Constipation and Laxative Use in the Community

Home , Laxative, Linaclotide

Barry L. Werth

Bachelor of Pharmacy (Honours) (University of Queensland)

Master of Business Administration (Deakin University)

A thesis submitted in fulfilment of the requirements

for the degree of Doctor of Philosophy

Susan Wakil School of Nursing and Midwifery

Faculty of Medicine and Health

The University of Sydney

2019

Dedication

To the memory of Helen “Trean” Werth RN (1954 - 2013)

who would have preferred the thesis title:

“Constipation and Aperient Use in the Community”

Table of Contents

Statement of originality viii

Publications and conference presentations arising from this research ix

Authorship attribution statement x

Acknowledgements xii

Abstract xiv

List of abbreviations xvii

List of tables xviii

List of figures xx

List of appendices xxi

Glossary of terms xxii

Chapter 1: Introduction 1

1.1 Background 2

1.1.1 Constipation: Definition and classification 4

1.1.2 Prevalence of constipation in the community 6

1.1.3 Factors associated with constipation in population-based studies 6

1.1.4 Laxative use: Definition and classification 8

1.1.5 Prevalence of laxative use in the community 10

1.1.6 Characterisation of laxative use 10

1.2 Research aims and objectives 12

1.3 Thesis outline 12

1.4 Significance of this research 16

1.5 References 17

Chapter 2: Epidemiology of constipation in adults: why estimates of prevalence differ 25

2.1 Abstract 26

2.2 Introduction 27

2.3 Methods 29

2.4 Search results 30

2.5 Prevalence of constipation 31

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2.5.1 Prevalence estimates in general adult populations 31

2.5.2 Prevalence estimates in older adult populations 40

2.6 Why prevalence estimates differ 43

2.6.1 Country/region 43

2.6.2 Definition of constipation 43

2.6.3 Data collection method 45

2.6.4 Sample characteristics 46

2.7 Conclusion 47

2.8 References 49

Chapter 3: Defining constipation to estimate its prevalence in the community: results

from a national survey 57

3.1 Abstract 58

3.2 Introduction 59

3.3 Methods 60

3.3.1 Study population 60

3.3.2 Constipation definitions 61

3.3.3 Sample size 63

3.3.4 Analysis 63

3.3.5 Ethics approval 64

3.4 Results 65

3.4.1 Study population 65

3.4.2 Prevalence 67

3.4.3 Performance of simple definitions 69

3.5 Discussion 71

3.6 Conclusion 74

3.7 References 75 Chapter 4: Chronic constipation in the community: a national survey of Australian adults 78

4.1 Abstract 79

4.2 Introduction 80

4.3 Methods 81

4.3.1 Study design and population 81

4.3.2 Questionnaire design 81

4.3.3 Sample size 82

4.3.4 Analysis 82

4.3.5 Ethics approval 83

4.4 Results 83

4.4.1 Study population and prevalence of chronic constipation 83

4.4.2 Factors associated with chronic constipation 85

4.5 Discussion 89

4.5.1 Prevalence of chronic constipation 89

4.5.2 Factors associated with chronic constipation 89

4.5.3 Strengths and limitations 91

4.6 Conclusion 92

4.7 References 93

Chapter 5: Use of over-the-counter laxatives by community-dwelling adults

to treat and prevent constipation: a national cross-sectional study 97

5.1 Abstract 98

5.2 Introduction 99

5.3 Methods 100

5.3.1 Study population and recruitment 100

5.3.2 Survey questionnaire 101

5.3.3 Sample size 102

5.3.4 Analysis 102

5.3.5 Ethics approval 102

5.4 Results 103

5.5 Discussion 110

5.5.1 Utilisation of laxatives 110

5.5.2 Healthcare professional recommendation of laxatives 112

5.5.3 Effectiveness of laxatives 113

5.5.4 Strengths and limitations 114

5.6 Conclusion 114

5.7 References 115

Chapter 6: Laxative use and self-reported constipation in a community-dwelling

elderly population 119

6.1 Abstract 120

6.2 Introduction 121

6.3 Methods 122

6.3.1 Data source 122

6.3.2 Study population and inclusion criteria 122

6.3.3 Constipation 123

6.3.4 Medications and laxative use 123

6.3.5 Potential risk factors for constipation 123

6.3.6 Statistical analyses 124

6.3.7 Ethics approval 124

6.4 Results 124

6.4.1 Study population characteristics 124

6.4.2 Laxative use 126

6.4.3 Constipation prevalence and risk factors 128

6.5 Discussion 132

6.6 Conclusion 135

6.7 References 136

Chapter 7: A longitudinal study of constipation and laxative use in a

community-dwelling elderly population 139

7.1 Abstract 140

7.2 Introduction 141

7.3 Methods 143

7.3.1 Data source 143

7.3.2 Study population 143

7.3.3 Self-reported constipation 144

7.3.4 Medication use 144

7.3.5 Potential risk factors for constipation 144

7.3.6 Analysis 145

7.4 Results 145

7.4.1 Study population 145

7.4.2 Constipation 147

7.4.3 Laxative use 150

7.4.4 Constipation and laxative use 151

7.5 Discussion 151

7.5.1 Constipation 151

7.5.2 Laxative use 153

7.5.3 Limitations 154

7.6 Conclusion 156

7.7 References 157

Chapter 8: Discussion, conclusion & future research directions 161

8.1 Discussion 162 8.1.1 The prevalence of constipation and laxative use 162 8.1.2 Factors associated with constipation in the community 165 8.1.3 Characterisation of laxative use in the community 167

8.2 Strengths and limitations 170

8.3 Conclusion 171

8.4 Recommendations for future research 172

8.5 References 173

Appendices

Appendix 1: Survey questionnaire 177

Appendix 2: Ethics approval letter 192

Appendix 3: Participant information statement 195

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Publications and Conference Presentations Arising from this Research

Publications:

Publication 1:

Werth, B.L., Williams, K.A., & Pont, L.G. (2015). A longitudinal study of constipation and laxative use in a community-dwelling elderly population. Archives of Gerontology & Geriatrics 60,418- 424.

Publication 2:

Werth, B.L., Williams, K.A., & Pont, L.G. (2017). Laxative use and self-reported constipation in a community-dwelling elderly population. Gastroenterology Nursing 40 (2), 134-141.

Publication 3:

Werth, B.L. (2019). Epidemiology of constipation in adults: Why estimates of prevalence differ. Journal of Epidemiological Research 5(1),37-49.

Publication 4:

Werth, B.L., Williams, K.A., Fisher, M.J. & Pont, L.G. (2019). Defining constipation to estimate its prevalence in the community: results from a national survey. BMC Gastroenterology 19, 75.

Conference Presentations:

Oral presentations:

Werth, B. (2013): Constipation and laxative use in a community-based elderly population, The 12th National Conference of Emerging Researchers in Ageing, Sydney, 25-26th Nov, 2013.

Poster presentations:

Werth, B. (2012): A longitudinal study of constipation and laxative use in a community-dwelling elderly population, ASCEPT-APSA Joint Conference, Sydney, 2-5th Dec, 2012.

Werth, B. (2015): Laxative use and constipation in community-dwelling adults in Australia, ASCEPT- APSA Joint Scientific Meeting, Hobart, 29th Nov – 2nd Dec, 2015.

Acknowledgements

This thesis would not have been possible without the assistance of many people and I wish to acknowledge the contributions of each.

Firstly, my supervisory team must be acknowledged for their patience, support and generous amounts of time. I thank Professor Kylie Williams, my original primary supervisor, for taking me on in 2010 and finding the funds for the survey. Kylie’s academic experience and knowledge were invaluable in assisting me every step of the way. I appreciated being challenged with my writing and thinking, and will forever remember to ask the “so what?” question.

I thank Associate Professor Murray Fisher, a latecomer to the team, for his expert guidance, professional judgement and encouragement to continue over the past few years. Murray was always available when needed and always provided sage advice.

I am indebted to Associate Professor Lisa Pont, my primary supervisor for the bulk of my candidature. Lisa stuck with me even though she moved faculties and universities three times during my candidature. Lisa provided expert advice and tuition in the academic world. I have learned so much from Lisa whose intelligence and knowledge were inspirational.

Throughout my lengthy candidature some adversities were encountered in the form of family tragedies, and personal illness and injury. The understanding and support provided by all supervisors at these difficult times was very much appreciated.

Beyond the supervisory team, I also acknowledge the contributions of several others. At the School of Nursing and Midwifery, the support and encouragement provided by Associate Professor Tom Buckley, Associate Professor Jenny Fraser and especially Sybèle Christopher were instrumental in getting me through to the end. The expert statistical assistance provided by Judith Fethney, Sydney Nursing School Biostatistician, was invaluable in the analysis of data. I am very grateful for the generous amounts of time, helpful advice and patience provided by Judith. Also, I acknowledge the assistance provided by Associate Professors Terry Bolin (UNSW), Danny Stiel (USyd) and Philip Dinning (UNSW and now Flinders University) in reviewing the survey questionnaire.

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I must acknowledge and thank two special people who supported me along the way. At the beginning of my candidature, my late wife Trean encouraged me to pursue my ambition and assisted with some early work based on her nursing experience. Over the past few years, my partner Jennifer has helped me by understanding the time commitment required, encouraging me to continue whenever I contemplated giving it away and generally supporting me in my PhD endeavours.

Finally, as a candidate of mature age, I thank the University of Sydney for approving my candidature and allowing me to pursue this research.

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Abstract

Introduction

Constipation is often self-diagnosed and self-managed, using over-the-counter (OTC) laxatives, without healthcare professional involvement. Poorly managed constipation has serious consequences for the individual and for healthcare systems. Wide variations in estimated prevalence of constipation and laxative use impede the ability to determine the extent of the problem.

Increasing constipation-related costs may stem from failures to manage constipation effectively with laxatives. Unrestricted availability and consumer advertising of OTC laxatives often result in a lack of confidence in selecting appropriate laxatives for prevention or for treatment of the condition.

Knowledge of the prevalence of constipation and laxative use, and of utilisation of laxatives among community-dwelling adults, is needed if improvements in the management of constipation in the community are to be realized.

Aim

The aim of this thesis was to explore constipation and laxative use in the community-dwelling

Australian adult population.

Methods

The research comprised five studies conducted in two parts. The first part was a cross-sectional survey exploring constipation and laxative use in the community-dwelling general adult population.

A large nationally representative sample of adults completed a detailed online questionnaire. One study examined the impact of different constipation definitions on prevalence estimates when compared to the gold standard Rome III definitions. A second study focussed on the prevalence of chronic constipation and associated factors. The third study investigated laxative choice, including

xiv recommendations from healthcare professionals, and effectiveness of chosen laxatives, for the treatment and prevention of constipation.

The second part of the research explored constipation and laxative use in a sample of older

Australians. Data from the Australian Longitudinal Study of Ageing was used to examine changes in the prevalence of constipation and laxative use over an 11-year period from 1992-93 to 2003-04.

Using the same sample, another study examined in more detail constipation and laxative use in

2003-04.

Results

The online questionnaire was completed by 2,024 participants. A quarter of participants (24%) had chronic constipation as per the Rome III criteria. The constipation definition had a considerable impact on estimated prevalence with prevalence varying from 9% to 59% with different definitions.

Over a third of participants (37%) reported using laxatives for either treatment or prevention of constipation. Of the laxatives used, 44% were chosen without healthcare professional recommendation and 46% were perceived to be ineffective.

In the studies of older adults (n=239), the prevalence of constipation increased from 14% to 21% and laxative use increased from 6% to 15% over 11 years. In 2003-4, only 24% of participants reporting constipation used laxatives and 67% of those using laxatives did not report constipation.

Conclusion

Constipation and laxative use are common among Australian adult and older adult populations.

Chronic constipation affects a substantial proportion of the community-dwelling adult population.

Definitions used for constipation have considerable impact on prevalence estimates. Standard definitions based on Rome criteria would facilitate comparisons of prevalence between studies. The prevalence of laxative use in the community appears to be high with similar OTC laxatives being used

xv for both prevention and treatment of constipation. However, laxatives are often perceived to be ineffective and healthcare professionals are not always involved in the choice of laxatives.

The prevalence of both constipation and laxative use increase with age among older populations.

Discrepancies between the prevalence of laxative use and constipation suggest the possibility of suboptimal management with laxatives, especially among older adults. Modified guidelines which address the use of laxatives for both treatment and prevention, and increased healthcare professional involvement in the choice and use of laxatives, may be required to improve constipation management in the community.

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List of Abbreviations

ADL Activities of daily living

ALSA Australian Longitudinal Study of Ageing

ATC Anatomical Therapeutic Classification

BM Bowel motions/movements

CI Confidence interval

GSQ Gastrointestinal Symptoms Questionnaire

HCP Healthcare professional

IBS Irritable bowel syndrome

IBS-C Constipation-predominant irritable bowel syndrome

LU Laxative use

NPV Negative predictive value

NSAID(s) Non-steroidal anti-inflammatory drug(s)

NTP Not time period specified

OTC Over-the-counter

PBS Pharmaceutical Benefits Scheme

PPV Positive predictive value

Rx Prescribed

SRC Self-reported constipation

SRH Self-reported health

UK United Kingdom

US(A) United States (of America)

WHO World Health Organization

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List of Tables

Table 1.1: Rome III and Rome IV criteria for functional constipation 5

Table 1.2: OTC laxatives available in Australia 9

Table 2.1: Rome diagnostic criteria for chronic constipation 28

Table 2.2: Range of constipation prevalence estimates by region 33

Table 2.3: Range of constipation prevalence estimates by factor in general adult populations 39

Table 2.4: Range of constipation prevalence estimates by factor in older adult populations 42

Table 3.1: The Rome III diagnostic criteria for defining chronic constipation 62

Table 3.2: Study population characteristics 66

Table 3.3: Impact of constipation definitions on prevalence estimate 67

Table 3.4: Prevalence of symptoms associated with constipation as per Rome III criteria 68

Table 3.5: Sensitivity, specificity, positive and negative predictive values for the five simple definitions compared to Rome III criteria and modified Rome III criteria as gold standards 70

Table 4.1: Participant characteristics compared to the Australian adult population 84

Table 4.2: Factors associated with chronic constipation on univariate analysis 86

Table 4.3: Adjusted odds ratios for factors associated with chronic constipation 88

Table 5.1: Participant characteristics 104

Table 5.2: Number of laxatives used by laxative class and purpose of use 106

Table 5.3: Healthcare professional recommendation regarding laxative choice by laxative class 108

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Table 5.4: Participant perception of laxative effectiveness by laxative class 109

Table 6.1: Cohort characteristics 125

Table 6.2: Type of laxative used 127

Table 6.3: Univariate analysis of potential risk factors for constipation 129

Table 6.4: Risk factors associated with self-reported constipation on multifactorial analysis 131

Table 7.1: Participant characteristics, including self-reported constipation, bowel motions and laxative use 146

Table 7.2: Potential risk factors for self-reported constipation 149

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List of Figures

Figure 2.1: Results of literature search 30

Figure 7.1: Choice of laxatives used 151

List of Appendices

Survey questionnaire 171

Ethics approval letter 186

Participant information statement 189

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Glossary of Terms

Terms for constipation used in this thesis and the meaning of each term

Any constipation: Refers to both chronic and acute or sporadic constipation.

Acute constipation: Refers to short term, occasional or sporadic constipation. This is typically less than 1 week duration.

Chronic constipation: Refers to long term constipation, generally more than 4 weeks duration, or in accordance with Rome criteria, more than 3 months duration. For Rome III/IV criteria, symptom onset is 6 months prior to diagnosis.

Sub-chronic constipation: Refers to long term constipation in accordance with Rome criteria, more than 3 months duration but without symptom onset of 6 months prior to diagnosis.

Sources:

Camilleri, M., Ford, A. C., Mawe, G. M., Dinning, P. G., Rao, S. S., Chey, W. D., . . . Chang, L. (2017). Chronic constipation. Nature Reviews Disease Primers, 3, 17095.

Koloski, N. A., Jones, M., Young, M., & Talley, N. J. (2015). Differentiation of functional constipation and constipation predominant irritable bowel syndrome based on Rome III criteria: a population-based study. Alimentary Pharmacology & Therapeutics, 41(9), 856-866.

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Chapter 1: Introduction

1.1 Background

Constipation is a common problem globally (Rao, Rattanakovit, & Patcharatrakul, 2016; Sbahi &

Cash, 2015). Despite the availability of numerous clinical guidelines (Tian et al., 2016), the management of constipation appears to be suboptimal. This is indicated by the low levels of satisfaction with laxatives (Harris, Horn, Kissous-Hunt, Magnus, & Quigley, 2017; Johanson &

Kralstein, 2007; Muller-Lissner, Tack, Feng, Schenck, & Specht Gryp, 2013) and frequent failures of laxatives to adequately manage the condition (Guerin, Carson, et al., 2014) as well as increasing hospital admissions related to constipation (Sommers et al., 2015; Ansari, Ansari, Hutson , &

Southwell, 2014). Clearly more effective pharmacological approaches are needed (Camilleri et al.,

2017). An understanding of constipation prevalence, factors associated with constipation and laxative use is required before any new approaches to management can be considered (World

Health Organisation, 2003). Adult constipation in the community is often self-diagnosed and self- managed (Enck, Leinert, Smid, Kohler, & Schwille-Kiuntke, 2016; Galvez et al., 2006). As a result, there are many aspects of constipation and its management with laxatives in the community which are not clear. This thesis investigates constipation and laxative use in community-dwelling adults in

Australia in order to clarify the situation. Five chapters in the thesis present results of research conducted in two surveys, one national survey of the general adult population and one survey of an older adult population.

Constipation represents a major health problem in the community (Talley, 2004). Constipation imposes a major financial burden on both patients and healthcare systems in terms of the direct costs of treatment including laxative product costs, doctor consultation costs, diagnostic testing and hospitalisation costs. Although no published Australian data is available to quantify all of these costs,

US studies have estimated that there are over 8 million doctor consultations annually (Wald, 2016) and the annual direct costs associated with chronic constipation are as high as US$7,500 per patient

(Cai et al., 2014; Nellesen, Yee, Chawla, Lewis, & Carson, 2013) with hospitalisation costing over

US$1.6 billion in 2011 (Sommers et al., 2015). Failures in the management of constipation are frequent and lead to additional annual costs of up to US$3,000 per patient (Guerin, Carson, et al.,

2014). Various indirect costs such as absenteeism, restricted activity, reduced work productivity and caregiver costs must also be included. Absenteeism resulting from any constipation is estimated to be 0.4 days per year and 2.7 hours per week for chronic constipation (Sonnenberg & Koch, 1989) with an additional 20% or up to 3 days per month loss in productivity (Heidelbaugh, Stelwagon,

Miller, Shea, & Chey, 2015; Neri et al., 2014). The costs associated with constipation are increasing

(Choung et al., 2012; Sommers et al., 2015) and will continue to increase with aging populations and increased life expectancy (Pinto Sanchez & Bercik, 2011).

The consequences of poorly managed constipation are however not limited to financial considerations. Physical and psychological consequences are also possible (Johanson & Kralstein,

2007; Koloski, Talley, & Boyce, 2000). The most significant impact of constipation is on quality of life.

The various symptoms of constipation can affect quality of life to the same extent as other more serious medical conditions (Belsey, Greenfield, Candy, & Geraint, 2010; Dennison et al., 2005; Glia &

Lindberg, 1997). The impact is proportional to the severity of constipation (Dennison et al., 2005) but can be reversed with successful treatment (Belsey et al., 2010). Physical and mental consequences include faecal impaction, faecal incontinence, haemorrhoids, anal fissures, rectal prolapse (Gallagher & O'Mahony, 2009), and psychological distress (Dennison et al., 2005). More serious complications are rare and may include bowel perforation (Dennison et al., 2005) and colorectal cancer (Guerin et al., 2014; Mody et al., 2014).

Both pharmacological and non-pharmacological interventions are the mainstays of constipation management (Camilleri et al., 2017; Rao et al., 2016; Sbahi & Cash, 2015) and both these interventions are included in international and Australian management guidelines for healthcare professionals (Wald, 2016; Selby & Corte, 2010; Australian Medicines Handbook, 2019). Non- pharmacological interventions are normally the first step in any management guidelines and include

3 dietary and lifestyle modifications (Camilleri et al., 2017; Tack et al., 2011). Laxatives, specifically over-the-counter (OTC) laxatives, represent the main form of pharmacological therapy (Pare &

Fedorak, 2014; Selby & Corte, 2010) and are normally introduced as the second step in any management guidelines (Australian Medicines Handbook, 2019; Camilleri et al., 2017; Tack et al.,

2011). The laxative market is substantial with global sales of laxatives estimated to be US$5 billion

(Credence Inc., 2018). Annual sales of OTC laxatives exceed US$1.3 billion in the USA (Statista Ltd,

2019) and A$100 million in Australia (Corte, 2014).

