribing physicians to modify the medication.

Patient follow-up

The patients’ treatment status at six months was categorized into three groups: treatment continuation, treatment completion, or treatment discontinuation. Treatment completion was defined as treatment termination after consent with the patient. It was considered to be treatment discontinuation if patients were lost to follow-up prior to treatment completion. Changes in the severity of xerostomia were assessed as three levels; the patients as improvement, no improvement, and exacerbation. The salivary flow rate at six months was measured when possible. If follow-up did not continue until six months, the data at the time of completion were treated as data at six months.

Statistical analysis

Continuous variables are presented as median and range and categorical variables are presented as frequency. Cross-tabulations were performed with the chi-square test or Fisher’s exact test for categorical variables, and the Cochran–Armitage test was used for categorical variables with three or more categories. Univariate analyses were performed to identify factors associated with the presence or absence of subjective improvement of xerostomia at six months. The no improvement group included patients who reported no improvement or exacerbation after six months, and the improvement group included patients who reported improvement after six months. Analyses were performed in all patients as well as in a subgroup of patients who received anticholinergics. Univariate logistic regression analyses were performed using xerogenic medications or ACB scale scores as the explanatory variable and the presence or absence of subjective improvement at six months as the objective variable. In the analysis by treatment method, the pattern of 10% or more of cases was analyzed.

The salivary flow rates at the initial visit and those after six months of treatment were tested for normality using the Shapiro-Wilk and analyzed using the Wilcoxon test. The Mann-Whitney test was performed to examine the association between the presence or absence of improvement in xerostomia and the unstimulated salivary flow. Effect size was calculated by the difference in mean score divided by the SD of the baseline score. All statistical analyses were performed using SAS version 9.4 statistical software (SAS Institute Inc., Cary, NC, USA). Statistical significance was set at P<0.05.

Results

Patient characteristics

We included 490 of the 1,378 patients in this study on the basis of the selection criteria. The median age of the patients was 70 years (range: 17–89 years), and 68.4% of the patients were aged ≥65 years (Table 1 and S1 Table). Most patients (n = 415; 84.7%) were female. The median disease duration was 19 months (range: 0–360 months). The most common comorbidity was hypertension (n = 182; 37.1%), followed by dyslipidemia (n = 107 patients; 21.8%). The median number of medications used was five (range: 1–22 medications), and the median number of xerogenic medications used was three (range: 1–14 medications). The most commonly used xerogenic medications were central nervous system drugs (n = 130 patients; 26.5%). Any type of anticholinergics were administered to 242 patients (49.4%): 134 (55.4%) received one anticholinergic, 67 (27.7%) received two anticholinergics, and 41 (16.9%) received three or more anticholinergics. The median ACB scale score was 2 points (range: 1–10 points), and 77 patients (44.3%) had an ACB scale score ≥3 points.

Table 1. Patient characteristics.

Age ≥ 65 years	335 (68.4)
Sex (Female)	415 (84.7)
Disease duration ≥ 19 months	244 (49.8)
Medical history
Hypertension	182 (37.1)
Dyslipidemia	107 (21.8)
Gastrointestinal diseases	87 (17.8)
Psychiatric disorders	84 (17.1)
Cerebrovascular diseases	50 (10.2)
Medication
Total number of medications ≥ 6 drugs	213 (43.5)
Xerogenic medications ≥ 3 drugs	268 (54.7)
Therapeutic category
Central nervous system drugs	130 (26.5)
Cardiovascular drugs	49 (10.0)
Gastrointestinal drugs	38 (7.8)
Urological drugs	17 (3.5)
Respiratory system drugs	1 (0.2)
Anticholinergics
1 drug	134 (55.4)
2 drugs	67 (27.7)
≥ 3 drugs	41 (16.9)
Anticholinergic Cognitive Burden scale ≥ 3 points	77 (15.7)
General Health Questionnaire (≥ 7 points)	235 (48.0)
Unstimulated salivary flow rate
Mild	78 (15.9)
Moderate	86 (17.6)
Severe	326 (66.5)
Diagnosis
Medication-induced xerostomia alone	42 (8.6)
Concomitant stress-induced xerostomia	334 (68.2)
Concomitant evaporation-induced xerostomia	200 (40.8)
Concomitant Sjögren’s syndrome	91 (18.6)
Treatment methods
SGM+OL	229 (46.7)
SGM+OL+Japanese herbal medicine	165 (33.7)
SGM+OL+sialogogues	51 (10.4)
SGM+OL+Japanese herbal medicine+sialogogues	24 (4.9)
SGM+OL+dose reduction/drug discontinuation	18 (3.7)

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SGM: salivary gland massage OL: Oral lubricant.

Data are expressed as number (percentage).

At baseline, the median 15-minute unstimulated salivary flow was 0.013 mL/min (range: 0.0–0.1 mL/min), and 326 patients (66.5%) had severe hyposalivation. Forty-two patients (8.6%) were diagnosed with medication-induced xerostomia only, whereas the remaining patients (n = 448; 91.4%) were diagnosed with more than one type of xerostomia—334 patients (68.2%) were also diagnosed with psychological stress-induced xerostomia, 200 (40.8%) were also diagnosed with evaporation-induced xerostomia, and 91 (18.6%) were also diagnosed with Sjögren’s syndrome. A total of 229 patients (46.7%) were treated with salivary gland massage and oral lubricants, and 165 patients (33.7%) were treated with Japanese herbal medicine, massage, and lubricants. Sialogogues (pilocarpine hydrochloride or cevimeline hydrochloride hydrate) were prescribed to 51 patients (10.4%). Dose reduction or drug discontinuation was achieved in two patients (0.4%). One patient changed the gastrointestinal drug and the other changed the urological drug. Neither was an anticholinergic drug.

