Does Systemic Disease Aggravate the Severity of Dry Mouth by Anticholinergics in Overactive Bladder Patients? Keon-Cheol Lee1*, Bong-Mo Seong2 Purpose: In overactive bladder (OAB) patients with systemic diseases, dry mouth tends to be more prominent owing to the effects of systemic diseases or related medications. We evaluated how systemic diseases affect dry mouth before and after anticholinergic treatment. Materials and Methods: OAB patients were enrolled in this study. The patients were divided according to the presence or absence of systemic diseases. Patients with systemic diseases were sub-grouped by the number of systemic diseases (only one or more than one disease). OAB symptoms score (OABSS), visual analogue scale (VAS) score for dry mouth, and body mass index (BMI) were measured. The statistical assessments were done with independent T-tests and ANCOVAs. Results: One hundred and four OAB patients were enrolled in this study. Seventy (67.3%) patients had systemic diseases and thirty-four (32.7%) patients did not. Age and BMI were higher in the systemic diseases group. The baseline VAS score of OAB in the systemic diseases group (15.9 ± 19.5) was higher than that in the OAB without systemic diseases group (4.1 ± 6.4) (P = .002). Even after age and BMI adjustment, the difference was significant. The follow-up VAS score was also different (P = .028), but the change in VAS score was not different (P = .280). In a sub-analysis, the change in VAS score in the group with two or more systemic diseases (23.6 ± 18.1) was higher than that in the group with only one systemic disease (12.5 ± 13.2) (P = .012). Conclusion: The severity of xerostomia after treatment with anticholinergics in OAB increases in patients with one systemic disease parallel to its severity before starting treatment. However, in patients with two or more sys- temic disease the magnitude of change in xedrostomia score is higher that we would expect in patients with no or one systemic diasese. Keywords: body mass index; cholinergic antagonists; systemic diseases; urinary bladder, overactive; xerostomia 1 Department of Urology, Inje University School of Medicine, Ilsanpaik Hospital, Goyang, Korea. 2 Department of Urology, COMWEL Incheon Hospital, Incheon, Korea. *Correspondence: Department of Urology, Inje University Ilsanpaik Hospital, 2240, Daehwa-dong, Goyang, Gyeonggi, Korea. Postal code : 10380 Tel: +82 31 9107230. Fax: +82 31 9107239. E-mail: kclee@paik.ac.kr. Received October 2016 & Accepted March 2017 INTRODUCTION Anticholinergics are very useful and are current-ly the most commonly prescribed medication in overactive bladder (OAB) patients. However, they have a well-known side effect profile that includes dry mouth, constipation, voiding difficulty, and so on.(1) Dry mouth is the most common side effect; it occurs in 8-87% of OAB patients after administration of various anticholinergics depending on the particular formula- tion of each anticholinergic agent.(2-5) Anticholinergics work by blocking muscarinic receptors in the bladder, and dry mouth caused by anticholinergics appears to be the result of blocking muscarinic receptors in salivary glands. Many systemic diseases appear to be related to dry mouth through various mechanisms. For example, di- abetes, which is a common disease of the endocrine system, has a high dry mouth rate, up to 40-60%, even in children,(6) and the mechanisms are thought to be multifactorial and include dehydration, polyuria, and MISCELLANEOUS autonomic abnormalities.(7) The medications used to treat systemic diseases also frequently cause dry mouth. (8) Therefore, patients with systemic diseases could al- ready be predisposed towards a risk of dry mouth be- fore treatment with anticholinergics. Also, it may be that underlying systemic disease status affects side ef- fect profiles in OAB patients treated with anticholin- ergics. The interaction between anticholinergics and some drugs that interfere with the cytochrome P450 pathway has been reported to potentiate the side effects of anticholinergics.