Clearly the total costs associated with constipation are not trivial amounts and cannot be ignored.

They represent a substantial economic burden for both patients and healthcare systems. To prevent further cost increases, improved management techniques are required which need to be preceded by an improved understanding of current practice in the community.

1.1.1 Constipation: Definition and classification

Constipation is generally characterised by infrequent bowel movements and/or difficult defaecation

(Pare, 2011). Constipation may be either acute (short term/occasional/sporadic) or chronic (long term) (Camilleri et al., 2017; Rao et al., 2016). Chronic constipation is classified as either primary

(idiopathic or functional) constipation referring to constipation of which there is no obvious cause, or secondary constipation which refers to constipation caused by either a medical/anatomical disorder or a medication (Sbahi & Cash, 2015; Wald, 2016). The four main subtypes of primary constipation are normal transit constipation which is the most common, slow transit constipation which is common in females, outlet delay/anorectal dysfunction, and constipation-predominant irritable bowel syndrome (Camilleri et al., 2017; Sibanda, Meyer, Maponya & Motha 2018).

Constipation-predominant irritable bowel syndrome overlaps with normal transit constipation

(Camilleri et al., 2017; Sibanda et al., 2018). In this thesis, the subtypes are not differentiated and irritable bowel syndrome is not specifically included as these are outside of the thesis scope.

There are many symptoms of constipation and any definition that fails to incorporate all symptoms would be inaccurate (Rao, 2007). A consensus of international experts has established a definition of functional constipation known as the Rome criteria which are based on a set of clinical symptoms.

The definitions have been updated three times since they were first introduced in 1994 (Drossman,

2016). The current Rome IV criteria are very similar to the previous Rome III criteria and are shown in Table 1.2. The criteria are intended for diagnostic use particularly in clinical research and have also been used in epidemiological studies to define chronic constipation.

Table 1.1: Rome III and Rome IV Criteria for Functional Constipation

Rome III (2006) Rome IV (2016)

Diagnostic criteria* Diagnostic criteria*

1. Must include two or more of the following: 1. Must include two or more of the following:

a. Straining during at least 25% of a. Straining during more than 25% of defaecations defaecations b. Lumpy or hard stools in at least 25% of b. Lumpy or hard stools (BSFS 1-2) more than defaecations 25% of defaecations c. Sensation of incomplete evacuation for at c. Sensation of incomplete evacuation more least 25% of defaecations than 25% of defaecations d. Sensation of anorectal d. Sensation of anorectal obstruction/blockage for at least 25% of obstruction/blockage more than 25% of defaecations defaecations e. Manual manoeuvres to facilitate at least e. Manual manoeuvres to facilitate more than 25% of defaecations (e.g. digital evacuation, 25% of defaecations (e.g. digital evacuation, support of the pelvic floor) support of the pelvic floor) f. Fewer than 3 defaecations per week. f. Fewer than 3 spontaneous bowel movements per week.

2. Loose stools are rarely present without the use of 2. Loose stools are rarely present without the use of laxatives laxatives

3. Insufficient criteria for irritable bowel syndrome 3. Insufficient criteria for irritable bowel syndrome

Note. * Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis

BSFS 1-2 = Bristol Stool Form Scale Type 1 or 2.

1.1.2 Prevalence of constipation in the community

Since constipation is frequently self-diagnosed, determining the prevalence of adult constipation in the community can be challenging. Estimates in community-dwelling adults vary widely from 2% to

40% (Mugie, Benninga, & Di Lorenzo, 2011; Suares & Ford, 2011). In older adults, constipation prevalence appears to increase gradually beyond the ages of 50 to 60 years (McCrea, Miaskowski,

Stotts, Macera, & Varma, 2009; Mugie et al., 2011). Older adults tend to have more comorbid conditions and use more medications, both of which may be secondary causes of constipation (Song,

2012; Talley et al., 1996).

In Australia, there has been no national survey conducted in a representative sample of the community-dwelling adult population to determine the prevalence of constipation. Prevalence rates in various geographical regions ranging from 3 to 30% have been reported in studies of the general adult population (Boyce, Talley, Burke, & Koloski, 2006; Howell, Quine, & Talley, 2006) and older adult population (Fragakis, Zhou, Mannan, & Ho, 2018; Pit, Byles, & Cockburn, 2008).

1.1.3 Factors associated with constipation in population-based studies

Certain medical conditions and medications may cause secondary constipation (Rao et al., 2016;

Sbahi & Cash, 2015). In population-based studies, haemorrhoids and other anorectal disorders

(Schmidt & Santos, 2014; Talley, Lasch, & Baum, 2009), depression and anxiety (Haug, Mykletun, &

Dahl, 2002; Koloski, Talley, & Boyce, 2002; Nellesen, Chawla, et al., 2013), some gastrointestinal disorders (Nellesen, Chawla, et al., 2013; Talley et al., 2009), multiple sclerosis and Parkinson’s disease (Choung et al., 2016; Fosnes, Lydersen, & Farup, 2011) have been associated with constipation. There is conflicting evidence for obesity (Markland et al., 2013; Moezi et al., 2018;

Nellesen, Chawla, et al., 2013) and limited evidence for diabetes (Nellesen, Chawla, et al., 2013), cardiovascular disorders (Choung et al., 2016; Fosnes et al., 2011) and musculoskeletal conditions

(Fosnes et al., 2011; Moezi et al., 2018). For medications, opioid analgesics (Kalso, Edwards, Moore,

& McQuay, 2004; Moore & McQuay, 2005) and non-steroidal anti-inflammatory drugs have been associated with constipation (Jones & Tait, 1995; Thomas, Straus, & Bloom, 2002) in population- based studies. There is limited evidence for other drug classes including antipsychotics (De Hert et al., 2011), antidepressants (Schurink et al., 2014), diuretics (Wong, Wee, Pin, Gan, & Ye, 1999), calcium channel blockers (Wong et al., 1999) and iron (Rimon et al., 2005).

Apart from medical conditions and medications, a variety of other factors are commonly considered to be associated with constipation (Annells & Koch, 2003; Hinrichs, Huseboe, Tang, & Titler, 2001) but for most of these factors the evidence is either non-existent or conflicting (Leung, 2007; Muller-

Lissner et al., 2005). Constipation prevalence is consistently higher in females in almost all population-based studies (Mugie et al., 2011; Schmidt & Santos, 2014; Suares & Ford, 2011). Age is not commonly associated with constipation except in older populations where prevalence increases with age, particularly above 70 years (McCrea et al., 2009; Mugie et al., 2011; Schmidt & Santos,

2014). Certain types of surgery (Andy et al., 2016; Chiarelli, Brown, & McElduff, 2000; Choung et al.,

2016) and poor self-rated health (Andy et al., 2016; Ebling et al., 2014) are associated with increased constipation prevalence. Evidence for low physical activity levels (Moezi et al., 2018; Rey, Balboa, &

Mearin, 2014; Wald et al., 2008), low fluid intakes (Markland et al., 2013; Rey et al., 2014), and alcohol consumption (Dukas, Willett, & Giovannucci, 2003; Fosnes et al., 2011) is limited. There is no evidence that low fibre intakes are associated with constipation in population-based studies (Hinkel et al., 2009; Markland et al., 2013; Rey et al., 2014). Socioeconomic factors such as education and income levels tend to vary by country with some countries showing an association with constipation but not others (Higgins & Johanson, 2004; Wald et al., 2010; Wald et al., 2008).

1.1.4 Laxative use: Definition and classification

Laxatives are substances that accelerate colonic transit and/or induce defaecation (Hallmann, 2000;

Klaschik, Nauck, & Ostgathe, 2003). Excluding certain foods and prescription medications with laxative properties, all laxatives are widely available from pharmacies and non-pharmacy outlets without prescription both internationally and in Australia. These are generally referred to as over- the-counter or OTC laxatives which are classified based on the primary mode of action (Muller-

Lissner, 1999). There are four main classes of OTC laxatives: bulk-forming laxatives, softeners & lubricants, contact/stimulant laxatives and osmotic laxatives (Klaschik et al., 2003; Selby & Corte,

2010). Bulk-forming laxatives act by expanding in the presence of water, increasing bulk of stools, softeners have emulsifying and wetting actions on stools, whilst lubricants have emollient effects on stools (Sibanda et al., 2018). Contact or stimulant laxatives act by increasing colonic peristaltic contractions, reducing transit time, whilst osmotic laxatives act by generating an osmotic gradient, encouraging water retention in stools (Sibanda et al., 2018). Most OTC laxatives are available as oral dosage forms but some are also available for rectal use in the form of suppositories and enemas

(Klaschik et al., 2003).

Despite their widespread use, rigorous evidence of the efficacy and safety of most OTC laxatives in treating or preventing constipation is lacking. Several systematic reviews have assessed the evidence for laxatives in the treatment of constipation based on clinical trial data and have graded

OTC laxatives accordingly (Wald, 2016; Ford & Suares, 2011; Ramkumar & Rao, 2005; Brandt,

Prather, Quigley, Schiller, Schoenfield & Talley, 2005). Only one OTC laxative, macrogol, has high quality evidence of efficacy based on published studies indicating that further research is unlikely to change this assessment. This assessment of macrogol is common to all systematic reviews however the grading of other OTC laxatives varies. Bisacodyl, lactulose and ispaghula have moderate quality evidence of efficacy based on some systematic reviews indicating that further research is required which may change the grading. For all other OTC laxatives, either the quality of evidence is low or no

8 evidence is available. Laxatives are classified internationally using the ATC classification system which is based on the mode of action of each agent. OTC laxative products available in Australia have been classified using this system in Table 1.2. The only prescription laxative products available in Australia as per the ATC classification are prucalopride and peripheral opioid receptor antagonists

(methylnaltrexone, naloxegol and naloxone).

Table 1.2: OTC laxatives available in Australia

ATC Class Laxative agent Available brands in 2015

A06AA Softeners, Docusate sodium Coloxyl tablets emollients Poloxamer Coloxyl drops Paraffin liquid Parachoc, Agarol A06AB Contact laxatives Senna glycosides (Cassia) Senokot, Sennetabs, Laxettes, Prunelax, Ford Tabs, Nu-Lax Cascara (Frangula) Bisacodyl Dulcolax, Bisalax, Lax-Tab Sodium picosulfate Dulcolax SP Castor oil Senna combinations Coloxyl with Senna, Soflax, Co- Senna, Colaxsen, Laxsol, Agiolax, Herb-a-Lax, Colon Care Cascara combinations Normacol, Bowel Clear, Laxeze, Peritone A06AC Bulk-forming Ispaghula (Psyllium) Metamucil, Fybogel, Agiofibe laxatives Sterculia Normafibe Triticum (wheat dextrin) Benefiber Ispaghula combinations Nucolox, Quick Fibre Plus A06AD Osmotically acting Magnesium salts Epsom salts laxatives Sodium phosphate Fleet Phospho Soda Sorbitol Sorbilax, Sorbisol Lactulose Duphalac, Actilax, Gen-Lac, Lactocur, Lac-Dol Macrogol (polyethylene Movicol, Osmolax, Clear Lax, glycol) Laxacon, Lax-Sachets, Molaxole A06AG Enemas drugs Sodium phosphate Fleet enema Bisacodyl Bisalax enema, Fleet suppositories, Dulcolax suppositories Glycerol Glycerol suppositories Sodium laurylsulfoacetate Microlax, Micolette

1.1.5 Prevalence of laxative use in the community

Since adult constipation is frequently self-managed, determining the prevalence of OTC laxative use in the community can be challenging. In general adult populations, laxatives are used by 4% to 14% of the population (Enck et al., 2016; Galvez et al., 2006). In older adult populations, estimates also vary from 2% to 25%. (Chaplin, Curless, Thomson, & Barton, 2000; Goh, Vitry, Semple, Esterman, &

Luszcz, 2009). Such wide variations make it difficult to determine what the true prevalence is. No study of the general adult population in Australia has reported the prevalence of laxative use in the community. In Australian community-dwelling older adults, prevalence of OTC laxative use varies from 2% to 7% (Fragakis et al., 2018; Goh et al., 2009).

1.1.6 Characterisation of laxative use

As well as the difficulties in determining the extent of OTC laxative use in the community, it is also challenging to ascertain how OTC laxatives are chosen and used in the community because of the widespread availability of these products. Very few studies have investigated these aspects of OTC laxative use.

OTC laxatives are intended for use in the management of constipation although they are sometimes used by consumers for other purposes such as weight loss (Roerig, 2010). In managing constipation,

OTC laxatives may serve a dual purpose – prevention and treatment of constipation. Treatment refers to the use of a laxative to relieve the symptoms of constipation once they have occurred and prevention refers to use of a laxative to prevent the symptoms of constipation occurring. Whilst the literature frequently refers to OTC laxatives being used for treatment of constipation, use of OTC laxatives for prevention of constipation is rarely mentioned and clinical studies are scarce (Petticrew,

Watt, & Sheldon, 1997). Prophylactic use of OTC laxatives is only well publicised in the case of opioid-induced constipation (Reimer et al., 2009). How OTC laxatives are used in the community for prevention and treatment of chronic or any constipation is unknown.

Four studies have reported laxative classes used for the overall management of constipation (Harris et al., 2017; Irvine, Ferrazzi, Pare, Thompson, & Rance, 2002; Motola et al., 2002; Muller-Lissner et al., 2013), but no studies have investigated which OTC laxatives are chosen for each purpose, i.e. for prevention or treatment of constipation. Appropriate OTC laxative choice for the intended purpose should be based on the onset of action (Selby & Corte, 2010). Although numerous algorithms and guidelines are available for healthcare professionals (Wald, 2016; Tack et al., 2011; Selby & Corte,

2010; Australian Medicines Handbook, 2019), none address the dual use of laxatives. Only a few guidelines specifically refer to prevention of constipation and this is with non-pharmacological interventions (Tian et al., 2016).

Constipation is frequently self-managed by community-dwelling adults. Most adults prefer to manage the condition themselves (Annells & Koch, 2002) and attempt self-management in the first instance (Ferrazzi, Thompson, Irvine, Pare, & Rance, 2002; Harris et al., 2017). Healthcare professional consultation does not occur in over 60% of cases (Heidelbaugh et al., 2015; Pare,

Ferrazzi, Thompson, Irvine, & Rance, 2001; Rey et al., 2014) and healthcare professional involvement with OTC laxative product selection does not occur in 40 to 80% of purchases (Motola et al., 2002;

Shibata et al., 2016). There is concern that OTC laxative choice and use may not always be appropriate (Motola et al., 2002). Without advice from a healthcare professional, appropriate product selection and directions for use are challenging for the consumer (Shibata et al., 2016) who may be influenced by other less reliable sources of information (Motola et al., 2002).

For the majority of OTC laxatives, clinical trial data is scarce (Wald, 2016; Ford & Suares, 2011;

Ramkumar & Rao, 2005) but in any case, outcomes of use in everyday practice are not necessarily reflected in clinical trials (World Health Organisation, 2003). Knowledge of the effectiveness of laxatives in practice is essential to improving the management of constipation. Studies of satisfaction levels with laxatives in the management of chronic and any constipation show that 50 to 60% of laxative users are dissatisfied (Ferrazzi et al., 2002; Harris et al., 2017; Johanson & Kralstein, 2007;

Muller-Lissner et al., 2013). Only one study investigated the level of satisfaction by laxative class and reported no differences in managing constipation (Muller-Lissner et al., 2013). Concurrent use of multiple laxatives in older adults indicates that single agents are sometimes ineffective (Annells &

Koch, 2002; Ruby, Fillenbaum, Kuchibhatla, & Hanlon, 2003). The effectiveness of OTC laxatives for prevention and treatment of constipation in the community has not been reported.

1.2 Research aims and objectives

The aim of this research was to explore constipation and laxative use in community-dwelling adults in Australia.

The objectives of the research were:

1. To estimate the prevalence of constipation and OTC laxative use.

2. To identify factors associated with chronic constipation.

3. To characterise OTC laxative use.

1.3 Thesis outline

In this thesis, the analysis of data from two large research projects is presented. Data from a large national survey of constipation and laxative use in the Australian community-dwelling adult population was used in three of the studies presented in this thesis. In Chapter 3, data from this national survey was used to explore the impact of constipation definition on prevalence estimates within a population. In Chapter 4, the prevalence of constipation and associated factors in the

Australian adult population was determined while in Chapter 5 data from this national survey was used to understand how laxatives are used in the management of constipation.

To further understand constipation and laxative use in community-dwelling adults, two studies using data from a longitudinal cohort of older adults in South Australia were conducted. The Australian

Longitudinal Study of Ageing (ALSA) commenced in 1992/93 with a cohort of adults aged 65 years

12 and older. Data collected at baseline and in 2003/04 included information on constipation and medications including laxatives. In Chapter 6, a cross-sectional approach using the ALSA data was used to determine the prevalence of constipation and laxative use among community-dwelling elderly adults. To understand how constipation and laxative use change with age in older adults, a longitudinal study using the ALSA cohort was undertaken and this study is presented in Chapter 7.

Chapter 1: Introduction

This first chapter presents an overview of constipation and laxatives as well as the aims and objectives of this thesis. Chapter 1 also includes an overview of the individual chapters of this thesis and their relationship to each other, as well as the significance of the research.

Chapter 2: Epidemiology of constipation in adults: Why estimates of prevalence differ

This chapter presents a narrative literature review examining the prevalence of constipation in community-dwelling adults from an international perspective. Although the review was not systematic, considerable variation was found in the prevalence of constipation in both adult and older adult populations. The variation in prevalence estimates was both within and between geographical regions, suggesting that while culture and other country-specific factors may play a role in the prevalence of constipation, other factors should also be considered. Data collection methods and sampling issues such as sample size also appeared to influence prevalence estimates. Finally, the review also identified a wide variation between studies with regard to how constipation was defined. This lead to the study described in the following chapter in which the impact of definition on constipation prevalence estimates was quantified.

Chapter 3: Defining constipation to estimate its prevalence in the community: results from a national survey

In the study in this chapter, the relationship between constipation definition and prevalence estimates was quantified. From the literature review in Chapter 2, five simple definitions commonly

13 used to identify constipation in epidemiological research were identified. Using the national survey data, a wide range of prevalence estimates was found using the different definitions. The Rome III criteria, the current diagnostic standard at the time the study was conducted, were considered the gold standard for identification of constipation. Using statistical methodology for comparing diagnostic tests, the ability of the simple definitions to identify individuals with constipation was compared to that of the Rome III criteria. The sensitivity, specificity and predictive values of each definition were determined and it was found that none of the simpler definitions were adequate compared to the Rome III criteria for identifying individuals with constipation in the research context. This study concluded that the Rome criteria should be used to define constipation in epidemiological research.

Chapter 4: Chronic constipation in the community: a national survey of Australian adults

Based on the findings from the previous chapter, the study in this chapter uses the Rome III criteria to determine the prevalence of constipation in the Australian community-dwelling adult population using data from the national survey. The results show that one in four Australian community- dwelling adults experience constipation, demonstrating a relatively high prevalence. The study also provided insights into lifestyle, medication and health related factors associated with constipation in the adult community, information which could be useful in the diagnosis and treatment of constipation.

Chapter 5: Use of over-the-counter laxatives by community-dwelling adults to treat and prevent constipation: a national cross-sectional study

To better understand current behaviours among Australian adults regarding the management of constipation with OTC laxatives, a third study was conducted using the national survey data. In this chapter, factors influencing laxative choice were examined. Since it was expected that laxative choice may differ when being used for treatment of current constipation rather than prevention of constipation, laxative choice for treatment and prevention of constipation were considered

14 separately. To further understand the influences on laxative use and choice, involvement of healthcare professionals in laxative selection and perceived effectiveness of laxatives were also examined. This study demonstrated that laxatives are commonly used for both prevention and treatment of constipation, but that there was little difference regarding choice of laxative class when used for either purpose. Furthermore, the findings suggest that healthcare professionals could have a greater role in the management of constipation among community-dwelling adults.