Factors associated with improvement of xerostomia

At six months, 297 patients (60.6%) were continuing treatment, 157 patients (32.1%) had completed treatment, and 36 (7.3%) had discontinued treatment. Data regarding the improvement of xerostomia were available for 449 patients at six months, including 338 patients (75.3%) who reported improvement, 109 who reported no improvement (24.3%), and two (0.4%) who reported exacerbation.

The improvement of xerostomia is shown in Table 2. The improvement rate was significantly lower in patients with psychiatric disorders (63.6%) (P = 0.009) as well as among those who received anticholinergics (60.3%) (P = 0.010). No statistically significant difference was observed between patients treated with and without anticholinergics. However, the incremental improvement decreased as the number of anticholinergics increased, 78.7% among patients receiving one anticholinergic, 70.8% among patients receiving two anticholinergics, and 59.5% among patients receiving three or more anticholinergics (P = 0.018). Among patients receiving anticholinergics, the improvement rate tended to be low in patients with a lower unstimulated salivary flow.

Table 2. Subjective improvement in xerostomia.

		Total patients (n = 449)			Patients on anticholinergics (n = 224)
		n	Improved	P	n	Improved	P
Age
< 65 years		141	99 (70.2)	0.092^a	76	47 (61.8)	0.006^a
≥ 65 years		308	239 (77.6)	0.092^a	148	117 (79.1)	0.006^a
Sex
Male		68	52 (76.5)	0.805^a	34	24 (70.6)	0.707^a
Female		381	286 (75.1)	0.805^a	190	140 (73.7)	0.707^a
Disease duration
≤ 18 months		225	173 (76.9)	0.528^a	120	89 (74.2)	0.752^a
≥ 19 months		218	162 (74.3)	0.528^a	101	73 (72.3)	0.752^a
Medical history
Hypertension	Yes	173	136 (78.6)	0.195^a	91	70 (76.9)	0.300^a
Hypertension	No	276	202 (73.2)	0.195^a	133	94 (70.7)	0.300^a
Dyslipidemia	Yes	98	80 (81.6)	0.099^a	45	40 (88.9)	0.008^a
Dyslipidemia	No	351	258 (73.5)	0.099^a	179	124 (69.3)	0.008^a
Gastrointestinal diseases	Yes	82	64 (78.0)	0.52^a	40	29 (72.5)	0.910^a
Gastrointestinal diseases	No	367	274 (74.7)	0.52^a	184	135 (73.4)	0.910^a
Psychiatric disorders	Yes	77	49 (63.6)	0.009^a	58	35 (60.3)	0.010^a
Psychiatric disorders	No	372	289 (77.7)	0.009^a	166	129 (77.7)	0.010^a
Cerebrovascular diseases	Yes	47	36 (76.6)	0.825^a	29	20 (69.0)	0.580^a
Cerebrovascular diseases	No	402	302 (75.1)	0.825^a	195	144 (73.8)	0.580^a
Medication
Number of medications
≤ 5 drugs		197	141 (71.6)	0.108^a	139	98 (70.5)	0.241^a
≥ 6 drugs		252	197 (78.2)	0.108^a	85	66 (77.6)	0.241^a
Xerogenic medications
< 3 drugs		203	161 (79.3)	0.072^a	52	42 (80.8)	0.160^a
≥ 3 drugs		246	177 (72.0)	0.072^a	172	122 (70.9)
Anticholinergics
Yes		224	164 (73.2)	0.312^a	—	—	—
No		225	174 (77.3)	0.312^a	—	—	—
1 drug		—	—	—	122	96 (78.7)	0.018^b
2 drugs		—	—		65	46 (70.8)
≥ 3 drugs		—	—		37	22 (59.5)
Degree of anticholinergic burden
< 3 points on ACB scale		—	—	—	88	68 (77.3)	0.557^a
≥ 3 points on ACB scale		—	—	—	71	52 (73.2)	0.557^a
GHQ
≤ 6 points		139	107 (77.0)	0.366^a	65	51 (78.5)	0.168^a
≥ 7 points		216	157 (72.7)	0.366^a	109	75 (68.8)	0.168^a
Unstimulated salivary flow rate
Mild		71	58 (81.7)	0.131^b	36	31 (86.1)	0.052^b
Moderate		78	60 (76.9)		39	29 (74.4)
Severe		300	220 (73.3)		149	104 (69.8)
Diagnosis
The number of diagnosed types
Medication-induced xerostomia alone		40	32 (80.0)	0.468^a	24	19 (79.2)	0.486^a
Multiple types		409	306 (74.8)	0.468^a	200	145 (72.5)	0.486^a
Stress-induced xerostomia	Yes	306	225 (73.5)	0.209^a	155	111 (71.6)	0.417^a
Stress-induced xerostomia	No	143	113(79.0)	0.209^a	69	53(76.8)	0.417^a
Evaporation-induced xerostomia	Yes	182	128 (70.3)	0.045^a	98	67 (68.4)	0.149^a
Evaporation-induced xerostomia	No	267	210 (78.7)	0.045^a	126	97 (77.0)	0.149^a
Sjögren’s syndrome	Yes	77	51 (66.2)	0.043^a	32	20 (62.5)	0.139^a
Sjögren’s syndrome	No	372	287 (77.2)	0.043^a	192	144 (75.0)	0.139^a
Treatment methods ^c
SGM+OL		211	170 (80.6)	0.155^b	116	89 (76.7)	0.437^b
SGM+OL+Japanese herbal medicine		154	111 (72.1)		70	48 (68.6)
SGM+OL+sialogogues		43	32 (74.4)		18	14 (77.8)

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^aPearson χ2 test.