(9) However, clinical reports proving this hypothesis are rare. We can assume that underlying systemic diseases make some patients more vulnerable to the adverse effects of anticholinergics. Therefore, we evaluated how systemic diseases affect dry mouth before and after anticholinergic treatment in OAB pa- tients. PATIENTS AND METHODS OAB patients were enrolled in this study. The Institu- tional Review Board (IRB) of Inje University, Ilsanpaik Vol 14 No 02 March-April 2017 3035 were made again. To exclude the effects of age and BMI because age and BMI could be the risk factor of dry mouth, statistical adjustment for age and BMI was made and the data were re-analyzed. The group with two or more systemic diseases was compared with the group with only one systemic dis- ease for the above mentioned clinical parameters. The statistical program used was SPSS 12.0 for Windows and the normality of any variables was confirmed be- fore running statistical comparison. Employed statisti- cal methods were independent T-tests and ANCOVAs. P values less than 0.05 were regarded as statistically significant. RESULTS Between June 2012 and February 2013, a total of one hundred and four OAB patients were enrolled in this study. There were 40 (38.5%) male patients and 64 (61.5%) female patients in the studied group of patients. The mean age of the patients was 64.1 ± 10.2 years (range: 43-82) in the OAB with systemic diseases group and 56.6 ± 11.6 years (range: 38-80) in the OAB with- out systemic diseases group (P = .001). OAB symptom duration before study was 83.5 ± 68.8 months (range: 3-240) for the OAB with systemic diseases group and 49.3 ± 44.7 months (range: 3-120) for the OAB without systemic diseases group (P = .003). Baseline OABSS of the OAB with systemic diseases group (6.8 ± 3.5, range: 3-15) was not different from that of the OAB without systemic diseases group (6.5 ± 4.2, range: 3-14). Both groups showed significant improvements in OABSS after treatment. All patients completed three-month fol- low-up. The follow-up OABSS of OAB with systemic diseases group (4.5 ± 2.8, range: 0-12) was also not dif- ferent from that of the OAB without systemic diseases group (3.9 ± 4.2, range: 0-14) (Table 1). The baseline VAS scale of the OAB with systemic dis- eases group (15.9 ± 19.5, range: 0-50) was higher than Effect of systemic diseases on dry mouth-Lee et al. Hospital approved this study (IB-1108-037). It follows the guidelines of the Declaration of Helsinki and all patients provided written informed consent. Inclusion criteria were: age older than 20 years, total overactive bladder symptoms score (OABSS) more than three, including question 3 score more than two, without the presence of any exclusion criteria, such as narrow angle glaucoma, urinary retention, gastro-intestinal slow tran- sit, myasthenia and any anticholinergics use during last three months. The patients were divided into two groups according to the presence or absence of systemic diseases. A sys- temic disease is one that affects a number of organs and tissues, or affects the body as a whole and usually is dealt with in the internal medicine department. After thorough chart review, we used following categories as systemic diseases in this study (hypertension, endocrin- ologic diseases including diabetes, coronary artery dis- eases, cerebrovascular conditions, auto-immune con- ditions, hepato-biliary diseases, etc.). Seventy (67.3%) patients had systemic diseases and thirty-four (32.7%) patients did not. Patients with systemic diseases were sub-divided into two groups, those with only one sys- temic disease and those with two or more systemic dis- eases. Drugs taken by the patients for the treatment of those systemic diseases were recorded via a full chart review or by asking the patients. Before anticholinergic treatment, OABSS and visual analogue scale (VAS) score ranging from 0 to 100 for dry mouth was examined using self-administered ques- tionnaire forms. Body weight and height of the patients were measured in order to calculate body mass index (BMI). The clinical parameters of the systemic diseases group were compared with those of the non-systemic disease group. All patients received solifenacin 5 mg for the treatment of OAB. After 3 months of solifenacin treatment, VAS for dry mouth and OABSS were meas- ured again and comparisons between the two groups Variables OAB with Systemic Diseases(n=70) OAB without Systemic Diseases(n=34) P-Value Age, year, mean ± SD 64.1 ± 10.2 56.7 ± 11.6 0.001 Male(%) 45.7(32/70) 23.5(8/34) Female(%) 54.3(38/70) 76.5(26/34) OAB-SS mean ± SD Baseline 6.8 ± 3.5 6.5 ± 4.2 0.453 Follow-up 4.5 ± 2.8 3.9 ± 4.2 0.258 Symptom duration, month, mean ± SD 83.5 ± 68.8 49.3 ± 44.7 0.010 BMI, kg/m2, mean ± SD 23.8 ± 3.5 22.3 ± 1.9 0.024 Baseline VAS, mean ± SD 15.9 ± 19.5 4.1 ± 6.4 0.002 Age-adjusted difference 0.023 BMI-adjusted difference 0.002 Follow-up VAS, mean ± SD 33.1 ± 26.4 21.8 ± 20.1 0.028 Changes of VAS, mean ± SD 17.0 ± 16.2 13.2 ± 14.1 0.280 Table 1. Patient demographics and comparisons of VAS score between the group of patients with OAB and systemic diseases and the group with OAB without systemic diseases before and after anticholinergic treatment. Abbreviations: OAB, OverActive Bladder; OAB-SS, OAB-Symptoms Score; BMI, Body Mass Index; VAS, Visual Analogue Scale. Miscellaneous 3036 that of the OAB without systemic diseases group (4.1 ± 6.4, range: 0-20) (P = .002). Even after age-adjustment, the difference