Chapter 6: Laxative use and self-reported constipation in a community-dwelling elderly population

Since age-related changes in lifestyle and health may potentially increase the risk of constipation, this chapter focusses on constipation and laxative use in the elderly community-dwelling population.

Secondary analysis of data from the longitudinal ALSA cohort using a cross-sectional design was conducted to determine the prevalence of constipation and laxative use. While the findings from

Chapter 3 indicate that constipation should be defined using the Rome criteria in prevalence studies, this research pre-dated that work, and as a secondary analysis of the ALSA data, the analysis was limited to using the simplified definition of constipation used in the ALSA survey. Despite this limitation, this study demonstrated that constipation and laxative use were relatively common among elderly adults.

Chapter 7: A longitudinal study of constipation and laxative use in a community-dwelling elderly population

To further understand constipation and laxative use among older community-dwelling adults, this chapter describes a longitudinal analysis which was conducted to provide insights into the impact of aging on constipation and laxative use. Tracking individuals in the ALSA cohort from 1992/3 to

2003/4 showed that both constipation and laxative use increased over time. Interestingly in this study, the association between laxative use and constipation was poor, further supporting the findings from Chapter 5 which indicated a lack of awareness of the difference between the use of

15 laxatives for prevention and treatment of constipation, and highlighting the need for further research in this area.

Chapter 8: Discussion, Conclusion and Future Directions

From the five studies and narrative literature review presented in this thesis, there is compelling evidence that constipation and laxative use are common among community-dwelling Australian adults. One in four adults experience constipation and one in three use a laxative. Health, lifestyle and medication related factors potentially increase the risk of constipation for an individual and there appear to be opportunities for healthcare professionals to be more involved in the prevention and treatment of constipation, and thus improve the way laxatives are used in the community.

1.4 Significance of this Research

Indications are that constipation in the community is not always well-managed but without an understanding of constipation and laxative use in the community it is difficult to commence any consideration of how to better manage the condition. The problem is that there is an insufficiency of available data mainly because of the frequency of self-diagnosis of constipation and self- management with OTC laxatives. The research presented in this thesis provides useful information and insights regarding these issues which ultimately may assist in improving the future management of adult constipation in the community. Possible improvements in management resulting from this research might include more judicious use of laxatives, better educated healthcare professionals and better informed consumers. Without improved management, the financial burden will continue to increase particularly as the population ages and as no breakthrough laxative medications appear to be in development. The consequences of any improvements in constipation management may include reductions in the financial burden, improvements in quality of life and decreased likelihood of clinical complications.

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Chapter 2: Epidemiology of constipation in adults: why estimates of prevalence differ

Werth, B.L. (2019). Epidemiology of constipation in adults: Why estimates of prevalence differ. Journal of Epidemiological Research 5(1), 37-49.

2.1 Abstract

This review of over 80 studies published in the last 30 years shows that estimates of the prevalence of chronic constipation in community-dwelling adults varied widely from 2.4% to 39.6% in general adult populations and from 4% to 25.8% in older adult populations. Estimates of the prevalence of any constipation (including both chronic and sporadic constipation) also varied widely from 2.6% to

31.0% in general adult populations and from 4.4% to 44.5% in older adult populations. Apart from any country or regional differences, this wide range of estimated prevalence may be attributed to different definitions used for both chronic and any constipation as well as different data collection methods and sampling differences. Sampling issues include sample size, representativeness and age range of populations sampled. Further research is required to examine the impact of different definitions on prevalence estimates to help determine the best definitions for use in future epidemiological studies. If standard definitions can be universally agreed and used along with appropriate sampling and data collection methods, more precise estimates of constipation prevalence should be attained. This would allow more meaningful comparisons between countries and may also provide the ability to pool results.

2.2 Introduction

Constipation is a common problem in the community (Talley, 2004). Because constipation represents a substantial financial burden due to the associated costs of diagnosis and treatment, and may have a considerable impact on quality of life (Dennison et al., 2005), it is important to understand its prevalence in the community. However, constipation is largely self-diagnosed and its prevalence is difficult to gauge. Many studies have attempted to estimate the prevalence of constipation in community-dwelling adult populations and a wide range of estimates have been reported (Mugie, Benninga, & Di Lorenzo, 2011; Suares & Ford, 2011). However, this wide range of estimates makes it challenging to determine the true prevalence. It is important to understand the reasons why prevalence estimates vary so much and to consider how epidemiological studies could be improved to minimize variance. However there appears to be very little published about these issues in the literature.

The prevalence of constipation ranges widely between countries (Mugie et al., 2011). Country- specific factors such as dietary and cultural factors may partly explain this variance but individual study-specific factors relating to aspects of study design may also contribute to this variation, complicating any comparisons of countries and making it impossible to pool data. One factor is the use of different definitions of constipation. There appears to be no universal definition of constipation used in research although distinction is generally made between chronic constipation and any constipation, the latter including both chronic and sporadic constipation. For chronic constipation, the symptom-based Rome criteria has been internationally recognized as the gold standard definition since 1994 (Rome I). The criteria were revised in 2000 (Rome II), 2006 (Rome III) and 2016 (Rome IV) (Table 2.1) (Drossman, 2016). Prior to 1994, definitions were largely based on bowel motion (BM) frequency but it was not always clear if it was chronic or any constipation. For any constipation, a variety of other definitions has been used, the most common being self-reported and self-defined constipation within a specified time period.

Table 2.1: Rome diagnostic criteria for chronic constipation

Rome I Rome II Rome III Rome IV

Either two or more of the At least 12 weeks, which need Diagnostic criteria* Diagnostic criteria* following complaints present not be consecutive, in the for at least 12 months: preceding 12 months of two Must include two or more of Must include two or more of or more of: the following: the following: 1. Straining on at least 25% of bowel movements 1. Straining >1/4 of g. Straining during at least 1. Straining during more when not taking laxatives defaecations 25% of defaecations than 25% of defaecations 2. Lumpy or hard stools h. Lumpy or hard stools in 2. Lumpy or hard stools 2. Feeling of incomplete >1/4 of defaecations at least 25% of (BSFS 1-2) more than evacuation after at least 3. Sensation of incomplete defaecations 25% of defaecations 25%of bowel movements evacuation >1/4 of i. Sensation of incomplete 3. Sensation of incomplete when not taking laxatives defaecations evacuation for at least evacuation more than 4. Sensation of anorectal 25% of defaecations 25% of defaecations 3. Hard or pellet stools on obstruction/blockage j. Sensation of anorectal 4. Sensation of anorectal at least 25% of bowel >1/4 of defaecations obstruction/blockage for obstruction/blockage movements when not 5. Manual manoeuvres to at least 25% of more than 25% of taking laxatives facilitate >1/4 of defaecations defaecations defaecations (e.g. digital k. Manual manoeuvres to 5. Manual manoeuvres to evacuation, support of facilitate at least 25% of facilitate more than 25% 4. Stools less frequent than the pelvic floor) and/or defaecations (e.g. digital of defaecations (e.g. 3 per week without 6. <3 defaecations per evacuation, support of digital evacuation, laxatives week. the pelvic floor) support of the pelvic Or l. Fewer than 3 floor) defaecations per week. 6. Fewer than 3 Fewer than two bowel Loose stools are not present, m. Loose stools are rarely spontaneous bowel movements per week on and there are insufficient present without the use movements per week average, present for at least criteria for irritable bowel of laxatives 7. Loose stools are rarely 12 months syndrome. n. Insufficient criteria for present without the use irritable bowel syndrome of laxatives 8. Insufficient criteria for irritable bowel syndrome

* Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis

It is generally considered that constipation prevalence increases with age, particularly in older adults, and this has been demonstrated in a number of studies (Mugie et al., 2011). There have been a large number of studies conducted in older adult populations but this subpopulation has not been reviewed separately in published reviews, nor have reviews separated the types of constipation. It is important to distinguish between older adult populations and general adult populations, and to distinguish between chronic constipation and any constipation, when reviewing studies. This would provide a clearer understanding of the prevalence of constipation in community-dwelling adults.

The aim of this review is to report the prevalence of chronic constipation and any constipation in community-dwelling adult and older adult populations. In particular, the review seeks to explain why prevalence estimates vary so widely in the literature.

2.3 Methods

A search of literature published in the period 1988 to 2018 was conducted in December 2018. The search was conducted using Medline and Embase, as well as searching the references of articles retrieved, and was limited to human studies and English language articles. The following key search terms were used as MeSH headings and keywords: constipation, prevalence, epidemiology. Studies were included if they reported or described the prevalence of constipation in community-dwelling adult and older adult populations and included review articles. Studies conducted in other subpopulations such as females and males were excluded, as were studies where the sample size was fewer than 100 participants or if published prior to 1988. Titles and abstracts of articles were initially reviewed to determine if a study was eligible for further consideration. Eligible articles were then reviewed in full to ensure that the inclusion criteria were met. Articles meeting the criteria were segmented into general adult and older adult populations based on the age range of the sample. Because the definition of the term “elderly” is not always agreed (Singh & Bajorek, 2015), this review has used the term “older adults” which refers to populations over the age of 50 years, as a subpopulation of the general adult population. The articles regarding general adult populations were grouped into five geographical regions. All studies were subdivided into chronic constipation

29 and any constipation according to the definition of constipation used in the study. Studies included in the systematic reviews were also included with the individual studies but only if they met the inclusion criteria of this review.

2.4 Search results

Eighty-three articles met the inclusion criteria (Figure 2.1). Of these, 7 were systematic reviews and

76 were individual studies of which 59 were studies of general adult populations and 17 were of older adult populations. In 7 studies, the prevalence of constipation was not stated but was able to be calculated from the published data. Three systematic reviews were global, two related to specific regions and two related to specific countries; one country review included reviews of both general adult and older adult populations.

Articles meeting inclusion criteria (n = 83)*

Articles relating to Articles relating to general adult older adult populations populations (n = 66) (n = 18)

Systematic reviews Individual studies Systematic reviews Individual studies of general adult of general adult of older adult of older adult populations* populations populations* populations (n = 7) (n = 59) (n = 1) (n = 17)

* One article was a systematic review which separated general adult and older adult populations

Figure 2.1: Results of Literature Search

2.5 Prevalence of constipation

2.5.1 Prevalence estimates in general adult populations

Global prevalence

In the individual studies included in this review, the prevalence of chronic constipation ranged from

2.4% to 39.6%, and the prevalence of any constipation ranged from 2.6% to 31.0% (Table 2.2). A global systematic review and meta-analysis of 41 studies published up to 2010 found that the prevalence of chronic constipation ranged from 2.4% to 35% and the pooled prevalence was 14%

(Suares & Ford, 2011). Because various definitions were used in the studies reviewed including self- report and different Rome criteria, it is not valid to pool prevalence rates when different definitions have been used in different studies (Grant & Booth, 2009). Two other global reviews did not pool data from studies using different definitions. A systematic review of 50 population-based studies published from 1966 to 2010 reported that the prevalence of constipation in adult and elderly populations ranged from 2.5% to 39.6% (Mugie et al., 2011). A third global review of only 11 studies of adult populations published from 2005 to 2011 reported that the prevalence ranged from 2.6% to

26.9% (Schmidt & Santos, 2014).

North America

Ten North American studies conducted from 1964 to 2000 were included in a systematic review

(Higgins & Johanson, 2004). Data collection methods varied: 5 studies used mail surveys (Drossman et al., 1993; Hammond, 1964; Pare, Ferrazzi, Thompson, Irvine, & Rance, 2001; Talley, Weaver,

Zinsmeister, & Melton, 1993; Talley, Zinsmeister, Van Dyke, & Melton, 1991), 4 studies used face-to- face interviews (Everhart et al., 1989; Harari, Gurwitz, Avorn, Bohn, & Minaker, 1996; Johanson,

Sonnenberg, & Koch, 1989; Sandler, Jordan, & Shelton, 1990) and one used a phone survey (Stewart et al., 1999). Various definitions were used to assess constipation including self-report and different

Rome criteria; prevalence rates ranged from 1.9% in a US study published prior to 1988 (Hammond,

1964) to 27.2% in a Canadian study published in 2000 (Pare et al., 2001). An average prevalence of

14.8% was calculated however this may not be valid because of the different definitions and data collection methods (Grant & Booth, 2009). Since publication of the systematic review, nine more studies using various definitions have been located (Chang, Locke, Schleck, Zinsmeister, & Talley,

2007; Choung, Locke, Zinsmeister, Melton, & Talley, 2006; Choung et al., 2016; Heidelbaugh,

Stelwagon, Miller, Shea, & Chey, 2015; Johanson & Kralstein, 2007; Markland et al., 2013; Palsson et al., 2016; Tuteja, Talley, Joos, Woehl, & Hickam, 2005; Wald et al., 2008). The lowest prevalence of

3.1% was calculated using a definition of <3BM/week (Markland et al., 2013) whilst the highest prevalence of 31.0% was based on self-report of chronic constipation during the past 12 months

(Choung et al., 2016). Again, various data collection methods were used including mail surveys, phone and face-to-face interviews as well as internet surveys. The populations sampled also varied from predominantly Caucasian (e.g. Olmsted County in Minnesota) to general US adult populations in national surveys. Only one recent study claims to have used a large nationally representative sample (Markland et al., 2013). In addition to these studies, a longitudinal study of constipation has been conducted in the USA. First published in 2007 using 12 years of data from Olmsted County and modified Rome II criteria, the researchers found the prevalence at baseline to be 4.3% and 12 years later to be 4.1% (Halder et al., 2007). In 2012, 20 years of data were published and it was found that

3% had persistent chronic constipation and 21% had non-persistent chronic constipation (Choung et al., 2012).

Table 2.2: Range of constipation prevalence estimates by region

Region Number of Chronic constipation Any constipation studies

General adult 68 Lowest % Highest % Lowest % Highest % populations

North America 19 3.6 19.4 3.5 31.0

Europe 20 4.1 39.6 2.6 29.8

Asia 16 2.4 28.0 3.9 28.4

South America 5 - 14.6 9.7 21.7

Australasia 8 2.8 30.7 6.3 9.2

Older adult 17 Lowest % Highest % Lowest % Highest % populations

North America 7 5.7 24.4 4.7 44.5

Europe 2 - 24.4 4.4 13.8

Asia 3 4 25.8 - 16.5

Africa 1 - - - 42.9

Australasia 3 - 16.9 - 22.0

Europe

A systematic review of studies published from 1986 to 2006 included 7 studies in general adult populations of 5 countries (France, Spain, Sweden, Norway & Italy) (Peppas, Alexiou, Mourtzoukou,

& Falagas, 2008). Two studies used face-to-face interviews (Frexinos et al., 1998; Gaburri et al.,

1989), four studies used a mailed questionnaire (Garrigues et al., 2004; Haug, Mykletun, & Dahl,

2002; Siproudhis et al., 2006; Walter, Hallbook, Gotthard, Bergmark, & Sjodahl, 2002) and one study was prospective using a daily diary (Bassotti et al., 2004). It was found that the average prevalence of constipation was 17.1%; however, because various definitions were used to assess constipation including self-report and Rome criteria, and different data collection methods were used, calculation of average prevalence lacks validity (Grant & Booth, 2009). Prevalence rates ranged from 5% when defined as <3BM/week (Bassotti et al., 2004) to 29.5% with self-reported constipation (Garrigues et al., 2004).

Including the studies in the systematic review, 17 studies of general adult populations conducted in

11 European countries were located (Bassotti et al., 2004; Ebling et al., 2014; Enck, Leinert, Smid,

Kohler, & Schwille-Kiuntke, 2016; Esteban y Pena et al., 2010; Fosnes, Lydersen, & Farup, 2011;

Garrigues et al., 2004; Haug et al., 2002; Meinds, van Meegdenburg, Trzpis, & Broens, 2017; Pamuk,

Pamuk, & Celik, 2003; Papatheodoridis, Vlachogiannakos, Karaitianos, & Karamanolis, 2010; Rey,

Balboa, & Mearin, 2014; Siproudhis et al., 2006; van Kerkhoven, Eikendal, Laheij, van Oijen, &

Jansen, 2008; Wald et al., 2008; Walter et al., 2002). Prevalence estimates ranged from 2.6% (Enck et al., 2016) to 39.6% (Pamuk et al., 2003) with the highest estimate being for chronic constipation

(see Table 2.2). A variety of constipation definitions have been used as well as various data collection methods, sample sizes and sample age ranges. Within each country, different studies have produced different results. This is mainly due to different definitions which have been used but it may also be due to different data collection methods, different age ranges and differences in the representativeness of the sample. For example, three studies have been conducted in Spain with

34 results ranging from 4.1% to 29.5% (Esteban y Pena et al., 2010; Garrigues et al., 2004; Rey et al.,

2014). Each study used a different definition, different data collection method, different age range and only one study claimed to use a nationally representative sample (Rey et al., 2014).

Asia

A broad range of prevalence estimates has been reported in 15 studies conducted in 10 Asian countries which were located for this review (Adibi, Behzad, Pirzadeh, & Mohseni, 2007; Chang et al., 2012; Chen, Ho, & Phua, 2000; Cheng, Chan, Hui, & Lam, 2003; Herz et al., 1996; Ho, Kang, &

Seow, 1998; Jeong et al., 2008; Jun et al., 2006; Lu, Chang, Chen, Luo, & Lee, 2006; Moezi et al.,

2018; Rajput & Kumari Saini, 2014; Sorouri et al., 2010; Tamura et al., 2016; Wald et al., 2010; Wald et al., 2008). Prevalence estimates for chronic and any constipation ranged from 2.4% to 28.4%

(Table 2.2). This could be attributed to different cultures in different countries but it also may be the result of different definitions used as well as different data collection methods. In general, self- report definitions of any constipation yielded higher prevalence estimates than definitions of chronic constipation based on Rome criteria but this was not always the case – in one Japanese study they were very similar (Tamura et al., 2016) and in one Iranian study Rome II criteria yielded a much higher estimate than self-report (Adibi et al., 2007). An example of different prevalence estimates using the same definition is found in two Korean studies. Both studies used Rome II criteria as the definition with similar sample sizes, each representative of the Korean population. The first study used a telephone survey of 1,029 subjects 15 years or older which resulted in a prevalence of 9.2% for chronic constipation using Rome II criteria (Jun et al., 2006). In the second study, face-to face interviews using a questionnaire based on Rome II criteria were conducted in 1,417 subjects (Jeong et al., 2008). A prevalence of 2.6% was found for chronic constipation which was much lower than the previous study. This low result may have been because the ages of the subjects were restricted to 18 to 69 years and because the face-to-face interview lacked the relative anonymity of a telephone interview.

A systematic review and meta-analysis of 15 prevalence studies conducted in China reported an overall prevalence of 8.2% in the general adult population (Chu et al., 2014). However, four of the studies included paediatric age groups within the adult populations studied so the result is not strictly of the adult population. In any case, the major problem with the meta-analysis is that four different definitions were used in the studies rendering calculation of an average invalid (Grant &

Booth, 2009); nine studies used Rome II criteria, three used Rome III criteria, two used <3BM/week and one used <2BM/week. The average prevalence using Rome criteria was 6.9% compared to

13.4% in studies using bowel motion frequency but again it is not appropriate to calculate averages for different definitions. Nevertheless, this result is different to that reported for other countries where definitions based on bowel motion frequency generally yield lower prevalence values. Apart from any cultural differences, a possible explanation for this is the inclusion of paediatric age groups within four of the populations studied.

A systematic review of 10 studies conducted in Iranian adult populations showed that the prevalence of any constipation ranged from 1.4% to 37% and the prevalence of chronic constipation based on either Rome II or Rome III criteria ranged from 2.4% to 11.2% (Iraji et al., 2012).

South America

Four studies (Chinzon, Dias-Bastos, Medeiros da Silva, Eisig, & Latorre, 2015; Schmidt, de Gouveia

Santos, de Cassia Domansky, & Neves, 2016; Wald et al., 2010; Wald et al., 2008), have estimated prevalence in Brazil, Argentina and Colombia. In Brazil prevalence ranged from 9.7% (Chinzon et al.,

2015) when defined as <3BM/week to 14.6% (Schmidt et al., 2016) when using modified Rome III criteria to 16.7% for self-reported constipation (Wald et al., 2008) (Table 2.2).