^bCochran-Armitage test.

^cAnalyzed for patterns of more than 10% of cases.

SS: Sjögren’s syndrome.

SGM: salivary gland massage.

OL: Oral lubricant.

Data are expressed as median (range).

The improvement rate did not differ significantly according to the number of types of xerostomia diagnosed. The improvement rate was significantly lower in patients diagnosed with evaporation-induced xerostomia (70.3%) (P = 0.045) and Sjögren’s syndrome (66.2%) (P = 0.043) than in patients without these types. The improvement rate did not differ between patients undergoing different treatment methods.

According to the logistic regression analysis, the use of an increased number of xerogenic medications was significantly associated with a lower improvement rate of xerostomia (P = 0.014) whereas the ACB scale score was not significantly associated with the improvement rate (P = 0.091).

Factors associated with the salivary flow rate at six months

Overall, the salivary flow rate was significantly higher than at baseline in the 91 patients in whom the unstimulated salivary flow was measured at six months (Table 3). The effective size was grater in the patient whose unstimulated salivary flow rate was mild.

Table 3. Salivary flow rates.

		n	Before treatment	At 6 months	P	effect sizes
Age
< 65 years		30	0.37±0.45	0.82±0.86	<0.001	1.00
≥ 65 years		63	0.42±0.47	0.94±0.99	<0.001	1.11
Sex
Male		17	0.56±0.50	1.31±0.92	<0.001	1.50
Female		76	0.37±0.45	0.81±0.93	<0.001	0.98
Disease duration
≤ 18 months		53	0.41±0.45	1.13±1.04	<0.001	1.60
≥ 19 months		37	0.43±0.49	0.63±0.73	0.001	0.41
Medical history
Hypertension	Yes	43	0.47±0.47	1.04±1.06	<0.001	1.21
Hypertension	No	50	0.34±0.46	0.78±0.83	<0.001	0.96
Dyslipidemia	Yes	26	0.45±0.45	1.33±1.16	<0.001	1.96
Dyslipidemia	No	67	0.38±0.47	0.74±0.80	<0.001	0.77
Gastrointestinal diseases	Yes	12	0.39±0.52	0.81±0.89	0.012	0.81
Gastrointestinal diseases	No	81	0.40±0.46	0.91±0.96	<0.001	1.11
Psychiatric disorders	Yes	19	0.32±0.45	0.82±0.82	<0.001	1.11
Psychiatric disorders	No	74	0.42±0.47	0.92±0.98	<0.001	1.06
Cerebrovascular diseases	Yes	9	0.54±0.55	0.71±0.91	0.297	0.31
Cerebrovascular diseases	No	84	0.39±0.46	0.92±0.95	<0.001	1.15
Medication
The number of medications
≤ 5 drugs		51	0.37±0.45	0.80±0.75	<0.001	0.96
≥ 6 drugs		42	0.44±0.48	1.02±1.15	<0.001	1.21
Xerogenic medications
< 3 drugs		42	0.39±0.47	0.78±0.78	<0.001	0.83
≥ 3 drugs		51	0.42±0.47	1.00±1.06	<0.001	1.23
Anticholinergics
Yes		48	0.42±0.48	0.94±1.06	<0.001	1.08
No		45	0.38±0.46	0.86±0.82	<0.001	1.04
1 drug		26	0.47±0.52	1.01±1.17	0.003	1.04
2 drugs		17	0.34±0.41	0.89±1.05	0.012	1.34
≥3 drugs		5	0.48±0.54	0.74±0.52	0.155	0.48
Degree of anticholinergic burden
< 3 points on ACB scale		18	0.26±0.29	0.68±0.88	0.009	1.45
≥ 3 points on ACB scale		16	0.41±0.53	1.17±1.08	0.002	1.43
GHQ
≤ 6 points		38	0.33±0.42	0.71±0.69	<0.001	0.90
≥ 7 points		55	0.46±0.49	1.03±1.08	<0.001	1.16
Unstimulated salivary flow rate
Mild		18	1.20±0.14	1.95±1.06	0.009	5.36
Moderate		14	0.69±0.14	1.01±0.74	0.108	2.29
Severe		61	0.10±0.14	0.57±0.70	<0.001	3.36
Diagnosis
Medication-induced xerostomia alone		6	0.40±0.52	0.92±0.63	0.006	1.00
Concomitant stress-induced xerostomia		70	0.42±0.47	1.00±1.02	<0.001	1.23
Concomitant evaporation-induced xerostomia		45	0.40±0.47	0.94±0.99	<0.001	1.15
Concomitant Sjögren’s syndrome		18	0.20±0.37	0.33±0.52	0.036	0.35
Treatment methods ^a
SGM+OL		21	0.43±0.51	1.09±0.98	0.005	1.29
SGM+OL+Japanese herbal medicine		51	0.45±0.46	0.99±1.02	<0.001	1.17
SGM+OL+sialogogues		7	0.44±0.59	0.70±0.91	0.137	0.44

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^aAnalyzed for patterns of more than 10% of cases.

SGM: salivary gland massage.

OL: Oral lubricant.

Data are expressed as mean±SD.