in baseline VAS scale between the two groups was still significant (P = .023). The follow-up VAS scale score of the OAB with systemic diseases group (33.1 ± 26.4, range: 0-90) remained higher than that of the OAB without systemic diseases group (21.8 ± 20.1, range: 0-60) (P = .028). However, the extent of change in VAS score in the OAB with systemic diseases group (17.0 ± 16.2, range: 0-60) was not different from that of the OAB without systemic diseases group (13.2 ± 14.1, range: 0-50) (P = .280). The BMI of the OAB with systemic diseases group (23.8 ± 3.5, range: 16.4- 31.6) was higher than that of the OAB without systemic diseases group (22.3 ± 1.9, range: 17.6-26.5) (P = .024) and, after adjustment for BMI, the VAS score of the OAB with systemic diseases group was still higher than that of the OAB without systemic diseases group (P = .002) (Table 1). The mean number of systemic diseases in each patient in the systemic disease group was 1.7 ± 1.0 (range: 1-4) and the mean number of drugs prescribed for the treat- ment of systemic diseases was 3.8 ± 2.5 (range: 1-11). Hypertension was the most common systemic disease (60%, 42/70), followed by diabetes (24/70), coronary artery diseases (20/70), cerebrovascular accidents (16/70), liver cirrhosis (8/70), autoimmune diseases (8/70), and end stage renal disease (2/70). In the sub-divided group comparison, the number of drugs prescribed for the treatment of systemic diseases in the two or more systemic diseases group (5.8 ± 2.6) was higher than that for the one systemic disease group (2.5 ± 1.3) (P = .000). Although the baseline VAS score was comparable between the two groups, the change in VAS score of the two or more systemic diseases group (23.6 ± 18.1) was significantly higher than that of the one systemic disease group (12.5 ± 13.2) (P = .012) (Table 2). DISCUSSION Dry mouth, or xerostomia, is the subjective feeling experienced by patients suffering from hypofunction of the salivary glands.(10) In the elderly, the prevalence of xerostomia is 12-47%, which is higher than in the younger population, and age appears to be directly pro- portional to dry mouth.(11,12) In this study, the patients with systemic diseases and more severe dry mouth were older than the patients in the group without systemic diseases. So, we performed age-adjustment with statis- tical methods, and found that the severity of dry mouth of the OAB with systemic diseases group was still sig- nificantly higher than that of the OAB without systemic diseases group. The causes of dry mouth have been attributed to the use of medications, chronic disorders, and radiation therapy of the head and neck region.(13) Dry mouth can cause dental and oral diseases such as dental caries, periodon- tal diseases, and problems with dentures, and can be accompanied by alterations in taste, speech, eating, and swallowing, so, it is an important problem that should not be overlooked.(14) Various systemic diseases or medications used to treat those diseases can cause dry mouth. For example, endocrine diseases, infections, au- toimmune or granulomatous diseases, end-stage renal disease, and Parkinson’s disease are known to be relat- ed with hypofunction of the salivary glands and subjec- tive feelings of xerostomia via various mechanisms.(15) Various systemic diseases could have different effect profiles on xerostomia, so, some diseases could have more effect and some less. We analyzed one systemic disease group patients in this study and failed to find any difference among various systemic diseases. But, we think more profound analysis including patients with many types of systemic diseases would reveal this important hypothesis. Patients with systemic diseases usually take many different types of drugs, some of which have anticholinergic effects. The summation of the anticholinergic effects of these drugs could be an important factor in dry mouth in systemic disease pa- tients.(16) Overactive bladder is a complex of symptoms includ- ing increased frequency, urgency, and nocturia, and it has a profoundly negative impact on the psychosocial functioning and quality of life of patients.