Australia

Australia exemplifies the problem where a number of different studies in the same country have produced a wide range of prevalence estimates so it is difficult to determine the true prevalence

(Table 2.2). Eight studies of general adult populations were located, each surveying different populations and using different definitions. Consequently, estimates have from ranged from 2.8% to

30.7%.(Boyce, Talley, Burke, & Koloski, 2006; Bytzer et al., 2001; Howell, Quine, & Talley, 2006;

Koloski, Jones, Young, & Talley, 2015; Koloski, Talley, & Boyce, 2002; Lam, Kennedy, Chen, Lubowski,

& Talley, 1999; Ng, Nassar, Hamd, Nagarajah, & Gladman, 2015; Talley, Boyce, & Jones, 1998) Except for one study conducted in general practice clinics, all surveys were conducted by mail in population samples drawn from specific geographical regions which may not have been nationally representative.

A study using modified Rome III criteria (excluding the loose stools question) surveyed a convenience sample which was not nationally representative in general practices in western Sydney and reported a prevalence of 8.1% (Ng et al., 2015). Other studies have been conducted in regional or urban areas using samples aged 18 years or older. The most recent study used Rome III criteria and reported figures of 6.5% using strict criteria and 11.0% using modified criteria (excluding the requirement for 6 months onset of symptoms) (Koloski et al., 2015). An earlier study estimated prevalence of 9.2% using a symptom-based questionnaire (<3 BM per week or hard, lumpy stools or anal blockage) over a period of 3 months (Bytzer et al., 2001). Two other earlier studies used Rome I and Rome II criteria and reported prevalence estimates of 7.8% and 2.8% respectively (Boyce et al.,

2006; Koloski et al., 2002) whilst two other studies reported estimates of 6.3% and 13.5% using <3

BM/week over the last 12 months as the definition (Lam et al., 1999; Talley et al., 1998). In stark contrast to these estimates, a prevalence of 30.7% was reported using Rome II criteria in a study of community-dwelling adults in Sydney aged from 25 to 64 years (Howell et al., 2006). There are several possible reasons apart from the restricted age range which may explain this result. Firstly, the survey was conducted in a metropolitan population whereas others were conducted in regional areas. Also, although the bowel symptom questionnaire was based on Rome II criteria, it defined constipation differently. In this study, constipation was reported if there had been <3 BM/week, or hard/lumpy stools, or straining, or digital manipulation of stools, or incomplete evacuation experienced in the preceding 12 months. If this had been experienced often, or very often, or almost

37 always during this period, it was recorded as a positive response. This definition is quite different to the strict Rome II criteria and is probably the main reason for the high estimate reported.

Table 2.3: Range of constipation prevalence estimates by factor in general adult populations

Factor Variable Number of Lowest prevalence reported Highest prevalence studies (%) reported (%)

Definition of <3BM/week 5 2.7 17.4 constipation^

BSQ 2 9.2 13.5

GSQ 2 3.9 7.3

Rome I 8 3.6 39.6

Rome II 16 2.8 30.7

Rome III 12 2.4 24.5

Rome IV 2 6.3 8.9

Self-report (3 months) 2 16.5 27.2

Self-report (12 months) 13 3.5 31.0

Self-report (NTP) 7 6.3 28.4

Data collection method Face-to-face interview 21 2.4 24.8

Mail survey 25 2.8 30.7

Phone interview 8 2.6 19.4

Internet survey 4 5.5 28.4

Written questionnaire 7 4.4 26.2

Diary 2 5.0 31.4

Age range (years) >15 10 3.6 24.5

>16 3 2.4 7.3

>18 19 2.8 27.2

>19 1 N/A 4.4

>20 5 2.7 24.5

>21 or 25 2 16.8 31.0

Specific age range - 23 3.5 39.6 various

No age range reported 2 5.0 11.7

Sample size 100 - 499 5 5.0 39.6

500 - 999 13 2.8 24.8

1,000 – 1,999 10 3.5 30.7

2,000 – 4,999 21 4.4 26.2

5,000 – 9,999 6 3.1 28.4

>10,000 8 2.4 20.2

Note: BM/week = Bowel movements per week ^More than one definition used in some studies

GSQ = Gastrointestinal Symptoms Questionnaire

NTP = no time period specified

2.5.2 Prevalence estimates in older adult populations

Studies of older adult populations spanned 8 countries with seven studies conducted in US populations (Table 2.2) (Andy et al., 2016; Campbell, Busby, & Horwath, 1993; Chaplin, Curless,

Thomson, & Barton, 2000; Fragakis, Zhou, Mannan, & Ho, 2018; Harari, Gurwitz, Avorn, Bohn, &

Minaker, 1997; Lindeman et al., 2000; Lopez Cara et al., 2006; Meiring & Joubert, 1998; Pit, Byles, &

Cockburn, 2008; Song, 2012; Stewart, Moore, Marks, & Hale, 1992; Suyasa, Paterson, Xiao, & Lynn,

2011; Talley et al., 1996; Werth, Williams, & Pont, 2015; Whitehead, Drinkwater, Cheskin, Heller, &

Schuster, 1989; Wolfsen, Barker, & Mitteness, 1993; Wong, Wee, Pin, Gan, & Ye, 1999) The prevalence of chronic constipation has ranged widely from 4% in Indonesia (Suyasa et al., 2011) to

25.8% in Korea (Song, 2012). For any constipation, prevalence has ranged from 4.4% in Spain (Lopez

Cara et al., 2006) to 44.5% (Wolfsen et al., 1993) in the USA. Different definitions used in different studies are probably the major reason for this wide range although different populations, sample sizes and data collection methods may also contribute to these differences.

In a UK study, 596 elderly patients (aged over 65 years and registered in general practices) were interviewed face-to-face and it was found that, although 13.8% subjectively self-reported constipation (defined as their usual bowel habit with no time period specified), 24.4% had chronic constipation as per modified Rome II criteria (Chaplin et al., 2000). This result is the opposite to what is generally found – usually self-reported prevalence rates are higher than prevalence rates using

Rome criteria. This is possibly because the interview process lacked anonymity and participants were less likely to admit to suffering constipation. Also, the different definition of self-report used in this study has no doubt influenced the result as well as the fact that modified Rome II criteria were used.

Three Australian studies have reported the prevalence of constipation in older populations with different results. In one study, patients attending general practices in a regional area completed a written questionnaire (Pit et al., 2008). The population consisted of 849 patients aged 65 years and older, almost all of whom (95%) had used at least one medication for more than 6 months. It was found that 22% of patients self-reported having any constipation during the previous month. The

40 constipation may or may not have been a side effect of medication that was being taken at the time since 54% of patients were taking 5 or more medicines. A longitudinal study of 239 subjects aged 65 years and older found that self-reported constipation increased from 14% to 21% over a period of 11 years (Werth et al., 2015). A more recent Australian study surveyed 236 subjects aged 65 years or older in Western Sydney and reported a prevalence of 16.9% using modified Rome III criteria

(Fragakis et al., 2018).

In addition to the individual studies, a systematic review and meta-analysis of 7 Chinese studies has been published (Chu et al., 2014). Populations sampled were all 60 years or older except for one study sample which was 70 years or older. Five studies defined constipation as straining or hard stools or <3 BM/week, one study defined it as <3 BM/week and one study used Rome II criteria. The overall prevalence of constipation was 18.1% which was significantly different to that calculated for the general population (8.2%) although neither calculation is valid because of the different definitions used (Grant & Booth, 2009).

Table 2.4: Range of constipation prevalence estimates by factor in older adult populations

Factor Variable Number of Lowest prevalence reported Highest prevalence reported studies (%) (%)

Definition of <3BM/week 3 4.4 29.2 constipation^

Rome I 2 11.6 24.4

Rome II 2 24.4 25.8

Rome III 4 4.0 33.9

Self-report (1 month) 1 N/A 22.0

Self-report (12 2 5.7 40.1 months)

Self-report (NTP) 6 12.3 44.5

Data collection method Face-to-face 12 4.0 44.5 interview

Mail survey 3 4.4 40.1

Written questionnaire 1 N/A 22.0

Age range (years) >50 2 4.4 11.8

>60 4 4.0 25.8

>65 9 12.3 44.5

>70 1 N/A 22.8

Sample size 100 - 499 7 4.0 44.5

500 - 999 4 4.4 24.4

1,000 – 1,999 1 N/A 40.1

2,000 – 4,999 2 11.6 22.6

5,000 – 9,999 1 N/A 11.8

>10,000 1 N/A 5.7

Note: GSQ = Gastrointestinal Symptoms Questionnaire

BM/week = Bowel movements per week

NTP = no time period specified

^More than one definition used in some studies

2.6 Why prevalence estimates differ

From the foregoing discussion, it is evident that there are several possible explanations for the wide range of prevalence estimates.

2.6.1 Country/region

In studies reporting prevalence of chronic and any constipation, the intercontinental prevalence ranges are not dissimilar (Table 2.2) although it has been shown that prevalence can often differ between individual countries. When comparing countries, any differences could be attributed to differences in culture, diet, environment, socioeconomic conditions and healthcare systems as well as genetic differences (Mugie et al., 2011), however different constipation definitions, data collection methods and sampling make country comparisons difficult. One research group has conducted surveys in 11 countries using face-to-face interviews (except for two countries where telephone interviews were used) and using the same simple questionnaire which asked if constipation symptoms had been experienced during the prior year (Wald et al., 2010; Wald et al.,

2008). In each country, the sample size was 2,000 subjects, aged 15 years or older and representative of the country’s population. Using the same definition, sample size and data collection method in each country, should ensure that data is consistent and enable comparisons between countries. This was the case in all countries except China where the sample size was 2,100 and subjects aged 60 years or more were excluded. The prevalence estimates ranged from 5.4% in

Germany to 21.7% in Colombia.

2.6.2 Definition of constipation

A variety of different definitions of constipation have been used in the prevalence studies (Tables 2.3

& 2.4). The gold standard definition of chronic constipation is the Rome criteria, the version of which varies depending on when the study was conducted. Some studies have used modified Rome criteria, particularly Rome III, either explicitly or surreptitiously. Not all studies have revealed exact details of the Rome criteria used or the questionnaire used so it has to be assumed that the strict criteria have been applied although this may not necessarily have been the case. It should be noted

43 that prior to the publication of Rome II criteria in 1999, constipation as defined by Rome I would have included constipation-predominant irritable bowel syndrome (IBS-C). As a result, Rome I definitions tend to yield higher estimates than Rome II or III because of the non-exclusion of IBS-C in the Rome I criteria. Most, but not all, studies using Rome II and Rome III criteria exclude IBS-C however there is significant overlap of symptoms so whether or not these are strictly distinct entities has been widely debated in the literature (Ford et al., 2014; Siah, Wong, & Whitehead, 2016;

Wong et al., 2010). Nevertheless, IBS-C may account for an additional 3 to 4% prevalence if included

(Heidelbaugh et al., 2015; Koloski et al., 2015; Lu et al., 2006). For chronic constipation, Rome I and

Rome II definitions tended to yield higher estimates than Rome III possibly because of the 12 months assessment period in Rome I and II definitions compared to 3 months with 6 months onset in Rome

III, although eight of the Rome III studies have used modified criteria. The modifications have comprised not excluding IBS, not including the question about loose stools and not including the requirement of 6 months onset of symptoms. One study using Rome IV criteria reported low prevalence because the strict criteria were employed; conducted across USA, Canada and UK using nationally representative samples, the survey found the prevalence of chronic constipation to be

6.3% but, if irritable bowel syndrome and opioid-induced constipation were included, the prevalence would be 8.9% (Palsson et al., 2016).

Other studies have used self-report to estimate the prevalence of any constipation, which may include both sporadic and chronic constipation. In general, estimates of constipation prevalence using stool frequency (generally <3 BM/week) were consistently low and those using self-report were consistently high in the studies reviewed (Tables 2.3 & 2.4). Most studies using self-report have allowed the participants to define constipation themselves, but some have defined constipation based on stool frequency and/or stool consistency, or have used some other criteria as the definition. Variations in prevalence using self-report can also be attributed to the different time periods that have been used with 12 months being the most common. A good illustration of the variance of self-report with different time periods was seen in a recent German study. Different time

44 periods for self-reported constipation changed the prevalence estimate: 14.9% for 12 months, 5.8% for 4 weeks and 2.6% for current at the time of the survey (Enck et al., 2016).

In the majority of studies, the prevalence rates are considerably higher for any (self-reported) constipation compared to chronic constipation definitions based on Rome criteria. This is highlighted in a Spanish study where a questionnaire was mailed to adults aged 18 to 65 years, representative of the general population (Garrigues et al., 2004). Of the 349 respondents, 29.5% self-reported constipation in the prior year however this changed to 19.2% and 14% using Rome I and Rome II criteria respectively. Two other studies have similarly reported different prevalence estimates when comparing self-reported constipation to chronic constipation in the same sample. In Canada, 27.2% self-reported constipation in the prior 3 months however this changed to 16.7% and 14.9% using

Rome I and Rome II criteria respectively (Pare et al., 2001). In Iran, 9.6% self-reported constipation

(no time period was specified), 4.4% reported <3 BM/week and 22.9% were constipated based on

Rome II criteria – an unusual result which might be explained by the fact that the sample was 14 to

41 years old (Adibi et al., 2007). No studies have investigated the full impact of different definitions on prevalence comparing bowel motion frequency, self-report and Rome III or IV definitions in the same general adult population sample.

2.6.3 Data collection method

The data collection method used may influence the survey outcome. Six different methods have been used to collect data in general adult population surveys, the most common being face-to-face interviews and mail surveys (Table 2.3). The internet is being increasingly used for gastrointestinal research because it is cost effective and provides prompt data of high quality using representative population samples (Aziz et al., 2018). Surveys conducted by mail or internet tend to report higher prevalence rates because participants provide data anonymously and do not experience the potential embarrassment of an interview, particularly when questioning sensitive subjects such as bowel habits (Szolnoki & Hoffmann, 2013). For this reason, interviews conducted face-to-face or by phone, and written questionnaires completed in clinics, tend to report lower prevalence rates.

The use of questionnaires (mail, phone, internet or face-to-face) depends on the ability of participants to recall symptoms whereas the use of a daily diary does not rely on recall and therefore could be considered to be more credible. However, two prospective studies using a daily diary each showed quite different results – an Italian study (Bassotti et al., 2004) using Rome II criteria reported a prevalence of 5 to 11% of individual symptoms but a Turkish study (Pamuk et al., 2003) using Rome

I criteria reported a prevalence of 31.4%. Possible explanations for this difference may be because the latter used a one week diary and Rome I criteria whereas the Italian study used a four week diary and Rome II criteria.

The majority of studies in older populations (12 of the 17 studies) have used face-to-face interviews probably because this is the most reliable method of garnering information from older people due to physical and other problems associated with ageing (Reisenwitz & Wimbish, 1998) (Table 2.4).

Phone interviews have not been used possibly because of potential hearing difficulties. Internet surveys have not been employed, no doubt because of potentially low response rates relating to computer illiteracy of older generations although this may change in time.

2.6.4 Sample characteristics

Size

There have been a wide range of sample sizes used in prevalence studies with larger sample sizes tending to yield lower prevalence rates than smaller sample sizes. Most general adult population studies have used sample sizes from 2,000 to 5,000 (Table 2.3). Smaller sample sizes (100-1,000) are more commonly used in surveys of older adult populations with 11 of the 16 studies using samples of fewer than 1,000 participants (Table 2.4). This is possibly because overall older populations are of much smaller size than general adult populations. In both general adult and older adult surveys, sample size calculations have usually not been provided so it is not clear if the chosen sample sizes are appropriate.

Representativeness

Many general adult population surveys have used samples in regional areas rather than national surveys so the samples may not have been nationally representative. Several studies have shown that the prevalence of constipation can vary in regional areas within a country (Chu et al., 2014;

Ebling et al., 2014; Sandler et al., 1990). Representativeness of samples is sometimes mentioned in studies of general adult populations but evidence is not provided. In older populations, ten studies were conducted in regional areas but again it has been shown that prevalence may vary by region within a country (Johanson, 1998). Only one study of an older population used a sample claimed to be representative of the general elderly population (Wong et al., 1999). Inclusion of census data for the countries studied would demonstrate the representativeness of samples when compared to national data.

Age range

In the majority of studies in general adult populations, the lowest age has been 18 years with either no restriction on the highest age or a specific age as the highest limit (Table 2.3). This is presumably because in most countries 18 years is the minimum adult age. Specific age ranges have been used in some studies but generally no explanations have been given as to why particular age ranges were selected. In some studies, participants over 60, 65 or 70 years have been excluded. No distinct trends in prevalence by age range of samples can be identified. In older populations, the majority of studies (10 of the 17 studies) have used 65 years as the lower age limit presumably because this is generally accepted as the age of retirement in most countries (Table 2.4).

2.7 Conclusion

Constipation prevalence estimates in community-dwelling adults and older adults vary by up to twentyfold in the studies included in this review. This wide range of prevalence may be attributed to several factors. The most salient factor is that different definitions have been used for both chronic and any constipation. Different data collection methods may also play a role as well as differences in sampling, apart from any inherent country or regional differences. To quantify the impact of a range

47 of different definitions on prevalence estimates, studies using the same population sample are needed. This will help determine recommended definitions for use in future epidemiological studies.

Whilst it might appear that definitions based on Rome criteria would be best for chronic constipation, these criteria have not always been used in epidemiological research (Lacy et al., 2016) and when they are used, they have often been modified. Nevertheless, universally accepted standard definitions are needed for both chronic constipation and any constipation. Although the most commonly used definition for any constipation has been self-report over 12 months, research is required to establish the best definition to be used as a standard. Apart from standard definitions, there are other factors to consider in future epidemiological studies. For data collection, online surveys provide efficiency and anonymity, and can provide nationally representative samples.

Sample size calculations should always be provided to ensure that samples are at least the minimum size required.

Whilst the literature search was conducted in a systematic manner as outlined, a limitation of the review is that it was conducted by only one reviewer and the quality of the studies included was not critically appraised, therefore it does not meet the requirements of a systematic review. However, the review does indicate that, if standard definitions can be agreed and used along with appropriate sampling and data collection methods, more precise estimates of constipation prevalence should be attained with less variation. This would allow more meaningful comparisons between countries and may also provide the ability to pool results. Apart from demonstrating differences relating to cultural, dietary, genetic, environmental and socioeconomic factors, comparisons between countries would provide an indication of how public health programs, access to healthcare services and availability of medications impact prevalence. Pooling of data would provide an indication of how extensive the problem is worldwide and highlight any regional differences. This in turn may lead to improvements in management and improved health outcomes.

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Talley, N. J., Boyce, P., & Jones, M. (1998). Identification of distinct upper and lower gastrointestinal symptom groupings in an urban population. Gut, 42(5), 690-695.

Talley, N. J., Weaver, A. L., Zinsmeister, A. R., & Melton, L. J., 3rd. (1993). Functional constipation and outlet delay: a population-based study. Gastroenterology, 105(3), 781-790.

Talley, N. J., Zinsmeister, A. R., Van Dyke, C., & Melton, L. J., 3rd. (1991). Epidemiology of colonic symptoms and the irritable bowel syndrome.[Erratum appears in Gastroenterology 1992 Feb;102(2):746]. Gastroenterology, 101(4), 927-934.

Tamura, A., Tomita, T., Oshima, T., Toyoshima, F., Yamasaki, T., Okugawa, T., . . . Miwa, H. (2016). Prevalence and self-recognition of chronic constipation: Results of an internet survey. Journal of Neurogastroenterology and Motility, 22(4), 677-685.

Tuteja, A. K., Talley, N. J., Joos, S. K., Woehl, J. V., & Hickam, D. H. (2005). Is constipation associated with decreased physical activity in normally active subjects? American Journal of Gastroenterology, 100(1), 124-129. van Kerkhoven, L. A. S., Eikendal, T., Laheij, R. J. F., van Oijen, M. G. H., & Jansen, J. B. M. J. (2008). Gastrointestinal symptoms are still common in a general Western population. Netherlands Journal of Medicine, 66(1), 18-22.

Walter, S., Hallbook, O., Gotthard, R., Bergmark, M., & Sjodahl, R. (2002). A population-based study on bowel habits in a Swedish community: prevalence of faecal incontinence and constipation. Scandinavian Journal of Gastroenterology, 37(8), 911-916.

Werth, B. L., Williams, K. A., & Pont, L. G. (2015). A longitudinal study of constipation and laxative use in a community-dwelling elderly population. Archives of Gerontology & Geriatrics, 60(3), 418-424.