Xerostomia and the unstimulated salivary flow at six months

Of 91 patients in whom the unstimulated salivary flow was measured at six months, 74 (81.3%) reported improved xerostomia and 17 (18.7%) reported no improvement. The mean increase of unstimulated salivary flow was 0.033±0.053 mL/min in patients who reported xerostomia improvement and 0.013±0.02 mL/min in those who reported no improvement in xerostomia (P = 0.025). A total of 57 patients who reported improvement (77.0%) and 9 patients who reported no improvement (52.9%) had increased salivary flow rates at six months.

Discussion

This is the first study in which factors associated with the improvement of xerostomia and changes in the unstimulated salivary flow at six months were analyzed in patients with medication-induced xerostomia. Xerostomia improved in 59.5% of patients even if the patient who receiving three or more anticholinergics. This finding will contribute to physicians concerned with the patients who complaint with the side-effect of medications.

One of the treatment methods for patients with medication-induced xerostomia is replacing the medication causing hyposalivation or reducing the dose of the causative medication [24]. Although a previous study indicated that improvement was achieved in 41% of patients who changed medications [34], it is difficult to switch medications in actual clinical practice. In this study, dose reduction or drug discontinuation of the causative medication was achieved in only two patients (0.4%). However, the xerostomia was improved in 338 patients (75.3%), indicating that xerostomia can be alleviated via treatment in patients receiving medications that may cause xerostomia. Therefore, reduced drug compliance due to xerostomia may be preventable.

There are various pathogenic mechanisms of medication-induced xerostomia. Saliva secretion is controlled by the autonomic nervous system, whereas fluid secretion is controlled by the parasympathetic nervous system [1]. Mechanisms of hyposalivation drug action may involve drug interference with transmission at the parasympathetic neuroeffector junction, actions at the adrenergic neuroeffector junction, or the depression of central connections of the autonomic nervous system [35]. Diuretics may affect the movement of water and/or electrolytes through the cell membrane of salivary acinar cells [35]. Antihypertensive drugs can cause xerostomia due to their effects on the regulation of calcium, which has an essential role in saliva secretion [36]. Tricyclic antidepressants can cause the inhibition of cholinergic, histaminic, and α1 adrenergic receptors, resulting in xerostomia [36]. Thus, the mechanisms of hyposalivation are dependent on the causative medication. The incidence of hyposalivation also differs based on pharmacokinetic (such as drug dose, absorption, and interactions) and physiologic (such as age, sex, and body weight) factors. In this study, 8.6% of patients were diagnosed with only medication-induced xerostomia, and 91.4% were diagnosed with multiple types of xerostomia. As xerostomia is rarely caused by medications alone, it is very difficult to interpret.

In this study, the improvement of xerostomia was not significantly different between patients with and without polypharmacy. The definition of polypharmacy varies; it is defined as the use of two or more medications in some studies and as the use of 11 or more medications in others [37]. In this study, polypharmacy was defined as the use of six or more medications [38]. The findings of this study suggest that the more number of taking xerogenic medications are, the more difficult it is to improve xerostomia. Effort to reduce the number of xerogenic medications may lead to benefit to patients with xerostomia.

The most common therapeutic intervention in this study was the combination of salivary gland massage and oral lubricants. There were no significant differences in subjective improvement rates by additional treatments, namely Japanese herbal medicines or sialogogue. In Japan, sialogogues are approved to treat Sjögren’s syndrome or xerostomia associated with radiotherapy. In both diseases, the salivary glands are pathologically damaged [8], the salivary flow rate improvement may not have been achieved despite treatment. This theory is consistent with the finding that the improvement of xerostomia was significantly lower in patients with concomitant Sjögren’s syndrome causing xerostomia than in those without Sjögren’s syndrome. However, the treatment selection was biased in this study, as this was an observational study. Treatment methods were selected in based on the severity of xerostomia and at the requests of the patients. Thus, it is possible that drug therapy was selected only for patients with severe xerostomia, and that patients with mild xerostomia were treated only with massage and oral lubricants. Despite this limitation, the findings of this study suggest that treatment improves medication-induced xerostomia in 75.3% of patients. Previous studies have reported the effects of pilocarpine preparations [39, 40] and oral lubricants [41] for patients with medication-induced xerostomia. Because in these reports, only the changes in the salivary flow rate were evaluated, improvements in xerostomia are unclear in these previous studies. Although the degree of improvement was classified into three categories in this study, detailed studies using the visual analog scale and the Facial scale are necessary.

Although the salivary flow rate increased significantly more in patients who reported improvement of xerostomia than in those who reported no improvement of xerostomia, there was a large variation of increase rate. The salivary flow rate did not increase in 23.0% of patients who reported improved xerostomia. In contrast, 52.9% of patients who did not report improved xerostomia had increased salivary flow rates. The inconsistency between the xerostomia and the objective index of the salivary flow rate has been previously reported [42]. Due to these inconsistent findings, it is unclear how much the salivary flow rate must increase to improve xerostomia. The appropriate threshold to measure improvement in xerostomia is also unclear. In this study, any increase from the baseline salivary flow rate was regarded as an increase; however, the criteria for improvement should be examined in the future.