(17) Anticho- linergics are the first-line agents used to treat overactive bladder(18) and have some side effects. Of these side ef- fects, dry mouth is the most common problem and tends to be the most annoying to patients and doctors. The side effects as well as efficacy of anticholinergics in- crease with increased dosage,(19) so, a fixed single dose is preferable for proper analysis in studies of anticholin- ergics. Although recently introduced OAB drugs, such Table 2. Comparisons between the group with only one systemic disease and that with two or more systemic diseases before and after anticholinergic treatment. Variables One Systemic Disease (n=42) Two or more Systemic Diseases (n=28) P-value Age, year, mean ± SD 62.5 ± 11.4 66.6 ± 7.7 0.104 Symptom duration, month, mean ± SD 67.0 ± 59.8 108.2 ± 74.9 0.013 BMI, kg/m2, mean ± SD 24.1 ± 3.8 23.2 ± 2.9 0.327 Number of drugs for systemic diseases, mean ± SD 2.5 ± 1.3 5.8 ± 2.6 0.001 Baseline VAS, mean ± SD 12.5 ± 17.8 20.9 ± 21.1 0.120 Follow-up VAS, mean ± SD 28.6 ± 25.4 40.0 ± 26.7 0.075 Changes of VAS, mean ± SD 12.5 ± 13.2 23.6 ± 18.1 0.012 Abbreviations: VAS, Visual Analogue Scale; BMI, Body Mass Index. Effect of systemic diseases on dry mouth-Lee et al. Vol 14 No 02 March-April 2017 3037 as beta-3 agonists, have a low incidence of dry mouth compared with previous drugs that act through anticho- linergic mechanisms,(20,21) anticholinergic agents are still the main treatment tools used to manage overactive bladder and dry mouth is still the main concern. In this study, the severity of dry mouth in the group of OAB patients with systemic diseases was higher than in the group of OAB patients without systemic diseases before administration of anticholinergics, and the dif- ference in the severity of dry mouth was maintained after 3 months of anticholinergic use. This could be be- cause of the effects of the drugs used to treat systemic diseases or because of the diseases themselves. When we subdivided the systemic diseases group, the accu- mulated number of systemic diseases had a significant effect on dry mouth severity. The group with two or more systemic diseases showed increased dry mouth severity compared with the group with only one sys- temic disease. The number of drugs taken for systemic diseases was also greater in the group with two or more systemic diseases, which could result in those patients being more susceptible to the side effects of anticho- linergics. OAB patients with systemic diseases had higher base- line and follow-up dry mouth severity after anticholin- ergic treatment than did OAB patients without systemic diseases even after adjusting for the effects of age and BMI. In addition to the well-known age factor, system- ic diseases themselves affect baseline dry mouth, and this already high baseline xerostomia is accompanied by significantly more severe dry mouth after anticholin- ergic treatment in OAB patients with systemic diseases. Although the changes in the severity of dry mouth were not different between the systemic diseases group and the non-systemic diseases group, sub-classification of the systemic diseases group revealed an association be- tween the number of systemic diseases and the changes in dry mouth after anticholinergic treatment. Compared with the patients with only one systemic disease, those with two or more systemic diseases appear to be more susceptible to aggravation of dry mouth by anticholiner- gics. Therefore, when administering anticholinergics to OAB patients with systemic diseases, especially those with two or more systemic diseases, it is necessary to prepare for the aggravation of dry mouth. This study has several limitations. Firstly, age was not comparable between the systemic diseases group and the no systemic diseases group. Age is known to be di- rectly proportional with the rate of dry mouth, so, this difference could have caused a bias in our results. All else being equal, it is reasonable to assume that patients with systemic diseases would generally be older and in worse condition. We did not make intentional efforts to select patients as long as all inclusion criteria and no exclusion criteria were met. Simple allocation to groups was made according to the presence or absence of systemic diseases. We attempted to overcome this age discrepancy with statistical age-adjustment. Second limitation of this study is that accurate sample size was not calculated before study with the simple goal of at least 30 patients in each group for the proper statistical comparison including normality and the number of pa- tients were not the same among groups. Another limita- tion of this study is that gender distribution is not even in OAB without systemic disease group compared with OAB with systemic disease group. Male predominance in OAB without systemic disease group might have the possibility of gender difference bias in xerostomia al- though gender difference in xerostomia was not gener- ally proven. CONCLUSIONS The severity of xerostomia after treatment with anticho- linergics in OAB increases in patients with one system- ic disease parallel to its severity before starting treat- ment. However, in patients with two or more systemic disease the magnitude of change in xerostomia score is higher that we would expect in patients with no or one systemic disease. 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