Whitehead, W. E., Drinkwater, D., Cheskin, L. J., Heller, B. R., & Schuster, M. M. (1989). Constipation in the elderly living at home. Definition, prevalence, and relationship to lifestyle and health status. Journal of the American Geriatrics Society, 37(5), 423-429.

Wolfsen, C. R., Barker, J. C., & Mitteness, L. S. (1993). Constipation in the daily lives of frail elderly people. Archives of Family Medicine, 2(8), 853-858.

Wong, R. K., Palsson, O. S., Turner, M. J., Levy, R. L., Feld, A. D., von Korff, M., & Whitehead, W. E. (2010). Inability of the Rome III criteria to distinguish functional constipation from constipation-subtype irritable bowel syndrome. American Journal of Gastroenterology, 105(10), 2228-2234.

Chapter 3: Defining constipation to estimate its prevalence in the community: results from a national survey

Werth, B.L., Williams, K.A., Fisher, M.J. & Pont, L.G. (2019). Defining constipation to estimate its prevalence in the community: results from a national survey. BMC Gastroenterology 19, 75.

3.1 Abstract

Background: Different definitions of constipation have been used to estimate its prevalence in the community but this creates difficulties when comparing results from various studies. This study explores the impact of different definitions on prevalence estimates in the same population and compares the performance of simple definitions with the Rome III criteria.

Methods: The prevalence of constipation in a large nationally representative sample of community- dwelling adults was estimated using five simple definitions of constipation and compared with definitions based on the Rome III criteria. The sensitivity, specificity, and positive and negative predictive values, were calculated for each definition using the Rome III criteria as the gold standards for chronic and sub-chronic constipation.

Results: Prevalence estimates for the five simple definitions ranged from 9.4% to 58.9%, while the prevalence estimates using the Rome III criteria were 24.0% (95%CI: 22.1, 25.9) for chronic constipation and 39.6% (95%CI: 37.5, 41.7) for sub-chronic constipation. None of the simple definitions were adequate compared to the Rome III criteria. Self-reported constipation over the past 12 months had the highest sensitivity (91.1%, 95%CI: 88.8, 93.4) and negative predictive value

(94.5%, 95%CI: 93.1, 96.1) compared to the Rome III criteria for chronic constipation but an unacceptably low specificity (51.3%, 95%CI: 48.8, 53.8) and positive predictive value (37.1%, 95%CI:

34.4, 39.9).

Conclusions: The definition used to identify constipation within a population has a considerable impact on the prevalence estimate obtained. Simple definitions, commonly used in research, performed poorly compared with the Rome III criteria. Studies estimating population prevalence of constipation should use definitions based on the Rome criteria where possible.

3.2 Introduction

Constipation is a common condition in the community which represents a significant burden for both individuals and health care systems (Dennison et al., 2005). For the individual, constipation is associated with pain and symptoms which negatively impact quality of life (Belsey, Greenfield,

Candy, & Geraint, 2010). From the health care system perspective, considerable costs are associated with the diagnosis and treatment of constipation (Ansari, Ansari, Hutson, & Southwell, 2014;

Mohaghegh Shalmani et al., 2011; Nyrop et al., 2007; Singh et al., 2007; Sommers et al., 2015). Since constipation is such a burden, it is important to know its prevalence but estimating the prevalence of constipation in the community can be challenging.

Three large systematic reviews including 50 epidemiological studies of community-dwelling adult populations have shown that the prevalence varies widely, with estimates for constipation ranging from 2% to 35% (Mugie, Benninga, & Di Lorenzo, 2011; Peppas, Alexiou, Mourtzoukou, & Falagas,

2008; Suares & Ford, 2011). This wide range may be in part due to differences in populations, because of various factors such as age groups, culture, diet and environment, but it may also be due to differences in the way constipation was defined in each study (Mugie et al., 2011). Although the

Rome criteria have been developed for use as a standard definition of chronic constipation, most epidemiological studies have used a variety of other definitions of constipation. The various definitions used have included self-reported constipation or questions based on one or some of the symptoms as detailed in the Rome criteria.

The Rome criteria comprise a set of clinical symptoms which are internationally recognised as the gold standard in the diagnosis of chronic constipation (Drossman, Corazziari, Delvaux, Spiller, Talley,

Thompson, Whitehead, 2006; Longstreth et al., 2006). These criteria were first developed in 1994

(Rome I) and subsequently revised in 2000 (Rome II), 2006 (Rome III) and 2016 (Rome IV) (Drossman,

2016). Whilst useful in clinical research and pharmaceutical trials, the Rome criteria have been found cumbersome to use in clinical practice (Drossman, 2016) and have not always been used in epidemiological research (Lacy et al., 2016). The majority of epidemiological studies have not

59 investigated chronic constipation and have instead used simple definitions of constipation such as self-reported constipation over a defined time period, or specific symptoms, such as bowel motion frequency (Mugie et al., 2011; Schmidt & de Gouveia Santos, 2014).

It is not known to what extent the definition of constipation impacts prevalence estimates and whether any of these simple measures are valid alternatives to the Rome criteria for estimating the prevalence of chronic constipation. The aims of this study were to explore the impact that different definitions used to identify individuals with constipation have on population prevalence estimates and to compare the performance of simple definitions with the Rome III criteria.

3.3 Methods

This study compared the prevalence of constipation in the study population using five simple definitions with the prevalence estimated using the Rome III criteria. The sensitivity, specificity and predictive values for each of the simple definitions were determined using the Rome III criteria as the gold standard for chronic constipation and modified Rome III criteria for sub-chronic constipation.

3.3.1 Study population

Community-dwelling adults (aged 18 years and over) who were registered with a market research company (Research Now) in April 2015 were invited to participate in an online questionnaire exploring constipation and laxative use. This included questions regarding self-rated health, comorbidities and whether a healthcare professional had been consulted for constipation. The market research company received payment for the work and ensured that the final sample was representative of the Australian population with respect to gender, age and location by state.

Informed consent from all participants was obtained prior to completion of the online questionnaire and participants were paid a nominal fee by the market research company as compensation for their time. Survey responses were confidential and the identity of the participants was not revealed to the researchers.

3.3.2 Constipation definitions

Rome criteria

At the time that this survey was conducted (2015), the current Rome criteria were Rome III (Table 1).

Chronic constipation was defined as meeting the Rome III criteria i.e. two or more symptoms as outlined in Table 1 for the last 3 months, with onset of symptoms being at least 6 months prior. A modification to the Rome III criteria was recently proposed for the identification of sub-chronic constipation whereby symptoms are assessed over 3 months as per the definition of chronic constipation but without the requirement for 6 months onset of symptoms (Koloski, Jones, Young, &

Talley, 2015). This definition of sub-chronic constipation was also used since some simple definitions are based on a time period of 3 months. Both of these definitions were used as the gold standards in this study i.e. Rome III criteria for chronic constipation and the modified Rome III criteria for sub- chronic constipation.

In the online survey, validated questions regarding each of the symptoms specified in the Rome III criteria were used to determine chronic and sub-chronic constipation (Drossman et al, 2006).

Rome III Diagnostic Criteria (Drossman et al, 2006).

Diagnostic criteria* 1. Must include two or more of the following: a. Straining during at least 25% of defaecations b. Lumpy or hard stools in at least 25% of defaecations c. Sensation of incomplete evacuation for at least 25% of defaecations d. Sensation of anorectal obstruction/blockage for at least 25% of defaecations e. Manual manoeuvres to facilitate at least 25% of defaecations (e.g. digital evacuation, support of the pelvic floor) f. Fewer than 3 defaecations per week. 2. Loose stools are rarely present without the use of laxatives 3. Insufficient criteria for irritable bowel syndrome *Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis

Table 3.1: The Rome III diagnostic criteria for defining chronic constipation

Simple definitions

A literature search was conducted to identify simple definitions other than the Rome criteria, which have been used in studies reporting the prevalence of constipation. Five simple definitions were identified: self-reported constipation over the past 2 weeks, self-reported constipation over the past

3 months, self-reported constipation over the past 12 months, fewer than 3 bowel motions per week over the past 3 months and fewer than 3 bowel motions per week over the past 12 months.

In the online survey, self-reported constipation over 2 weeks, 3 months or 12 months was assessed using the questions: “Have you felt constipated at any time during the last 2 weeks (or 3 months or

12 months)?”. Constipation defined by fewer than 3 bowel motions per week over 3 months was assessed using the question: “Over the last 3 months, do you often have fewer than 3 bowel movements each week?”. Constipation defined by fewer than 3 bowel motions per week over 12 months was assessed using the question: “In the last 12 months, how many bowel movements did you usually have each week?”.

3.3.3 Sample size

Based on an estimated prevalence of 30% (Howell, Quine, & Talley, 2006), a minimum of 2000 participants were required to give a prevalence estimate within 2 percentage points using a 95% confidence interval (Epi-Info Version 7, Centers for Disease Control & Prevention).

3.3.4 Analysis

Descriptive statistics were used to describe the study population. Chi-squared testing was used to check the representativity of the study population against the national population in terms of gender, age, and location (Australian Bureau of Statistics, 2015).

The prevalence of constipation in the study population was calculated for each definition as the number of individuals identified with constipation according to each definition, divided by the number of individuals in the study population.

To determine how well each definition performed at identifying constipation compared with the gold standards, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for each simple definition using the Rome III criteria (chronic constipation) and modified Rome III criteria (sub-chronic constipation) as the gold standards.

Sensitivity was calculated as the proportion of participants who were considered “constipated” by the simple definition out of those considered “constipated” by the gold standard. Specificity was determined as the proportion of participants who were considered “not constipated” according to the test definition out of those considered “not constipated” by the gold standard. The positive predictive value (PPV) was calculated as the proportion of participants considered “constipated” by the gold standard out of those considered “constipated” by the simple definition and the negative predictive value (NPV), the proportion of participants considered “not constipated” by the gold standard out of those participants considered “not constipated” by the simple definition (Peacock &

Peacock, 2011).

A simple definition that could substitute for the Rome III criteria would have high values for sensitivity, specificity, PPV and NPV. Ideally each value should be close to 100% indicating that the

63 definition is correctly identifying those with and without constipation according to the gold standard

(Simundic, 2009).

All statistical analysis was conducted using IBM SPSS Statistics (Version 22, IBM Corporation).

3.3.5 Ethics approval

The study was reviewed and approved by the Human Research Ethics Committee of the University of

Sydney (Protocol number 2015/006) (Appendix 2).

3.4 Results

3.4.1 Study population

The market research company invited 29174 community-dwelling adults to participate in the online survey and the questionnaire was completed by 2376 (8.1%) respondents. After elimination of incorrectly completed questionnaires, the study population comprised 2024 participants.

Participants were representative of the Australian community-dwelling adult population in terms of gender, age and location (Table 3.2). Half of the study population were aged over 45 years (50.6 %) and half (50.7%) were female. In the past year, 13% of the study population had consulted a health care professional regarding constipation and 37% had used one or more laxatives. Detailed analysis of laxative use and healthcare professional consultation is presented in later chapters of this thesis.

Table 3.2: Study population characteristics (n=2024).

Characteristic % (Number of National p value participants) population (Australian n=2024 Bureau of Statistics, 2015)

Gender: Female 50.7% (1027) 50.6% 1

Age (years): 0.999

18-24 12.4% (250) 12.4%

25-34 17.8% (361) 18.2%

35- 44 17.6% (357) 18.8%

45-54 18.5% (374) 18.1%

55-64 14.6% (296) 15.3%

65+ 19.1% (386) 17.2%

Location (state): 0.999

NSW 30.9% (627) 32.0%

Vic 24.9% (504) 24.9%

Qld 20.9% (423) 20.1%

SA 8.1% (163) 7.2%

WA 10.0% (203) 11.0%

Tas 2.1% (42) 2.2%

NT 0.9% (19) 1.0%

ACT 2.1% (43) 1.6%

Self-rated health status: Poor 4.0% (80)

Comorbidities: IBSa 9.3% (189)

Diabetes 7.5% (152)

Depression 12.9% (262)

HCPb consulted for constipationc 13.2% (268)

Laxative usec 36.9% (747) a IBS = Irritable bowel syndrome (medically diagnosed) b HCP = Health care professional c In last 12 months

3.4.2 Prevalence

Using the Rome III criteria, 24.0% of the study population had chronic constipation and 39.6% had sub-chronic constipation (Table 3.3). Using the simple definitions, the prevalence estimates varied six-fold, from 9.4% using “fewer than 3 bowel motions per week in the past 12 months” to 58.9% with “self-reported constipation in the past 12 months”. The prevalence estimate using “self- reported constipation in the past 2 weeks” (24.9%, 95% CI 22.9-26.8) was comparable to that that obtained by the Rome III criteria for chronic constipation (24.0%, 95% CI 22.1-25.9).

The most common Rome III criteria symptoms reported by participants were straining, hard stools and a feeling of incomplete evacuation of stools, each of which were reported by approximately 80% of those with chronic constipation (Table 3.4). The least common symptom was the need for manual manoeuvres to assist defaecation. Approximately 40% of participants with chronic or sub-chronic constipation reported having fewer than 3 bowel motions per week.

Table 3.3: Impact of constipation definitions on prevalence estimate

Definition % Prevalence estimate

(95% Confidence Interval)

Chronic constipation (Rome III criteria) 24.0 (22.1, 25.9)

Sub-chronic constipation (modified Rome III criteria) 39.6 (37.5, 41.7)

Self-reported constipation in the past 2 weeks 24.9 (22.9, 26.8)

Self-reported constipation in the past 3 months 29.2 (27.2, 31.2)

Self-reported constipation in the past 12 months 58.9 (56.8, 61.0)

Fewer than 3 bowel motions per week in the past 3 months 19.6 (17.9, 21.3)

Fewer than 3 bowel motions per week in the past 12 months 9.4 (8.1, 10.7)

Table 3.4: Prevalence of symptoms associated with constipation as per the Rome III criteria

Symptom All participants Participants with chronic Participants with sub-chronic constipation according to the constipation according to the (n = 2024) Rome III criteria modified Rome III criteria

(n = 485) (n = 801)

Fewer than 3 bowel motions per week 19.6% (397) 46.2% (224) 42.1% (337)

Straining 29.2% (590) 79.2% (384) 70.8% (567)

Hard stools 36.8% (744) 78.8% (382) 75.8% (607)

Incomplete evacuation 38.4% (778) 82.9% (402) 77.3% (619)

Perceived blockage 22.5% (457) 64.1% (311) 55.8% (447)

Manual manoeuvres 11.0% (222) 35.5% (172) 26.2% (210)

3.4.3 Performance of simple definitions

No simple definition met our criteria for substitution of the Rome III criteria for either chronic or sub-chronic constipation i.e. none of the definitions had values greater than 80% (Peacock &

Peacock, 2011) for each statistical measure i.e. sensitivity, specificity, PPV and NPV (Table 3.5).

The simple definition with the highest sensitivity for identifying both chronic and sub-chronic constipation was “self-reported constipation over past 12 months”. This definition identified 91% of individuals who were considered to have chronic constipation according to the Rome III criteria.

While the sensitivity of this definition was high, the specificity was much lower (51%) indicating that the definition incorrectly classified 49% of participants who were not constipated according to the

Rome III criteria as being constipated. The PPV for this definition was 37%, finding that of all the participants considered constipated by this definition, only 37% were also considered constipated by the gold standard (Rome III). Similarly, for sub-chronic constipation, this definition correctly identified 84% of individuals but it had the lowest specificity (58%) and lowest PPV (57%) of any of the simple definitions when tested against the modified Rome III criteria.

The two simple definitions based on fewer than three bowel motions per week had high specificities, i.e. they correctly identified most participants who were not constipated using both the Rome III and modified Rome III criteria. However, the sensitivities associated with these definitions were very low

(17 to 46%), showing that these definitions were unable to identify all of those constipated according to the Rome III criteria.

Table 3.5: Sensitivity, specificity, positive and negative predictive values for the five simple definitions compared to the Rome III criteria and modified

Rome III criteria as gold standards

Gold standard Simple definition Sensitivity Specificity Positive Predictive Value Negative Predictive Value (PPV) (NPV) (95% Confidence (95% Confidence interval) interval) (95% Confidence interval) (95% Confidence interval)

Chronic Self-reported constipation over past 2 weeks 64.5% (60.2, 68.7) 87.7% (85.9, 89.2) 62.2% (57.9, 66.4) 88.7% (87.0, 90.2) constipation (Rome III criteria) Self-reported constipation over past 3 months 72.0% (67.8, 75.8) 84.3% (82.4, 86.1) 59.2% (55.1, 63.0) 90.5% (88.9, 91.9) Self-reported constipation over past 12 91.1% (88.8, 93.4) 51.3% (48.8, 53.8) 37.1% (34.4, 39.9) 94.5% (93.1, 96.1) months

Fewer than 3 bowel motions per week over 46.2% (41.8, 50.6) 88.8% (87.1, 90.2) 56.4% (51.5, 61.2) 84.0% (82.1, 85.7) past 3 months

Fewer than 3 bowel motions per week over 17.3% (14.2, 20.1) 93.0% (91.7, 94.2) 44.0% (37.1, 51.1) 78.1% (76.2, 80.0) past 12 months

Sub-chronic Self-reported constipation over past 2 weeks 50.6% (47.1, 54.0) 92.0% (90.3, 93.4) 80.5% (76.8, 83.7) 39.6% (37.5, 41.7) constipation (modified Rome III Self-reported constipation over past 3 months 61.3% (57.9, 64.6) 91.9% (90.3, 93.3) 83.2% (80.0, 86.0) 78.4% (76.2, 80.4) criteria) Self-reported constipation over past 12 84.3% (81.6, 86.6) 57.7% (54.9, 60.5) 56.6% (53.8, 59.4) 84.9% (82.3, 87.1) months

Fewer than 3 bowel motions per week over 42.1% (38.7, 45.5) 95.1% (93.7, 96.2) 84.9% (81.0, 88.1) 71.5% (69.2, 73.6) past 3 months

Fewer than 3 bowel motions per week over 16.9% (14.4, 19.6) 95.4% (94.1, 96.5) 70.7% (63.9, 76.7) 63.7% (61.4, 65.8) past 12 months

3.5 Discussion

This study found that the definition of constipation used to estimate prevalence has considerable impact on the estimates of prevalence obtained. We found six-fold differences in the prevalence of constipation estimated using different definitions. Using the Rome III criteria in a large nationally representative sample of community-dwelling adults, we estimate that one in four adults is chronically constipated. None of the simple definitions tested in this study performed well enough in terms of sensitivity, specificity, PPV and NPV to be considered as suitable proxies for definitions of chronic or sub-chronic constipation based on the Rome III criteria.

Using the Rome III criteria, we estimated the prevalence of chronic constipation in the Australian community-dwelling adult population to be 24.0%. Previous studies have estimated the prevalence of chronic constipation among Australian adults to range from 2.8 to 30.7% (Boyce, Talley, Burke, &

Koloski, 2006; Bytzer et al., 2001; Howell et al., 2006; Koloski et al., 2015; Koloski, Talley, & Boyce,

2002; Talley, Boyce, & Jones, 1998). Different definitions used in these studies may be the most important factor contributing to the wide range, however, differences in sample populations, sample sizes and data collection methods may also be relevant. Our survey was conducted online with a large nationally representative sample, whereas all previous Australian studies were mail surveys focussed on participants from certain geographical regions within Australia which were unlikely to be representative of the national population.

Although it is frequently difficult to achieve both high sensitivity and high specificity when testing against a gold standard (Peacock & Peacock, 2011), none of the commonly used simple definitions tested in our study adequately identified individuals with constipation compared with the Rome III criteria for either chronic or sub-chronic constipation. To some extent this might have been expected since we compared very simple definitions with a more complex definition as the gold standard but use of sensitivity, specificity, positive and negative predictive values is the appropriate method to quantify the accuracy of alternative diagnostic tests against a definitive gold standard diagnostic test (Peacock & Peacock, 2011). We observed considerable variation in prevalence 71

estimates with the different constipation definitions which indicates that differences in the way constipation is defined may explain the wide variation in the prevalence of constipation reported in the literature (Mugie et al., 2011; Peppas et al., 2008; Suares & Ford, 2011). It also illustrates the importance of using a suitable definition to identify individuals with constipation when conducting prevalence studies. The diversity of estimates of constipation prevalence in the Australian community further illustrates the issue of different results obtained in different studies with different definitions of constipation.