This study has several limitations. First, only the ACB scale was used to evaluate the anticholinergic burden in this study. The scales to measure the burden of anticholinergic effects include the Anticholinergic Risk Scale (ARS) [43], anticholinergic drug scale (ADS) [44], and the ACB scale. The ARS is applicable for 49 medications, and the ADS is not applicable to fesoterodine, propiverine, and solifenacin, which are therapeutic drugs commonly used for overactive bladder in Japan. Therefore, this study used the ACB scale, which was developed by Boustani et al. [45] to measure the accumulative anticholinergic cognitive burden resulting from the total medications taken by older adults. As this scale was not developed in Japan, the applicable medications may not encompass the anticholinergics administered to patients in this study. In addition, it is necessary to search the interaction of medications. Second, the number of patients who underwent measurement of the salivary flow rate at six months was small. In this study, unstimulated salivary flow was measured for 15 minutes according to the diagnostic criteria for Sjögren’s syndrome. Many patients had systemic diseases and had consultations in multiple clinical departments in our hospital, including internal medicine, urology, and orthopedic surgery, within a few hours. Therefore, it was difficult to set aside enough time to conduct salivary flow tests for all patients. There is an oral moisture-checking device called Mucus^Ⓡ, which differs from unstimulated salivary flow [46]. With this device, oral mucosal moisture can be measured within a few seconds. In future studies, the use of other methods of objective assessment should be considered.

Conclusion

This research indicated that 75.3% of patients treated with xerogenic medications reported improvement in xerostomia after six months of treatment with salivary gland massage and oral lubricants, and others. Although the improvement rate was lower among patients who were administered more anticholinergics, approximately 60% of patients who received three or more anticholinergics reported improvement. The doctors who prescribe xerogenic medications should attempt to manage xerostomia. This would prevent patients with xerostomia from no longer taking medicine for the primary disease.

Supporting information

S1 Table. Database.

(XLSX)

Click here for additional data file.^{(69.2KB, xlsx)}

Acknowledgments

We would like to express our appreciation to Shinichi Kanazawa at A2 Healthcare Corporation, who was involved in the data analyses and to Goki Jitsukata and Yuya Kanauchi at Pfizer Inc., who assisted in the composition of the discussion section.

Data Availability

All relevant data are within the manuscript and its Supporting information files.

Funding Statement

This study was funded by Pfizer Japan, Inc. One of the co-author belongs to Pfizer Japan, Inc. and she performed analysis and preparation of the manuscript.

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PONE-D-22-09854Characteristics of medication-induced xerostomia and factors associated with treatment responsePLOS ONE

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They have used something like triple spacing – which is not reader-friendly at all. I suggest that they use 1.5 spacing, which is much easier to read.

I am somewhat concerned by one of the authors being an employee of the private-sector funder (Pfizer). There needs to be a very careful explanation of how any associated conflicts of interest were managed in respect of this research.

The authors should be very clear about when they are referring to “xerostomia” (the symptoms of dry mouth) and when they are referring to low salivary flow (or salivary gland hypofunction, SGH). The subjective and objective aspects of dry mouth do not necessarily coincide, and the authors’ choice of terms should reflect that dichotomy. People with an unstimulated flow rate of <0.1 mL/min do not necessarily have xerostomia, but they definitely have SGH.

The study design is not clear, but I think I have worked it out – it could be described as a retrospective cohort study of a large clinical convenience sample, but there is an actual intervention, so it’s not strictly observational (and therefor enot a cohort study as such). I think it is a case series analysis a large clinical convenience sample for which there was an intervention (or interventions). The authors need to be very clear about their design, because the reader’s understanding of the findings is very much dependent on the design being explicit.

Always hyphenate “side-effect”. It is a compound word.

Headings and subheadings are huge – do we really need them that big?

Section comments

Title

This needs to better reflect the study design and the research question, and the term “xerostomia” should be replaced by “dry mouth”.

Abstract

Will need rewriting anyway, but some comments follow.

The logic of the first two sentences escapes me.

Use the past tense in describing findings. Do not rely on P vlues – put some actual data in the Results paragraph. Your study should not be a P value hunt – see Amrhein et al, Nature 2019; 567: 305-307.

Conclusion – that phrase “…can prevent decreased drug compliance for the primary disease” is also a mystery – what are you saying? By what logic?

Introduction

Overall, this should make a more compelling case for conducting the study.

Paragraph 1

Sentence 1 – change “decreased” to “low”. For a better and more recent estimation of prevalence rates, see Agostini BA et al. How common is dry mouth? Systematic review and meta-regression analysis of prevalence estimates. Brazilian Dental Journal 29: 606-618 (2018).

Last sentence – that is an unsupported sweeping statement – where is the evidence for that assertion?

Paragraph 2

Sentence 2 – medication-induced dry mouth accounts for well over 95% of cases of dry mouth – see the recent US Surgeon General’s Report on Oral Health.

Sentence 3 – That Sreebny list is far too inclusive, and you should avoid using those specific numbers.

Paragraph 3

See the Surgeon General report for a good overview of the therapeutic approaches for treating dry mouth – there is a very useful Table there. Last sentence of para 3 – change the awful “regarding” to “on”.

Paragraph 4

Sentence 1 – “…and eventual imrpovement of the primary disease” – really? That’s drawing a very long bow. How might that work? Next sentence – change “Therefore” to “Accordingly”. And specify the research question. The way the last sentence is worded is far too loose and woolly, and the reader has no idea of what the study is about.

Methods

Lines 93-94 – patients were not identified; the drugs were. Rewrite that sentence accordingly.

Lines 105-107 – express those as mL/min, not per 15 min.

Lines 111 to 113 – how do you know they “developed xerostomia”? Or did they “have” the condition?

Line 121 – “educated regarding” is poor wording – they were “made aware of” it, or taught how to do it – something like that is better.

Lines 126-7 – what herbal medicines? How given? When? Why? No reference – just a throwaway comment is given.

Line 135 – how exactly was xerostomia assessed? What was asked, and what were the response options?

Line 137 should be reworded.

Statistical analysis section – concentrate less onf the test stistics (such as chi-square tests) and more on the procedures – such as “cross-tabulations”, etc etc.