When considering the prevalence of individual symptoms, the most common symptoms were straining, hard stools and incomplete evacuation which have similarly been reported as the three most common core symptoms of constipation in other studies (Patimah, Lee, & Dariah, 2017). Only

42 to 46% of participants who were regarded as constipated (sub-chronic or chronic) by the Rome III criteria reported experiencing fewer than 3 bowel motions per week. Also, less than 20% of all participants reported fewer than 3 bowel motions per week yet almost 60% had self-reported constipation in the last 12 months. Similar findings have been reported in Japan where 28% of participants in an online survey considered themselves to be constipated, but only 8% reported a bowel motion frequency of fewer than 3 per week (Tamura et al., 2016). In our study, simple definitions for identifying constipation which used bowel motion frequency performed poorly against the Rome III criteria, demonstrating that bowel motion frequency should not be used to identify constipation, unless used as one of the symptoms of the Rome criteria.

Other research has found that estimates of prevalence using self-reported constipation are greater than prevalence figures for chronic constipation derived from Rome criteria in the same population

(Garrigues et al., 2004; Jun et al., 2006; Pare, Ferrazzi, Thompson, Irvine, & Rance, 2001; Sorouri et al., 2010). We found that self-reported constipation over 2 weeks approximated the Rome III prevalence estimate for chronic constipation. However, importantly both the sensitivity and PPV of the simple definition, “self-reported constipation in the past 2 weeks”, were low, indicating that this simple definition did not identify the same individuals with constipation as identified by the Rome III

criteria. One factor to consider is that self-reported constipation is any constipation experienced during the defined time period whereas unmodified Rome criteria provide an indication of chronic constipation only. A further consideration is that with self-reported constipation, constipation is self- defined and consequently different individuals may have different perceptions of constipation

(Mueller-Lissner & Wald, 2010; Mugie et al., 2011; Tvistholm, Munch, & Danielsen, 2017). It could be argued that this is the true definition of constipation which should be used in clinical practice but in prevalence studies of any constipation, our results suggest that defining constipation as “self- reported constipation for the last 3 months” might be considered as an alternative to other constipation definitions since it compared more favourably to the gold standards for both chronic and sub-chronic constipation than the other definitions in terms of sensitivity, specificity, PPV and

NPV. This definition could also possibly be considered for use in clinical practice as an alternative to the Rome III definitions, or at least to identify individuals prior to further clinical investigation of the extent of their constipation.

Our study showed that the period of time used in the simple definitions affected the estimated prevalence. Looking at the three definitions using self-reported constipation, as the time period increased the estimated prevalence also increased, as might be expected in any estimate of period prevalence (Harkness, 1995). Also, the time periods which have been used with self-reported constipation often differ to the periods specified in the Rome criteria. Many international epidemiological studies have used self-reported constipation over 12 months as the definition of any constipation but our results indicate that this may over-estimate the prevalence of constipation.

A major strength of our study is that it was conducted in a large population-based sample which was nationally representative in terms of age, gender and location of the Australian community-dwelling adult population. One limitation of our study was that although we asked if participants had been medically diagnosed with irritable bowel syndrome (IBS), we did not include questions regarding the

Rome III diagnostic criteria for IBS. Consequently, our estimated prevalence of 24.0% using the Rome

III criteria may include both functional constipation and constipation due to IBS. This may be one

reason why our prevalence estimates for chronic and sub-chronic constipation were much higher than the most recent study in Australia where it was estimated that almost 4% of the population may experience constipation-predominant IBS (Koloski et al., 2015). Furthermore, it should be noted that, although our survey was conducted prior to publication of Rome IV criteria, the Rome IV criteria for functional constipation are essentially the same as Rome III criteria (Lacy et al., 2016).

Laxative use was not considered in this analysis and may be a potential confounder in assessing stool frequency and self-reported constipation. A further limitation is the possibility that those with constipation were more likely to complete the questionnaire resulting in some selection bias which may in turn over-estimate the prevalence.

3.6 Conclusion

This study highlights the importance of careful selection of the definition since it has a major bearing on the estimated prevalence of constipation. All of the simple definitions included in this study are commonly used in research, yet none provided a valid alternative to the Rome III criteria which are considered to be the gold standard for diagnosis of chronic constipation, or to the modified Rome III criteria for diagnosis of sub-chronic constipation.

3.7 References

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Mueller-Lissner, S. A., & Wald, A. (2010). Constipation in adults. BMJ Clinical Evidence, 7:413.

Mugie, S. M., Benninga, M. A., & Di Lorenzo, C. (2011). Epidemiology of constipation in children and adults: a systematic review. Best Practice & Research in Clinical Gastroenterology, 25(1), 3- 18.

Nyrop, K. A., Palsson, O. S., Levy, R. L., Von Korff, M., Feld, A. D., Turner, M. J., & Whitehead, W. E. (2007). Costs of health care for irritable bowel syndrome, chronic constipation, functional diarrhoea and functional abdominal pain. Alimentary Pharmacology & Therapeutics, 26(2), 237-248.

Patimah, A. W., Lee, Y. Y., & Dariah, M. Y. (2017). Frequency patterns of core constipation symptoms among the Asian adults: A systematic review. BMC Gastroenterology, 17(1),115.

Peacock J.L., & Peacock, P.J. (2011). Oxford Handbook of Medical Statistics (1st ed.): Oxford University Press.

Peppas, G., Alexiou, V. G., Mourtzoukou, E., & Falagas, M. E. (2008). Epidemiology of constipation in Europe and Oceania: a systematic review. BMC Gastroenterology, 8(5).

Schmidt, F. M. Q., & Santos, V. L. C. d. G. (2014). Prevalence of constipation in the general adult population: an integrative review. Journal of Wound, Ostomy, & Continence Nursing, 41(1), 70-76.

Simundic, A. M. (2009). Measures of diagnostic accuracy: Basic definitions. EJIFCC, 19(4), 203-211.

Singh, G., Lingala, V., Wang, H., Vadhavkar, S., Kahler, K. H., Mithal, A., & Triadafilopoulos, G. (2007). Use of health care resources and cost of care for adults with constipation. Clinical Gastroenterology & Hepatology, 5(9), 1053-1058.

Talley, N. J., Boyce, P., & Jones, M. (1998). Identification of distinct upper and lower gastrointestinal symptom groupings in an urban population. Gut, 42(5), 690-695.

Tvistholm, N., Munch, L., & Danielsen, A. K. (2017). Constipation is casting a shadow over everyday life - a systematic review on older people's experience of living with constipation. Journal of Clinical Nursing, 26(7-8), 902-914.

Chapter 4: Chronic constipation in the community: a national survey of Australian adults

Werth, B.L., Williams, K.A., Fisher, M.J. & Pont, L.G. (2019). Chronic constipation in the community: a national survey of Australian adults. This manuscript has been submitted to Journal of Wound, Ostomy & Continence Nursing in September 2018.

4.1 Abstract

Purpose: The aim of this study was to determine the prevalence of chronic constipation and identify factors associated with chronic constipation in community-dwelling adults.

Design: Cross-sectional study.

Methods: A large sample of community-dwelling Australian adults completed an online questionnaire exploring symptoms, management and factors potentially associated with constipation. Chronic constipation was defined using the Rome III criteria. A multivariate logistic regression model was used to identify factors associated with chronic constipation.

Results: A total of 1,978 participants completed the survey. The prevalence of chronic constipation was 23.9%. Factors significantly associated with chronic constipation in the multivariate model were female gender (OR = 1.42), current employment (OR=1.45), regular smoking (OR=1.60), poor self- rated health (OR=2.57), thyroid disease (OR=1.77), depression (OR=1.49), haemorrhoids (OR=2.98), irritable bowel syndrome (OR=2.45), use of anti-inflammatory/antirheumatic medications (OR=2.06) and use of medications acting on the renin-angiotensin system (OR=0.47).

Conclusions: Chronic constipation is common among community-dwelling adults. Various factors associated with chronic constipation have been identified and knowledge of these factors may help health care professionals recognize individuals who are at high risk of chronic constipation.

4.2 Introduction

Chronic constipation has a considerable impact on both the individual and society. It adversely impacts health outcomes and quality of life (Dennison et al., 2005), and, because of the associated costs of health care professional consultations, diagnostic testing, treatments, and in some cases hospitalisation (Ansari, Ansari, Hutson, & Southwell, 2014), it represents a major financial burden in the community.

Systematic reviews have shown that the prevalence of constipation can vary from 2% to 35% of community-dwelling adult populations around the world (Mugie, Benninga, & Di Lorenzo, 2011;

Suares & Ford, 2011). One explanation for this wide range is that different definitions of constipation have been used in different studies despite the Rome criteria being an internationally accepted definition for the diagnosis of chronic constipation (Drossman, 2016). A further issue is the fact that many studies have used samples that are not necessarily representative of the general population and may not have adequate sample size to accurately estimate the prevalence.

A number of factors commonly associated with constipation have been identified in the literature.

These have included female gender, older age, low socioeconomic status and low levels of education

(Mugie et al., 2011; Peppas, Alexiou, Mourtzoukou, & Falagas, 2008; Schmidt & de Gouveia Santos,

2014; Suares & Ford, 2011). Other factors such as low exercise levels, dietary factors, low fluid intakes, certain medications and certain medical conditions are widely considered to be associated with constipation in community-dwelling adults but there is little evidence for these in population- based studies (Leung, 2007; Muller-Lissner, Kamm, Scarpignato, & Wald, 2005).

In view of the wide prevalence estimates and variable information on the factors associated with constipation, large-scale studies addressing these are needed. Therefore, the aim of this study was to determine the prevalence of chronic constipation and identify factors associated with chronic constipation in Australian community-dwelling adults.

4.3 Methods

4.3.1 Study design and population

A market research company was commissioned to provide a sample of 2,000 adults that was representative of the general Australian adult population with respect to gender, age groups and location by state. Community-dwelling adults (aged 18 years and over) registered with the market research company were invited in April 2015 to participate in an internet survey to explore constipation and laxative use. Informed consent from all participants was obtained online prior to completion of the questionnaire and participants were paid a nominal fee by the market research company as compensation for their time. Since the survey was conducted by the market research company, survey responses were confidential and the identity of the participants was not revealed to the researchers.

4.3.2 Questionnaire design

A draft questionnaire exploring constipation and its management was developed by the researchers.

Questions used to identify participants with chronic constipation were based on the symptoms detailed in the Rome III criteria (Longstreth et al., 2006). Questions regarding factors potentially associated with chronic constipation were based on various factors previously reported in the literature to be possibly associated with constipation (Leung, 2007; Mugie et al., 2011; Muller-

Lissner et al., 2005; Peppas et al., 2008; Schmidt & Santos, 2014; Suares & Ford, 2011). The draft questionnaire was reviewed by an expert panel of three gastroenterologists and three pharmacists to ensure face and content validity. It was then pilot tested in a sample of community-dwelling adults (n=21) of various ages to ensure that the questions were understandable and relevant.

Feedback from the expert panel and pilot sample was used to revise the questionnaire. The final questionnaire comprised 76 questions organised into six sections: participant demographics, symptoms, treatment, prevention, prescription and non-prescription medications used, and factors possibly associated with constipation including comorbidities (See Appendix 1 for copy of questionnaire). 81

4.3.3 Sample size

For the sample size calculation, a conservative estimate of 30% prevalence of constipation was used

(Howell, Quine, & Talley, 2006). Using this estimate, a sample size target of 2,000 participants would allow estimation of the prevalence of within 2 percentage points either side of the estimated prevalence using a 95% confidence interval. The sample size calculation was performed using Epi-

Info (Version 7, Centers for Disease Control & Prevention).

4.3.4 Analysis

Medications were coded using the World Health Organisation Anatomical Therapeutic Classification

(ATC) and all medications were analysed at the therapeutic sub-group level (ATC level 2) (WHO,

2017).

Categorical variables were described as numbers and percentages, and continuous variables as means and standard deviations. The prevalence of chronic constipation was calculated as the percentage of participants with chronic constipation as defined by the Rome III criteria divided by the total number of participants. One of the Rome III criteria, the presence of loose stools without laxative use, was excluded from the analysis as this question was not completed satisfactorily by the majority of participants. Also, although participants with medically-diagnosed irritable bowel syndrome (IBS) were identified, questions regarding diagnostic confirmation of IBS were not included so participants with IBS were therefore not excluded from the analysis. Such modifications to the Rome III criteria have been used previously by other researchers (Digesu et al., 2010;

Papatheodoridis, Vlachogiannakos, Karaitianos, & Karamanolis, 2010; Rey, Balboa, & Mearin, 2014;

Schmidt, de Gouveia Santos, de Cassia Domansky, & Neves, 2016).

Potential factors associated with chronic constipation were identified using Chi-squared tests for categorical variables and student’s t-test for continuous variables. Variables where the cell size was fewer than 10 participants were excluded from the analysis. This applied to 1 medical condition and

11 ATC drug groups.

All factors associated with chronic constipation on univariate analysis (p value  0.10) were included in the logistic regression model. Logistic regression was used in order to avoid potentially confounding effects by analysing the association of all the variables identified in univariate analysis.

The alpha level was set to 0.05 for all analyses unless otherwise specified, and no adjustment for multiple testing on univariate analysis was made. All statistical analysis was conducted using IBM

SPSS Statistics (Version 22, IBM Corporation).

4.3.5 Ethics approval

Ethical approval for this study was obtained from the Human Research Ethics Committee of the

University of Sydney (Protocol number 2015/006) (Appendix 2).

4.4 Results

4.4.1 Study population and prevalence of chronic constipation

The survey was completed by 2,033 participants but 55 (2.7%) were excluded from this study because of imprecise answers to questions regarding medications. This left 1,978 participants who were included in the analysis. The sample closely matched the Australian adult population with regards to gender, age and geographic location (Table 4.1). The mean participant age was 46.2 years and females represented 50.9% of the sample. The average completion time for the questionnaire was 12 minutes. The prevalence of chronic constipation was 23.9% and 12.7% of participants had consulted a health care professional for constipation.

Table 4.1: Participant characteristics compared to the Australian adult population (n=1978)

Characteristic Participants Australian adult P value population % n (%) (Australian Bureau of Statistics 2015)

Female 1006 (50.9) 50.6 0.964

Age (years): 0.999

18-24 244(12.3) 12.4

25-34 352 (17.8) 18.2

35-44 351 (17.7) 18.8

45-54 362 (18.3) 18.1

55-64 292 (14.8) 15.3

65 or more 377 (19.1) 17.2

Mean age (standard deviation) 46.20 (16.68)

Location (Australian state): 0.999

New South Wales 612 (30.9) 32.0

Victoria 491 (24.8) 24.9

Queensland 413 (20.9) 20.1

South Australia 158 (8.0) 7.2

Western Australia 200 (10.1) 11.0

Tasmania 42 (2.1) 2.2

Northern Territory 19 (1.0) 1.0

Australian Capital Territory 43 (2.2) 1.6

Education level: N/A

Did not complete high school 419 (21.1%)

Completed high school 703 (35.5%)

University education 856 (43.3%)

Annual household income: N/A

Low (<$50,000) 624 (31.5%)

Medium ($50,000 - $100,000) 777 (39.3%)

High (>$100,000) 577 (29.2%)

Chronic constipation (Rome III criteria) 472 (23.9%)

Reported laxative use in last 12 months 722 (36.5%)

Consulted health care professional for constipation 252 (12.7%) in last 12 months

N/A: Data from Australian Bureau of Statistics for 2015 were not available for comparison. 84

4.4.2 Factors associated with chronic constipation

On univariate analysis, 31 factors were significantly associated with chronic constipation (Table 4.2).

In the multivariate model (Table 4.3), female gender, current employment, smoking, self-rated health, haemorrhoids, irritable bowel syndrome and the use of anti-inflammatory & antirheumatic medications and medications blocking the renin angiotensin system (angiotensin converting enzyme inhibitors and angiotensin receptor blockers) remained associated with chronic constipation.

Comorbid haemorrhoids and irritable bowel syndrome had the strongest associations with chronic constipation.

The model as a whole explained 16.5% (Nagelkerke R squared) of the variance in the presence of chronic constipation.

Table 4.2: Factors associated with chronic constipation on univariate analysis

Factor Participants with Participants without Odds 95% CI P value chronic constipation chronic constipation Ratio

(n= 472) (n=1506)

n (%) n (%)

Female gender 286 (60.6) 720 (47.8) 1.679 1.360, 2.072 <0.001

Age: 0.005

18 to 24 years 60 (12.2) 184 (12.7) Ref

25 to 34 years 104 (22.0) 248 (16.5) 1.286 0.888, 1.863 0.183

35 to 44 years 89 (18.9) 262 (17.4) 1.042 0.714, 1.520 0.832

45 to 54 years 90 (19.1) 272 (18.1) 1.015 0.696, 1.479 0.939

55 to 64 years 64 (13.6) 228 (15.1) 0.861 0.576, 1.287 0.465

65 plus years 65 (13.8) 312 (20.7) 0.639 0.430, 0.949 0.026

Currently working (full or 320 (43.4) 920 (39.2) 1.341 1.077, 1.669 0.009 part-time)

Regular smoker (last 12 110 (23.3) 207 (13.7) 1.907 1.472, 2.470 <0.001 months)

Surgery (last 12 months) 88 (18.6) 189 (12.5) 1.597 1.210, 2.107 0.001

Travel (last 12 months) 296 (62.7) 1057 (70.2) 0.714 0.575, 0.887 0.002

Changed home 71 (15.0) 157 (10.4) 1.521 1.125, 2.057 0.006 environment (last 12 months)

Self-rated health: <0.001

Excellent 24 (5.1) 168 (11.2) 1

Very good 107 (22.7) 497 (33.0) 1.507 0.935, 2.426 0.091

Good 208 (44.1) 553 (36.7) 2.633 1.868, 4.156 <0.001

Fair 102 (21.6) 241 (16.0) 2.963 1.822, 4.818 <0.001

Poor 31 (6.6) 47 (3.1) 4.617 2.475, 8.612 <0.001

Relevant comorbidities:

Mean number of relevant 1.37 (1.53) 0.89 (1.17) <0.001 comorbidities (standard deviation)

Thyroid disease 45 (9.3) 56 (3.7) 2.729 1.816, 4.099 <0.001

Incontinence (urinary) 22 (4.7) 33 (2.2) 2.182 1.259, 3.781 0.004

Depression 97 (20.6) 151 (10.0) 2.321 1.755, 3.070 <0.001

Haemorrhoids 49 (10.4) 44 (2.9) 3.849 2.526, 5.865 <0.001

Arthritis 78 (16.5) 189 (12.5) 1.380 1.036, 1.838 0.027

Hay fever 78 (16.5) 187 (12.4) 1.396 1.048, 1.861 0.022

Anaemia 24 (4.9) 27 (1.8) 2.935 1.676, 5.137 <0.001

Obesity 54 (11.4) 111 (7.4) 1.624 1.152, 2.288 0.005

Irritable bowel syndrome 88 (18.6) 94 (6.2) 3.442 2.520, 4.702 <0.001

Medications:

Drugs for acid disorders 29 (6.1) 60 (4.0) 1.578 1.000, 2.489 0.048 (A02)

Minerals (A12) 52 (11.0) 107 (7.1) 1.619 1.142, 2.294 0.006

Renin-angiotensin agents 16 (3.4) 116 (7.7) 0.420 0.247, 0.717 0.001 (C09)

Lipid modifying agents (C10) 20 (4.2) 111 (7.4) 0.556 0.341, 0.906 0.017

Anti-inflammatory & 31 (6.6) 34 (2.3) 3.043 1.849, 5.009 <0.001 antirheumatic drugs (M01)

Analgesic drugs (N02) 48 (10.2) 83 (5.5) 1.941 1.339, 2.814 <0.001

Antiepileptic drugs (N03) 11 (2.3) 16 (1.1) 2.222 1.024, 4.822 0.038

Fluid intake:

Mean number of cups/day 9.22 (4.84) 8.21 (3.43) <0.001 (standard deviation)

Tea (3+ cups/day) 89 (18.9) 215 (14.3) 1.395 1.063, 1.832 0.016

Herbal or green tea (3+ 45 (9.5) 73 (4.8) 2.069 1.405, 3.046 <0.001 cups/day)

Chinese or Japanese tea (3+ 30 (6.4) 41 (2.7) 2.425 1.497, 3.930 <0.001 cups/day)

Coffee (3+ cups/day) 129 (27.3) 323 (21.4) 1.377 1.087, 1.746 0.008

Cola (3+ cups/day) 54 (11.4) 95 (6.3) 1.919 1.350, 2.727 <0.001

Juice (3+ cups/day) 39 (8.3) 65 (4.3) 1.997 1.323, 3.013 0.001

Note: Only factors with a significant relationship (p <0.05) with chronic constipation are shown (except for age groups).