Results

Line 159 makes no sense at all. Line 166 also has problems – “all types” – really? Do you mean “any type”?

Table 1 is just a list. What not make it more informative for readers by cross-tabulating by sex or age group? And no Table should continue onto a second page. Think about reducing your use of gridlines – they actually distract the eye from the data.

In the Results text, do not repeat Table data – the reader can see the data in the Tables; your job is to draw his/her attention to the important parts and features. Have one paragraph of Results text per Table – this helps the reader to navigate your paper – and introduce each Table at the beginning of its paragraph, not at the end. Concentrate on what the data show, NOT on the P values – they are far less important.

Avoid using the term "compared to" when making comparisons - use 'than' – for example, in Line 227, replace “increased compared to baseline” with “was higher than at baseline’.

Table 3 would be enhanced by presenting effect sizes (the difference in mean score divided by the SD of the baseline score, and prsented to 1 decimal place. For example, that for those <65 years is 1.0, which is a large effect. And you will be able to demonstrate that the ES for the Sjogren’s patients was lower (0.4) than for those with medication-induced xerostomia (1.0) – that is important information, and much more useful and informative than the P values – which you could indicate with a footnote anyway.

Discussion

This will need rewriting anyway – in its current form, it is too long and discursive. In the Discussion and conclusion, use the term 'findings' rather than 'results'. See Docherty and Smith, BMJ 1999; 318: 1224-5 for how to structure a Discussion section. It is a useful structure. As a general rule, the first paragraph of the Discussion should briefly reiterate what the study did and what it showed. The second paragraph should address the weaknesses of the study design and measures, etc. The paragraphs which follow should then discuss how the findings support or refute the current literature. The final paragraph should tie it all together – so what? Where next? What are the implications for practice?

The current conclusion is not useful – what’s the take-home message from this study?

Reference 23 – is that legit?

Reviewer #2: Dear authors,

Congratulations for the study. It will definitely contribute to the scientific field of Pharmacology. Though I would suggest small changes to improve the quality of the reported results.

Line 63 - You better explain what OAB stands for. Does it refer to overreactive bladder?

Line 72 - You better explain what QOL stands for. Does it refer to quality of life?

In the results section I would suggest you to diplay the results in tables only as the majority of them were explained in the text and repeated on the tables. You could have a small paragraph describing a little about what will be displayed without mentioning the figures. I would also suggest you to re-organize table 1 as data are not clear. For instance , I took some time to understand that data presented as 70 on line 2, stands for the median age, and on the next line the figure stands for the size of the sample >= 65 years old. Its seems confuse!

On the headline of the columns write to what the figure stands for and in brackets you could write frequency in %. You better verify the total percentage for medical history.

Line 183 - What kind of Japanese Herbal medicine was used? Do they all have the same mechanism of action?

Did the use of anticholinergic drugs present any type of pharmacological interaction with the other drugs in use by patients? Did you have this data on patient´s record? Nothing was mentioned on the text about it.

Best regards.

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Reviewer #2: No

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PLoS One. 2023 Jan 12;18(1):e0280224. doi: 10.1371/journal.pone.0280224.r002

Author response to Decision Letter 0

12 Dec 2022

Reviewers:

We thank the reviewers for the helpful comments on our manuscript. In accordance with the reviewers’ suggestions, we have carefully revised the manuscript, and we consider that it has been greatly improved as a result. Our responses to the reviewers’ comments are indicated below. All of the revised sections have been highlighted in blue.

Editor

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

We have modified our file to meet PLOS ONE’s style.

2. Thank you for stating the following in the Competing Interests:

"This study was funded by Pfizer Japan, Inc..　Naoko Izumi was involved in research and preparation of the manuscript as an employee of Pfizer Japan Inc."　We note that one or more of the authors have an affiliation to the commercial funders of this research study : Pfizer Japan, Inc.

This study was funded by Pfizer Japan, Inc. and Naoko Izumi, who is one of the co-authors, is an employee of Pfizer Japan Inc. and has contributed to preparation of the study design, data analysis, decision to publish and preparation of the manuscript. However, Pfizer Japan Inc. did not provide support in the form of salaries for authors other than Naoko Izumi. Pfizer is a marketing authorization holder of fesoterodine, which is an anti-cholinergic medicine for overactive bladder and pediatric neurogenic bladder. This information does not alter our adherence to PLOS ONE policies on sharing data and materials.

We have added the Supporting Information to the end of our manuscript.

Reviewer: 1

General comments:

1) Reviewer’s comment

They have used something like triple spacing - which is not reader-friendly at all. I suggest that they use 1.5 spacing, which is much easier to read.

We thank the reviewer for the advice. We have changed the spacing from 2 to 1.5.

2.I am somewhat concerned by one of the authors being an employee of the private-sector funder (Pfizer). There needs to be a very careful explanation of how any associated conflicts of interest were managed in respect of this research.

3.The authors should be very clear about when they are referring to "xerostomia" (the symptoms of dry mouth) and when they are referring to low salivary flow (or salivary gland hypofunction, SGH). The subjective and objective aspects of dry mouth do not necessarily coincide, and the authors' choice of terms should reflect that dichotomy. People with an unstimulated flow rate of <0.1 mL/min do not necessarily have xerostomia, but they definitely have SGH.

Thank you for your comments. As pointed out by the reviewer, subjective feeling and objective evaluation do not match. In our study, because all subjects’ unstimulated flow rate was <0.1 mL/min, all subjects had hyposalivation. Regarding medication-induced xerostomia, the mechanism of hyposalivation is clear with some medications, while that for others is not clear. Therefore, in this article, we defined xerostomia as the subjective feeling of dry mouth, and analyzed its characteristics and treatment effects.

4.The study design is not clear, but I think I have worked it out - it could be described as a retrospective cohort study of a large clinical convenience sample, but there is an actual intervention, so it's not strictly observational (and therefor enot a cohort study as such). I think it is a case series analysis a large clinical convenience sample for which there was an intervention (or interventions). The authors need to be very clear about their design, because the reader's understanding of the findings is very much dependent on the design being explicit.

We thank the reviewer for the advice. We have added the following text to the Methods section in the revised manuscript:

“This was a case series analysis of a large clinical convenience sample for which there was an intervention.”(line 77).

5.Always hyphenate "side-effect". It is a compound word.

In accordance with the reviewer’s comment, we have hyphenated this word as suggested.

6. Headings and subheadings are huge - do we really need them that big?

This is PLOS ONE’s style.

Section comments

Title

This needs to better reflect the study design and the research question, and the term "xerostomia" should be replaced by "dry mouth".

We thank the reviewer for the advice. We have changed the title to ‘Characteristics of medication-induced xerostomia and effect of treatment’. Regarding the term xerostomia, it is defined as a subjective feeling of dry mouth. Therefore, xerostomia and dry mouth have the same meaning. The term “xerostomia” is commonly used in the literature as well as “dry mouth.”

Abstract

Will need rewriting anyway, but some comments follow.

The logic of the first two sentences escapes me.

We have changed the sentence as follows:

“Side-effects of medications cause xerostomia. There have been cases where a medication has been discontinued owing to its severe side-effects.” (lines 22-23).

Use the past tense in describing findings. Do not rely on P vlues - put some actual data in the Results paragraph. Your study should not be a P value hunt - see Amrhein et al, Nature 2019; 567: 305-307.

We have changed this text to the past tense for describing findings. We have also added the actual data.

Conclusion - that phrase "…can prevent decreased drug compliance for the primary disease" is also a mystery - what are you saying? By what logic?

We changed the sentences as follows;

Introduction

Overall, this should make a more compelling case for conducting the study.

Paragraph 1

1. Sentence 1 - change "decreased" to "low". For a better and more recent estimation of prevalence rates, see Agostini BA et al. How common is dry mouth? Systematic review and meta-regression analysis of prevalence estimates. Brazilian Dental Journal 29: 606-618 (2018).

We have changed “decreased” to “low”, and we have added the prevalence of xerostomia (lines 46-47).

Last sentence - that is an unsupported sweeping statement - where is the evidence for that assertion?

We have added a reference (line54).

Paragraph 2

Sentence 2 - medication-induced dry mouth accounts for well over 95% of cases of dry mouth - see the recent US Surgeon General's Report on Oral Health.

We thank the reviewer for the advice. We are referring to patients who are specialized xerostomia outpatients. We have added a reference (recent US Surgeon General's Report on Oral Health) to the revised manuscript (line 67).

Sentence 3 - That Sreebny list is far too inclusive, and you should avoid using those specific numbers.

We agreed to the reviewer’s comment. We have deleted the relevant sentences.

Paragraph 3

See the Surgeon General report for a good overview of the therapeutic approaches for treating dry mouth - there is a very useful Table there. Last sentence of para 3 - change the awful "regarding" to "on".

In accordance with the reviewer’s advice, we have added a reference (line 67). We have also changed “regarding” to “on” in the revised manuscript (line 69).

Paragraph 4

Sentence 1 - "…and eventual imrpovement of the primary disease" - really? That's drawing a very long bow. How might that work? Next sentence - change "Therefore" to "Accordingly". And specify the research question. The way the last sentence is worded is far too loose and woolly, and the reader has no idea of what the study is about.

We have changed the following sentences:

“If xerostomia due to side-effects of medications can be improved by treatment, it will greatly contribute to the QOL of patients with xerogenic medications and may reduce the number of patients who discontinue medications. Accordingly, this study aimed to analyze the characteristics of patients with medication-induced xerostomia and the effect of treatment of xerostomia” (lines 71-74).

Methods

Lines 93-94 - patients were not identified; the drugs were. Rewrite that sentence accordingly.

We thank the reviewer for the comment. We have deleted the phrase “Patients taking” (line 94).

Lines 105-107 - express those as mL/min, not per 15 min.

We have changed the unit to mL/min．

Lines 111 to 113 - how do you know they "developed xerostomia"? Or did they "have" the condition?

We changed developed to onset. We defined psychological stress-induced xerostomia when psychological stress events and onset of xerostomia were occurred simultaneously (line113).

Line 121 - "educated regarding" is poor wording - they were "made aware of" it, or taught how to do it - something like that is better.

We have changed “educated” to “instructed” (line 121).

Lines 126-7 - what herbal medicines? How given? When? Why? No reference - just a throwaway comment is given.

We have added the name of the herbal medicines and a reference (lines 126-127).

Line 135 - how exactly was xerostomia assessed? What was asked, and what were the response options?

We have changed the sentence as follows:

“Changes in the severity of xerostomia were assessed as three levels;”(lines 135-136).

Line 137 should be reworded.

We have changed the sentence as follows:

“If follow-up did not continue until 6 months, the data at the time of completion were treated as data at 6 months.”(lines 138-139).

Statistical analysis section - concentrate less onf the test stistics (such as chi-square tests) and more on the procedures - such as "cross-tabulations", etc etc.