Table 4.3: Adjusted odds ratios for factors associated with chronic constipation

Factor Odds ratio 95% CI P value

Female gender 1.42 1.12, 1.81 0.004

Currently working 1.45 1.11, 1.88 0.006

(full time or part-time)

Regular smoker (last 12 months) 1.60 1.19, 2.14 0.002

Self-rated health – good* 2.50 1.54, 4.08 <0.001

Self-rated health – fair* 2.45 1.44, 4.16 0.001

Self-rated health – poor* 2.57 1.28, 5.19 0.008

Thyroid disease 1.77 1.21, 2.79 0.014

Depression 1.49 1.08, 2.06 0.016

Haemorrhoids 2.98 1.84, 4.83 <0.001

Irritable bowel syndrome 2.45 1.73, 3.46 <0.001

Anti-inflammatory & antirheumatic 2.06 1.15, 3.68 0.015 drugs (M01)

Agents acting on renin-angiotensin 0.47 0.24, 0.91 0.025 system (C09)

Note: * Reference: Self-rated health – excellent

4.5 Discussion

This study shows that almost one quarter of community-dwelling Australian adults have chronic constipation, with 13% of adults seeking healthcare professional advice for its management and 37% of adults reporting laxative use in the prior year. This is the first Australian study and one of few international studies to have explored chronic constipation in a large nationally representative sample of community-dwelling adults.

4.5.1 Prevalence of chronic constipation

Using the Rome III criteria, we found that 23.9% of Australian community-dwelling adults had chronic constipation. Differences in data collection, constipation definitions and sampling are likely to have considerable impact on the prevalence estimates reported in other studies. Our estimate of prevalence accords with that reported in the Netherlands (24.5%) which also used the Rome III criteria and online data collection method in a large nationally representative sample (Meinds, van

Meegdenburg, Trzpis, & Broens, 2017). The prevalence of chronic constipation in Australian community-dwelling adults has been determined previously using postal surveys of regional populations and the prevalence estimates using various Rome criteria have ranged from 2.8% to

30.7% (Boyce, Talley, Burke, & Koloski, 2006; Bytzer et al., 2001; Howell et al., 2006; Koloski, Jones,

Young, & Talley, 2015; Koloski, Talley, & Boyce, 2002; Ng, Nassar, Hamd, Nagarajah, & Gladman,

2015).

4.5.2 Factors associated with chronic constipation

In this study we identified a number of factors associated with chronic constipation and confirmed a number of factors that were not associated with chronic constipation. As reported also in some other studies, we found no significant association with chronic constipation and income levels

(Bytzer et al., 2001; Howell et al., 2006; Wald et al., 2008), educational levels (Enck, Leinert, Smid,

Kohler, & Schwille-Kiuntke, 2016; Higgins & Johanson, 2004; Wald et al., 2010; Wald et al., 2008),

physical activity (Curtin, Morabia, Bernstein, & Dederding, 1998; Hinkel et al., 2009) and fluid intake

(Hinkel et al., 2009; Rey et al., 2014).

Our results confirm various factors previously shown to be associated with constipation such as haemorrhoids (Chiarelli, Brown, & McElduff, 2000; Schmidt et al., 2016; Talley, Lasch, & Baum, 2009;

Werth, Williams, & Pont, 2017), depression (Haug, Mykletun, & Dahl, 2002; Nellesen, Yee, Chawla,

Lewis, & Carson, 2013), thyroid disease (Talley, Jones, Nuyts, & Dubois, 2003), irritable bowel syndrome (Siah, Wong, & Whitehead, 2016; Suares & Ford, 2011; Wong et al., 2010), female gender

(McCrea, Miaskowski, Stotts, Macera, & Varma, 2009; Mugie et al., 2011; Suares & Ford, 2011), and poor self-rated health (Enck et al., 2016; Werth, Williams, & Pont, 2015). However, we also identified a number of factors associated with chronic constipation in community-dwelling adults which have not been reported previously and require further exploration.

In our study, we found that chronic constipation was 45% higher among individuals who were currently employed than those who were not. Since employment is highly likely to be associated with age, it is probable that age, or other age-related factors, is driving this association rather than employment since there was a higher prevalence of chronic constipation in younger age groups.

Likewise, in our results we found that people who regularly smoked were 60% more likely to have chronic constipation than those who were not regular smokers. A population-based study in the USA

(Choung, Locke, Schleck, Zinsmeister, & Talley, 2007) has also reported an association between smoking and constipation, however because both studies were cross-sectional, further work to explore the temporal relationship between smoking and constipation is needed, particularly since this association has not been reported in population-based studies in other countries (Haug et al,

2002; Lu, Chang, Chen, Luo & Lee, 2006).

In terms of medications potentially associated with constipation, our findings differed considerably from those reported in the literature. There is extensive information regarding medications that increase the risk of constipation due to their pharmacologic actions. Opioids, calcium channel blockers, diuretics and medications with anticholinergic properties all have pharmacological effects

that potentially impact on bowel function and are known to be associated with constipation (Rossi,

2013; Branch, 2009). In our study, seven therapeutic groups were associated with chronic constipation on univariate analysis however once they were entered into the multivariate model the only associations were anti-inflammatory & antirheumatic drugs (ATC M01) and agents acting on the renin-angiotensin system (ATC C09). The ATC grouping of anti-inflammatory & antirheumatic agents comprises mainly systemic nonsteroidal anti-inflammatory medications which are commonly used to treat pain and musculoskeletal conditions. Further work is needed to determine if the potential association observed in our study is solely pharmacological or due to other factors such as limited mobility or other disease-related factors. Similarly, in our study, participants using medications acting on the renin-angiotensin system were less likely to have chronic constipation. This group of drugs is used to treat a number of cardiac conditions and again further work is needed to determine if underlying patient or disease-related factors are contributing to the potential association observed in our study.

It should be noted that the Rome III criteria were the international diagnostic gold standard for chronic constipation at the time this study was conducted. While the Rome IV criteria were released in 2016 the differences between Rome IV and Rome III in terms of chronic constipation were minimal and unlikely to affect interpretation of our results (Lacy et al., 2016).

4.5.3 Strengths and limitations

The main strength of our study is that we surveyed a large, nationally representative sample of community-dwelling adults. Almost 90% of Australian households have computers and internet access, thus an online survey represents an efficient means of conducting a national survey across a large geographical area such as Australia (Australian Bureau of Statistics, 2014-2015).

To improve recall, we provided a list of brands of non-prescription products and used a recall period of only two weeks for all medications. We also asked if the medication was used frequently (most days and/or nights) or only when required. Although the two weeks period improves product recall,

it does not correlate with the time period in the Rome III definition and this may have influenced potential associations between medications and constipation.

Because data was collected via an online questionnaire it is possible that this may influence participation and lead to some selection bias however any potential bias is probably no different to that of traditional survey methods (Aziz et al., 2018). Also, although the stratified sampling ensured that all age groups closely matched Australian census data, only 15.3% (n=59) of the 65+ years age group were 75+ years old.

There were a number of other limitations associated with our study. We asked participants if they had ever been medically diagnosed as having irritable bowel syndrome (IBS) but we did not ask questions regarding symptoms to determine if participants had IBS as per the Rome III criteria or to classify IBS sub-types. We powered the study to detect a prevalence estimate with a defined precision, but as a result the number of participants may have been inadequate for some individual factors. To ensure adequate sample size to explore potential associations between medications and chronic constipation, we grouped medications into therapeutic groups according to the ATC level 2.

However, for some therapeutic groups this includes a large number of individual agents with differing pharmacology and effects, for example N02 includes all analgesics, both opioid and non- opioid, and thus may have resulted in our inability to fully assess associations between the individual medications and constipation.

4.6 Conclusion

Chronic constipation affects a significant proportion of the Australian adult community-dwelling population. Given that only 1 in 10 individuals with constipation seeks advice from a health care professional, understanding the factors associated with constipation may help health care professionals identify individuals presenting for other reasons who are at risk of chronic constipation.

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Peppas, G., Alexiou, V. G., Mourtzoukou, E., & Falagas, M. E. (2008). Epidemiology of constipation in Europe and Oceania: a systematic review. BMC Gastroenterology, 8(5).

Rossi S., ed. Australian Medicines Handbook 2013 (Electronic edition). In: July 2013 ed. Adelaide: Australian Medicines Handbook Pty Ltd; 2013: http://www.amh.net.au/online. Accessed 23rd October 2013.

Schmidt, F. M. Q., & de Gouveia Santos, V. L. C. (2014). Prevalence of constipation in the general adult population: an integrative review. Journal of Wound, Ostomy, & Continence Nursing, 41(1), 70-76.

Talley, N. J., Jones, M., Nuyts, G., & Dubois, D. (2003). Risk factors for chronic constipation based on a general practice sample. American Journal of Gastroenterology, 98(5), 1107-1111.

Talley, N. J., Lasch, K. L., & Baum, C. L. (2009). A gap in our understanding: Chronic constipation and its comorbid conditions. Clinical Gastroenterology and Hepatology, 7(1), 9-19.

Werth, B. L., Williams, K. A., & Pont, L. G. (2017). Laxative use and self-reported constipation in a community-dwelling elderly population: A community-based survey from Australia. Gastroenterology Nursing, 40(2), 134-141.

WHO (World Health Organization) 2017, ATC/DDD Index 2017. https://www.whocc.no/atc_ddd_index/. Accessed 4th September 2017.

Chapter 5: Use of over-the-counter laxatives by community- dwelling adults to treat and prevent constipation: A national cross- sectional study

5.1 Abstract

Background: Constipation is commonly self-managed with over-the-counter laxatives. Little is known about laxative choices, healthcare professional recommendations in laxative selection and laxative effectiveness when used for treatment or prevention of constipation.

Purpose: The study aim was to explore laxative choice, healthcare professional recommendations and laxative effectiveness when laxatives are used for prevention and for treatment of constipation by community-dwelling adults.

Methods: A nationally representative sample of community-dwelling adults in Australia was surveyed. Participants completed an online questionnaire. Z tests for differences in proportions were used to compare the proportion of laxatives by class when used either for treatment or for prevention of constipation by choice of laxative, healthcare professional recommendation and perceived effectiveness.

Results: The questionnaire was completed by 2,024 participants. Laxatives were used by 37%

(n=747) of participants with 31.3%% using laxatives for treatment, 19.3% for prevention, and 49.7% using laxatives for both purposes. The most common laxatives used for treatment and prevention were contact laxatives (39.8% and 31.1% respectively) and bulk-forming laxatives (34.3% and 44.6% respectively). Of all laxatives used, 56.4% of laxatives were chosen with healthcare professional recommendation, and 53.5% of laxatives were found effective.

Conclusion: Laxatives were used both for treatment and for prevention of constipation. However, laxatives are often perceived to be ineffective and healthcare professionals are not always involved in laxative choice. Modified guidelines which address the use of laxatives for both treatment and prevention, and increased healthcare professional involvement in appropriate choice and use of laxatives, may be required to improve constipation management in the community.

5.2 Introduction

Constipation is a common problem in the community (Talley, 2004). In adult populations, the prevalence of chronic constipation can be as high as 30% (Mugie, Benninga, & Di Lorenzo, 2011).

Most community-dwelling adults self-manage the condition and do not seek medical advice (Enck,

Leinert, Smid, Kohler, & Schwille-Kiuntke, 2016; Galvez et al., 2006; Pare, Ferrazzi, Thompson, Irvine,

& Rance, 2001). Self-management usually involves the use of over-the counter (OTC) laxatives which are widely available without prescription from pharmacies, supermarkets and other outlets (Selby &

Corte, 2010; Shibata et al., 2016). OTC laxative products are advertised and promoted directly to consumers in most countries with global sales of over US$5 billion (Credence Research Inc., 2018).

However, advertising and packaging often cause uncertainty about the purpose of an OTC product and this may result in therapeutic failure because of inappropriate product selection (Rolita &

Freedman, 2008; Westerlund, Marklund, Handl, Thunberg, & Allebeck, 2001). Failure of laxatives to treat constipation is a common occurrence and may contribute significantly to the costs of management (Guerin et al., 2014; Selby & Corte, 2010).

Whilst OTC laxatives play an important role in the management of constipation, and healthcare professional guidelines for their use are available (Pare, 2011; Tack et al., 2011; Wald, 2016), laxative utilization by community-dwelling adults for self-management is not clear. Studies in a community- dwelling older population have found that in many cases laxatives are being used where constipation is not reported thus indicating potential use for prevention rather than use for treatment (Werth, Williams, & Pont, 2015; Werth, Williams, & Pont, 2017). This suggests that laxatives may be used for a dual purpose, prevention or treatment of constipation. However, it is unknown if different laxatives are being chosen for treatment and prevention, or if the laxative agents chosen are considered appropriate for the relevant purpose.

There is a paucity of research regarding OTC laxative choice. An Italian study found that family, acquaintances and advertisements can be important factors influencing laxative choice (Motola et 99

al., 2002). Lack of healthcare professional consultation may have implications on the appropriateness of laxative choice and this requires investigation (Shibata et al., 2016).

Although self-management of constipation with laxatives is common in the community, there are limited clinical trials evaluating the efficacy of most OTC laxatives for either treatment or prevention

(Ford & Suares, 2011; Ramkumar & Rao, 2005). Furthermore, studies assessing laxative use in North

American and European populations have reported widespread dissatisfaction with the effectiveness of laxatives in real world settings (Emmanuel et al., 2013; Harris, Horn, Kissous-Hunt,

Magnus, & Quigley, 2017; Johanson & Kralstein, 2007; Muller-Lissner, Tack, Feng, Schenck, & Specht

Gryp, 2013). These studies have focussed primarily on treatment of constipation and no research of laxative effectiveness for the prevention of constipation has been conducted.

The aim of this study was to explore laxative choice for prevention or treatment of constipation in a national sample of community-dwelling adults in Australia. Secondary aims were to determine how often laxatives are recommended by healthcare professionals and how individuals perceive the effectiveness of laxatives when used for treatment or prevention of constipation.

5.3 Methods

5.3.1 Study population and recruitment

A national survey exploring constipation and laxative use among community-dwelling adults was conducted. Participants were recruited using a market research company as an efficient method to recruit participants from a wide general population sample. Community-dwelling adults (aged 18 years and over) who were already registered with the market research company were invited to participate in an online survey. The market research company conducted stratified sampling to ensure that the study population was representative of the general Australian adult population with respect to gender, age group and location, the details of which have been previously published

(Werth, Williams, Fisher & Pont, 2019). Participants were paid a nominal fee by the market research company as compensation for their time. An information sheet was provided and informed consent

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was obtained from each participant prior to completion of a questionnaire. Survey responses were confidential and the identity of the participants was not revealed to the researchers.

5.3.2 Survey questionnaire

Survey participants completed a detailed questionnaire exploring constipation and laxative use. The questionnaire was reviewed by a panel of experts and pilot tested in a small sample (n=21) before being finalized for use in the survey. Questions included self-reported constipation in the past 12 months, as well as questions used to identify chronic constipation symptoms as per the Rome III criteria (Longstreth et al., 2006).

In the questionnaire, participants were asked to identify, from a comprehensive list of all OTC laxative products which were available in Australia at the time of the survey, all products they had used to treat or prevent constipation over the past 12 months. The list, including both brand and generic names of products, was compiled from market data and pharmacy wholesaler price lists.

OTC laxatives were defined as all medications available in Australia without prescription which are included in the WHO Anatomical Therapeutic Chemical (ATC) Classes: A06AA (Softeners, emollients),

A06AB (Contact laxatives), A06AC (Bulk-forming laxatives), A06AD (Osmotically acting laxatives),

A06AG (Enemas) and A06AX (Other drugs used for constipation) (WHO, 2017). Food products such as bran, and products only available on prescription such as peripheral opioid receptor antagonists

(A06AH) and prucalopride (A06AX05), were excluded.

Treatment of constipation was defined in the questionnaire as using laxative products to treat the problem when constipation is experienced in order to relieve the symptoms. Prevention was defined as using laxative products to prevent constipation occurring, which assumes that constipation had been experienced at some time in the past. For each laxative reported for treatment, participants were asked why the particular product was chosen, in particular if it was recommended by a doctor or pharmacist, and if they were satisfied that the laxative was effective for the treatment of constipation. Self-reported effectiveness was defined as successful treatment of most constipation

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symptoms. The same questions were repeated for laxative products used for prevention of constipation.

5.3.3 Sample size

The study was powered to detect a prevalence of chronic constipation of 30% to a precision of 2 percentage points either side of the estimated prevalence, giving a target sample size of 2,000

(Mugie et al., 2011). Based on a prevalence of laxative use of 14% (Chinzon, Dias-Bastos, Medeiros da Silva, Eisig, & Latorre, 2015; Galvez et al., 2006), 2,000 participants allow the prevalence of laxative use to be calculated with 95% confidence within a precision of 1.5 percentage points either side of the estimated prevalence. Sample size estimates were calculated using Epi-Info (Version 7,

Centers for Disease Control & Prevention).

5.3.4 Analysis

Laxatives were grouped using the WHO Anatomical Therapeutic Chemical (ATC) Classification level 4.

Since this classification level does not differentiate between oral and rectal use, with the exception of laxatives administered via enema, suppositories were grouped as “suppositories” rather than using the ATC classification.

Descriptive statistics were used to describe the study population. To examine differences in laxative choice for treatment and prevention, the proportion of laxatives from each laxative class was determined. Differences in the choice of laxatives, healthcare professional recommendation and perceived effectiveness of laxatives used for prevention and treatment were tested using Z tests for differences in proportions (Statistics).

Analysis of the survey data was conducted using IBM SPSS Statistics (Version 24, IBM Corporation).

5.3.5 Ethics approval

Ethical approval for the study was obtained from the Human Research Ethics Committee of The

University of Sydney (Protocol number 2015/006) (Appendix 2).

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5.4 Results

The survey questionnaire was completed by 2,024 participants. The mean participant age was 46.2 years and 50.7% of participants (n=1027) were female. The average completion time for the questionnaire was 12 minutes.

Approximately one third (747/2024, 36.9%) of participants reported using an OTC laxative product in the past 12 months (Table 5.1). Laxative users were slightly younger than non-users, more likely to be female and to have chronic constipation. Over 60% of laxative users (61.2%, n=457) reported using more than one laxative product during the previous 12 months, with slightly more laxative users using laxative products for treatment (85.9%, n=642) than for prevention (80.7%, n=603). Of those reporting laxative use, 19.3% (n=144) used laxatives only for prevention of constipation, 31.3%

(n=232) used laxatives only for treatment, and half used laxatives for both purposes (49.7%, n=371).

Also 14.5% of laxative users (n=108) did not report any constipation in the previous 12 months. Of those participants reporting constipation in the previous 12 months, 43.3% reported no laxative use at all.

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Table 5.1: Participant characteristics n (%)

Characteristic Laxative use in the past No laxative use in the 12 months past 12 months n=747 n=1277 Age category 18-24 87 (11.6) 163 (12.8) (years) 25-34 162 (21.7) 199 (15.6) 35-44 144 (19.3) 213 (16.7) 45-54 145 (19.4) 229 (17.9) 55-64 89 (11.9) 207 (16.2) >=65 120 (16.1) 266 (20.8) Gender Female 420 (56.2) 607 (47.5)

Constipation Chronic constipation 313 (41.9) 172 (13.5) (Rome III criteria)

Self-reported 639 (85.5) 553 (43.3) constipation in last 12 months Laxative 1 laxative product 290 (38.8) - products used in last 12 2 laxative products 255 (34.1) - months >2 laxative products 202 (27.0) - Mean number of 1.81 - laxative products used per person Reason for Treatment 642 (85.9) - laxative usea Prevention 603 (80.7) - a Figures do not total 100% as participants may identify the same laxative for both treatment and prevention of constipation.