We have changed the following sentence: “Cross-tabulations were performed with the chi-square test or Fisher’s exact test for categorical variables, and the Cochran–Armitage test was used for categorical variables with three or more categories.” (lines 143-145).

Results

Line 159 makes no sense at all. Line 166 also has problems - "all types" - really? Do you mean "any type"?

We have changed the following sentence:

“We included 490 of the 1,378 patients in this study on the basis of the selection criteria.” (line 165)

In addition, as you pointed, we have changed “all types” to “any type” (line 172).

This is the first evidence of the actual situation of patients with medication-induced xerostomia in Japan. Therefore, we consider that we need to show the patients’ background in detail.

In the Results text, do not repeat Table data - the reader can see the data in the Tables; your job is to draw his/her attention to the important parts and features. Have one paragraph of Results text per Table - this helps the reader to navigate your paper - and introduce each Table at the beginning of its paragraph, not at the end. Concentrate on what the data show, NOT on the P values - they are far less important.

We thank the reviewer for the advice. We have rewritten the results, and moved the tables to the beginning of the paragraph.

Avoid using the term "compared to" when making comparisons - use 'than' - for example, in Line 227, replace "increased compared to baseline" with "was higher than at baseline'.

We have changed "increased compared to baseline" to "was higher than at baseline" (line 228).

Table 3 would be enhanced by presenting effect sizes (the difference in mean score divided by the SD of the baseline score, and prsented to 1 decimal place. For example, that for those <65 years is 1.0, which is a large effect. And you will be able to demonstrate that the ES for the Sjogren's patients was lower (0.4) than for those with medication-induced xerostomia (1.0) - that is important information, and much more useful and informative than the P values - which you could indicate with a footnote anyway.

We thank the reviewer for the advice. We have added the effective score to Table 3.

Discussion

This will need rewriting anyway - in its current form, it is too long and discursive. In the Discussion and conclusion, use the term 'findings' rather than 'results'. See Docherty and Smith, BMJ 1999; 318: 1224-5 for how to structure a Discussion section. It is a useful structure. As a general rule, the first paragraph of the Discussion should briefly reiterate what the study did and what it showed. The second paragraph should address the weaknesses of the study design and measures, etc. The paragraphs which follow should then discuss how the findings support or refute the current literature. The final paragraph should tie it all together - so what? Where next? What are the implications for practice?

We have changed the term “results” to “findings” as suggested. We have also rewritten the Discussion.

The current conclusion is not useful - what's the take-home message from this study?

We have changed the conclusion as follows:

“The doctors who prescribe xerogenic medications should attempt to manage xerostomia. This would prevent patients with xerostomia from no longer taking medicine for the primary disease.” (line 323).

Reference 23 - is that legit?

We have changed the reference to number 26.

Reviewer #2:

Line 63 - You better explain what OAB stands for. Does it refer to overreactive bladder?

We thank the reviewer for the advice. We have changed “OAB” to “overactive bladder” (line 63).

Line 72 - You better explain what QOL stands for. Does it refer to quality of life?

We had already defined QOL on line 51 of the manuscript.

In the results section I would suggest you to diplay the results in tables only as the majority of them were explained in the text and repeated on the tables. You could have a small paragraph describing a little about what will be displayed without mentioning the figures. I would also suggest you to re-organize table 1 as data are not clear. For instance, I took some time to understand that data presented as 70 on line 2, stands for the median age, and on the next line the figure stands for the size of the sample >= 65 years old. Its seems confuse!

On the headline of the columns write to what the figure stands for and in brackets you could write frequency in %. You better verify the total percentage for medical history.

We thank the reviewer for the advice. We have modified Table 1 in accordance with this comment and the other reviewer’s comments. Because the medical history was duplicated, the total percentage was > 100.

Line 183 - What kind of Japanese Herbal medicine was used? Do they all have the same mechanism of action?

We have added the name of the herbal medicines and a reference. These medications facilitate the secretion of saliva.

Unfortunately, we could not determine the interaction of the medications. We have added this issue as a limitation to the revised manuscript (line 308).

Attachment

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Click here for additional data file.^{(36.6KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0280224.r003

Decision Letter 1

Sompop Bencharit

26 Dec 2022

Characteristics of medication-induced xerostomia and effect of treatment

PONE-D-22-09854R1

Dear Dr. Ito,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Additional Editor Comments (optional):

Thank you for the revision.

Reviewers' comments:

The authors have sufficiently addressed all comments.

PLoS One. doi: 10.1371/journal.pone.0280224.r004

Acceptance letter

Sompop Bencharit

3 Jan 2023

PONE-D-22-09854R1

Characteristics of medication-induced xerostomia and effect of treatment

Dear Dr. Ito:

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PERMALINK

Characteristics of medication-induced xerostomia and effect of treatment

Kayoko Ito

Naoko Izumi

Saori Funayama

Kaname Nohno

Kouji Katsura

Noboru Kaneko

Makoto Inoue

Roles

Abstract

Objective

Methods

Results

Conclusion

Introduction

Methods

Participants

Patient data

Measurement of the unstimulated saliva

Classification of xerostomia

Treatment methods

Patient follow-up

Statistical analysis

Results

Patient characteristics

Table 1. Patient characteristics.

Factors associated with improvement of xerostomia

Table 2. Subjective improvement in xerostomia.

Factors associated with the salivary flow rate at six months

Table 3. Salivary flow rates.

Xerostomia and the unstimulated salivary flow at six months

Discussion

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Sompop Bencharit

Roles

Author response to Decision Letter 0

Decision Letter 1

Sompop Bencharit

Roles

Acceptance letter

Sompop Bencharit

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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