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Bulk-forming and contact laxatives were the most commonly used classes for the treatment of constipation; the most commonly used laxative class for the prevention of constipation was bulk- forming agents (Table 5.2). Products containing ispaghula (n=237/724, 32.7%) were the most commonly used products for the prevention of constipation. For treatment of constipation, the most commonly used products were those containing ispaghula (n=234/961, 24.3%) and those containing senna (n=229/961, 23.8%). All laxative classes were used for both treatment and prevention of constipation. This included rectal preparations (suppositories and enemas) although total usage was relatively low. Laxative choices for treatment and prevention were similar for all classes except for contact laxatives and bulk-forming laxatives; the latter were more likely to be used for prevention and the former were more likely to be used for treatment. Laxatives were used daily in 20% of cases when used for treatment (20.0%,192/961) and in 26% of cases when used for prevention (26.2%,

190/724).

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Table 5.2: Number of laxatives used by laxative class and purpose of use

Laxative class Treatment of constipation Prevention of constipation pb Number (%) of laxatives used Number (%) of laxatives used Softeners, 78 (8.1) 59 (8.1) 0.984 emollients (A06AA)

Contact laxatives 382 (39.8) 225 (31.1) <0.001 (A06AB)

Bulk-forming 330 (34.3) 323 (44.6) <0.001 laxatives(A06AC)

Osmotically acting 126 (13.1) 89 (12.3) 0.617 laxatives (A06AD)

Enemas (A06AG) 29 (3.0) 15 (2.1) 0.226

Suppositoriesc 16 (1.7) 13 (1.8) 0.841

TOTAL 961 724

Note. b Z test for the difference in proportion c Includes products containing bisacodyl or glycerol as active ingredients

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No differences were found in the proportions of laxatives used for treatment or prevention where healthcare professional recommendations were involved (Table 5.3). In total, healthcare professional recommendations accounted for over half of the laxatives chosen (56.4%, n=950/1685), with doctors accounting for 36.4% (n=613/1685) and pharmacies accounting for 20.0%

(n=337/1685); self-selection (21.9%, n=369/1685) or recommendations from family or friends

(21.7%, n=366/1685) accounted for the remainder. The majority of pharmacy recommendations were made by a pharmacist (80.1%, 270/337), with other pharmacy staff accounting for the remainder. Three quarters of self-selected laxatives were chosen based on either product advertising (48.2%, n=178/369) or information from the internet (27.1%, n=100/369). More than half of the bulk-forming agents (54.4%, 355/653) and 40% of contact laxatives (42.7%, 259/607) used for either treatment or prevention were not recommended by a healthcare professional but were the result of family/friend recommendations and self-selection. One in five contact laxatives used for prevention were recommended by a healthcare professional (n=131/607, 21.6%). No differences were found between bulk-forming and contact laxatives used for treatment compared to prevention. Most rectal products were recommended by a healthcare professional (n= 62/73,

84.9%). Laxative products were purchased from pharmacies in almost 60% of cases (56.9%, n=959/1685), with supermarkets and health food stores accounting for the remainder.

Overall, the laxative agents used were perceived to be effective in relieving most symptoms of constipation in approximately half of the uses (53.5%, n=901/1685) with no differences between those used for treatment and those used for prevention except for bulk-forming laxatives which were considered to be less effective for treatment than for prevention (Table 5.4).

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Table 5.3: Healthcare professional recommendation regarding laxative choice by laxative class

Laxative class Percentage of laxatives recommended by a healthcare professional (N/total in class for each purpose (%)) Treatment Prevention pb Softeners, emollients (A06AA) 56/78 (71.8) 45/59 (76.3) 0.56 Contact laxatives (A06AB) 217/382 (56.8) 131/225 (58.2) 0.73 Bulk-forming laxatives(A06AC) 151/330 (45.8) 147/323 (45.5) 0.95 Osmotically acting laxatives 84/126 (66.6) 57/89 (64.0) 0.69 (A06AD) Enemas (A06AG) 24/29 (82.8) 13/15 (86.7) 0.73 Suppositoriesc 13/16 (81.3) 12/13 (92.3) 0.39 All laxative classes 545/961 (56.7) 405/724 (55.9) 0.75

b Note. Z test for the difference in proportion c Includes products containing bisacodyl or glycerol as active ingredients

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Table 5.4: Participant perception of laxative effectiveness by laxative class

Laxative class Perceived effectiveness by laxative class (Number of laxatives rated effective/total in class per purpose (%)) Treatment Prevention pb Softeners, emollients (A06AA) 46/78 (59.0%) 35/59 (59.3) 0.97 Contact laxatives (A06AB) 220/382 (57.6) 117/225 (52.0) 0.18 Bulk-forming laxatives(A06AC) 149/330 (45.2) 173/323 (53.6) 0.03 Osmotically acting laxatives 70/126 (55.6) 50/89 (56.2) 0.93 (A06AD) Enemas (A06AG) 16/29 (55.2) 6/15 (40.0) 0.34 Suppositoriesc 11/16 (68.8) 8/13 (61.5) 0.68 All laxative classes 512/961 (53.3) 389/724 (53.7) 0.86 b Z test for the difference in proportion c Includes products containing bisacodyl or glycerol as active ingredients

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5.5 Discussion

This study found that laxatives were commonly used by considerable laxative use among community-dwelling adults and provides new information about how they are chosen and used.

Laxatives were being used for prevention as well as treatment of constipation with all classes being used for both purposes. In participants reporting laxative use, healthcare professionals recommended products in half of the cases and laxatives were perceived by these participants to be effective in half of all uses.

5.5.1 Utilisation of laxatives

Our results indicate a high level of laxative use, with over a third of participants having used OTC laxatives during the preceding 12 months. This contrasts with surveys of community-dwelling adults in Spain, Germany, USA, Brazil and New Zealand where the prevalence of laxative use has ranged from 4% to 14% (Chinzon et al., 2015; Enck et al., 2016; Galvez et al., 2006; Harari, Gurwitz, Avorn,

Bohn, & Minaker, 1996; Lynch, Dobbs, Keating, & Frizelle, 2001; Rey, Balboa, & Mearin, 2014). This suggests higher laxative use in Australia however this difference may be wholly or partly due to differences in survey design. Firstly, these other surveys did not provide laxative definitions which means that the term was self-defined by participants, nor did they provide lists of available products to facilitate recall. Also, only one survey used a nationally representative sample and two of the surveys did not include older subjects in the samples. Furthermore, none of the surveys were conducted online.

Laxatives clearly play an integral role in the management of constipation in the community. and

However, we found in some cases laxatives were not used and this may have been because the constipation was mild and did not warrant laxative use or the constipation was managed by dietary or some other non-laxative means. When laxatives are used to manage constipation, we have found that all laxative agents, in fact mostly the same agents, are being used for both prevention and treatment of constipation. Although slightly more laxatives were used for treatment, use for prevention was also high. This is in contrast with an earlier Australian study in an older population 110

where it appeared that laxatives were used more for prevention than for treatment (Werth et al.,

2015).

Our results also suggest that laxatives are either being used successfully to prevent constipation, or are being used for a purpose other than constipation management, since 15% of participants reporting laxative use did not report any constipation in the last year. A larger percentage of participants using laxatives but not reporting constipation was found in an older adult population

(Werth et al., 2017), reinforcing the view that laxatives appear to be used successfully for prevention of constipation. This is also indicated by the laxative effectiveness rating of over 50% in preventing constipation by participants in our study.

Almost three quarters of laxatives used were bulk-forming or contact laxatives, the most popular agents being ispaghula and senna. However, the laxatives chosen for prevention and treatment of constipation did not always appear to be appropriate. There was high usage of bulk-forming products such as ispaghula for treatment. Whilst these products are appropriate for prevention, they may not always be the most effective for treatment of constipation (Ford & Talley, 2012).

Contact laxatives such as senna and bisacodyl were used mostly for treatment but they were also used for prevention in some cases. The use of such contact laxatives for prevention may be viewed with concern, particularly if used on a daily basis, because of the possibility of adverse effects such as ionic alterations, alterations in colonic motility, enteric changes and mucosal alterations including melanosis coli and colon cancer, with long-term use (Serrano-Falcon & Rey, 2017; Xing & Soffer,

2001). However, until rigorous long-term studies have been conducted, this remains a possibility

(Alsalimy, Madi, & Awaisu, 2018; Noergaard, Anderson, Jimenez-Solem, & Christensen 2019;

Vilanova-Sanchez et al. 2018).

The reality is that OTC laxatives are being used by consumers for both prevention and treatment, either with or without healthcare professional recommendation. However, this dual purpose concept does not appear to be reflected in any published algorithms for the healthcare professional management of constipation (Pare, 2011; Tack et al., 2011; Wald, 2016). Algorithms discuss

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management or treatment of constipation with laxatives but not prevention. It is suggested that constipation management guidelines may need modification to include laxative use for prevention and treatment of constipation, and to nominate which laxative agents are appropriate for each indication.

5.5.2 Healthcare professional recommendation of laxatives

Healthcare professional involvement in laxative product selection occurred in just over half of the cases. This suggests that, although many patients self-diagnose and self-treat constipation, they are not always confident in selecting an appropriate laxative and seek professional recommendation.

This was confirmed in a recent study which found that only 28% of consumers were confident in self- selecting an appropriate laxative (Shibata et al., 2016). Our results show that product advertising and internet information have a major influence on self-selection but this information may not always be reliable, particularly OTC product advertising which has been shown to be often misleading and inaccurate (Faerber & Kreling, 2013; Sansgiry, Sharp, & Sansgiry, 1999). However, pharmacist recommendations of OTC laxatives result in more appropriate choices, and offer the opportunity for providing advice regarding side effects, precautions and contraindications (Shibata et al., 2016).

Clearly there is a need for increased involvement of healthcare professionals in the choice of laxatives in order to optimize laxative use and improve the management of constipation in the community. Because our study showed that the majority of laxative purchases are made in a pharmacy, pharmacists have the potential to play an important role in ensuring appropriate choice and use of OTC laxative products (Horn, 2006; Kua, Ng, Lhode, Kowalski, & Gwee, 2012; Shibata et al., 2016).

Although we have not reported the periods of laxative use, laxatives are often used long-term

(Haring et al., 2013) and it has been postulated that such long-term use should be monitored by healthcare professionals in order to check efficacy and minimize side effects (Haring et al., 2013;

Serrano-Falcon & Rey, 2017). According to Australian clinical guidelines, contact laxatives such as senna should be reserved for short-term treatment (up to 4 weeks) (Selby & Corte, 2010; Australian

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Medicines Handbook, 2019), whereas bulk-forming laxatives such as ispaghula are best used long- term for prevention rather than short-term treatment (Collins & O'Brien, 2015). However, our survey indicates that, as reported by participants, healthcare professionals are not necessarily following this guidance in their recommendations. Of particular concern is the apparent recommendation of rectal products for prevention since such products are generally only used for treatment of acute episodes because of their rapid onset of action (Selby & Corte, 2010; Australian

Medicines Handbook, 2019).

5.5.3 Effectiveness of laxatives

Multiple laxatives were used by 60% of laxative users during the past 12 months, possibly indicating that correct choices for the intended purpose are not always being made, similar to a US study of chronic constipation where 50% switched laxatives during 12 months due to treatment failure

(Guerin et al., 2014). In an earlier Italian study, 70% chose another laxative due to lack of effectiveness (Motola et al., 2002). This is also reflected in our study where participants perceived them to be ineffective for the desired purpose (treatment or prevention of constipation) in almost

50% of uses. Other studies of laxative use in chronic constipation have shown very high levels of dissatisfaction chiefly because of lack of efficacy (Emmanuel et al., 2013; Harris et al., 2017;

Johanson & Kralstein, 2007; Muller-Lissner et al., 2013). This dissatisfaction may be related to the inappropriate choice of laxative agent for the particular constipation subtype or to the fact that not all constipation symptoms were relieved. Refractory cases may require referral to a gastroenterologist for further investigation to establish the subtype and appropriate laxative therapy.

Dissatisfaction with laxatives also extends to healthcare professionals (Harris et al., 2017), indicating that at both professional and patient levels there is a desire for more effective management of constipation. This could be achieved either through improved management guidelines or with more effective laxative agents. Unfortunately, none of the new prescription laxative agents such as lubiprostone, linaclotide, plecanatide and prucalopride have so far shown better efficacy than

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existing OTC laxative agents (Ford & Suares, 2011; Nelson et al., 2017), so revamped management guidelines together with education of healthcare professionals and consumers currently represent the only hope for improving management of constipation in the community.

5.5.4 Strengths and limitations

We used a nationally representative sample of the general adult population and provided an extensive list of laxative products in the questionnaire to enable accurate product recall (Gama,

Correia, & Lunet, 2009). Some potential limitations also need to be acknowledged. Because the survey was only available online, participants without computer access were excluded, however almost 90% of Australian households have internet access so this is unlikely to affect the results

(Australian Bureau of Statistics, 2014-2015). The questionnaire did not enable suppositories to be differentiated by laxative class and did not include questions regarding the use of laxatives for purposes other than constipation (e.g. weight loss). A further limitation is the possibility that those with constipation were more likely to complete the questionnaire resulting in some selection bias which may in turn over-estimate the prevalence of both constipation and laxative use.

5.6 Conclusion

This study indicates that constipation management guidelines may need to consider the use of laxatives for prevention of constipation as well as for treatment of constipation. Along with increased healthcare professional involvement with laxative choice, this could result in optimal use of OTC laxatives and improved management of constipation in the community.

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Australian Medicines Handbook (2019). Adelaide: Australian Medicines Handbook Pty Ltd; July 2019. Available from: https://amhonline-amh-net-au.

Collins, B. R., & O'Brien, L. (2015). Prevention and management of constipation in adults. Nursing Standard, 29(32), 49-58. doi:10.7748/ns.29.32.49.e9571

Credence Research Inc., C. R. (2018). Global laxatives market is expected to reach US$8,734.2 million by 2026 [Press release]. Retrieved from https://globenewswire.com/news- release/2018/03/19/1441968/0/en/Global-Laxatives-Market-is-Expected-to-Reach-US-8- 734-2-Million-By-2026-Credence-Research.html Accessed 27 Nov 2018.

Emmanuel, A., Quigley, E. M. M., Simren, M., Feng, Y., Muller-Lissner, S., Urbain, D., . . . Solomon, D. (2013). Factors affecting satisfaction with treatment in European women with chronic constipation: An internet survey. United European Gastroenterology Journal, 1(5), 375-384.

Faerber, A. E., & Kreling, D. H. (2013). Content analysis of false and misleading claims in television advertising for prescription and nonprescription drugs. Journal of General Internal Medicine 29(1), 110-118.

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Ford, A. C., & Talley, N. J. (2012). Laxatives for chronic constipation in adults. BMJ, 345, e6168.

Gama, H., Correia, S., & Lunet, N. (2009). Questionnaire design and the recall of pharmacological treatments: A systematic review. Pharmacoepidemiology and Drug Safety, 18(3), 175-187.

Guerin, A., Carson, R. T., Lewis, B., Yin, D., Kaminsky, M., & Wu, E. (2014). The economic burden of treatment failure amongst patients with irritable bowel syndrome with constipation or 115

chronic constipation: A retrospective analysis of a Medicaid population. Journal of Medical Economics, 17(8), 577-586.

Haring, B., Pettinger, M., Bea, J. W., Wactawski-Wende, J., Carnahan, R. M., Ockene, J. K., . . . Wassertheil-Smoller, S. (2013). Laxative use and incident falls, fractures and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative. BMC Geriatrics, 13, 38.

Harris, L. A., Horn, J., Kissous-Hunt, M., Magnus, L., & Quigley, E. M. M. (2017). The Better Understanding and recognition of the disconnects, experiences, and needs of patients with chronic idiopathic constipation (BURDEN-CIC Study): Results of an online questionnaire. Advances in Therapy, 34(12), 2661-2673.

Horn, J. (2006). Managing constipation in adults: Patient counseling and triage. U.S. Pharmacist, 31(1), 67-76.

Johanson, J. F., & Kralstein, J. (2007). Chronic constipation: a survey of the patient perspective. Alimentary Pharmacology & Therapeutics, 25(5), 599-608.

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Chapter 6: Laxative use and self-reported constipation in a community- dwelling elderly population

Werth, B.L., Williams, K.A. & Pont L.G. (2017). Laxative use and self-reported constipation in a community-dwelling elderly population. Gastroenterology Nursing 40 (2), 134-141.

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6.1 Abstract

Objectives: To determine the prevalence of laxative use and self-reported constipation, and identify risk factors associated with constipation, in a community-dwelling elderly population.

Methods: A retrospective cross-sectional survey using data from the Australian Longitudinal Study of

Ageing (ALSA) was used to explore laxative use and constipation in a cohort of community-dwelling older persons.

Results: The prevalence of laxative use was 15% and the prevalence of self-reported constipation was 21%. Females were more likely to report constipation and use laxatives. Of those using laxatives, men were more likely to have their laxatives prescribed by a doctor while women were more likely to self-medicate. Poor self-rated health and a higher need for assistance with activities of daily living were identified as risk factors for constipation.

Conclusions: Constipation is a common condition affecting the community-dwelling elderly. There is scope to optimise the management of constipation and use of laxatives in such populations.

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6.2 Introduction

The Australian population is ageing with the majority of the elderly population residing in the community (Luszcz, et al., 2007). Constipation is a major public health issue in the Australian community as it is in most countries (Dennison, et al., 2005; Pinto Sanchez & Bercik, 2011); it is also relatively common condition which is usually self-managed with laxatives (Gallagher & O'Mahony,

2009; McCrea, et al., 2009). For the elderly individual, constipation may have a considerable impact on quality of life and optimal management of constipation is an important health consideration

(Belsey, et al., 2010; Dennison, et al., 2005; Wald, et al., 2007).

The increasing prevalence of constipation in age groups above 60 years has been well documented internationally (Schmidt & de Gouveia Santos, 2014; Suares & Ford, 2011). North American data indicates that the largest increases occur after 70 to 75 years of age (McCrea, et al., 2009).

Internationally there is a wide variation in the prevalence of constipation reported for community- dwelling elderly populations, ranging from 11 to 55% (Chaplin, et al., 2000; Wong, et al., 1999).

Similarly, there is also variation in reported laxative use in this population, ranging from 3% to 15%

(Cusack, et al, 2012; Hanlon, et al, 2001). The reported prevalence of constipation and of laxative use may vary according to study design and the definitions of each used in the study. In contrast to these international studies, the 1995 National Health Survey in Australia reported a prevalence of only

1.9% for laxatives in those aged 65 years or more, with a female/male prevalence ratio of 1.57

(Australian Bureau of Statistics, 1999), while the prevalence of self-defined constipation in the community-dwelling elderly in Australia has been reported to be 22% (Pit, Byles, & Cockburn, 2008).

In addition to increasing age, several other risk factors have been proposed to be associated with constipation in elderly populations. It is generally considered that females are more likely to report constipation than males (Gallegos-Orozco, et al, 2012). Other risk factors which have been reported in elderly populations include low levels of physical activity (Brown, et al., 2000), medical conditions such as stress, stroke, heart conditions (Wong, et al., 1999), and haemorrhoids (Chiarelli, Brown, &

McElduff, 2000), and medications such as diuretics, anticholinergic agents, calcium, nonsteroidal 121

anti-inflammatory drugs, calcium channel blockers, antidepressants and hypnotics (Chiarelli, et al.,

2000; Gallegos-Orozco, et al, 2012; Wong, et al., 1999).

Although there have been a number of studies exploring the prevalence of constipation, less is known about the management of constipation and the use of laxatives in community-dwelling elderly populations. Our study aimed to determine the prevalence of both laxative use and constipation in an elderly cohort residing in the community. We also aimed to explore various risk factors associated with constipation, particularly medical conditions and medications.

6.3 Methods

6.3.1 Data source

Data for this research was provided by the Centre for Ageing Studies, Flinders University. The

Australian Longitudinal Study of Ageing (ALSA) is a study of ageing in the community (Luszcz, et al.,

2007). The study was conducted in South Australia and commenced in 1992 with a cohort of 2,087 participants aged 65 years or older. Participants included in the stratified sample were randomly drawn from the electoral roll. Over the next 14 years, all participants were interviewed and data collected at eight time points. The number of participants was reduced over this time due to a variety of reasons including refusal to participate further, ill health, death or being un-contactable.

The detailed methodology including selection of subjects and survey methods used by ALSA has been published previously (Luszcz, et al., 2007).

While routine data was collected at all data points, additional questions with a specific focus were asked at defined data collection points. In 2003/04, participants were asked questions regarding constipation and medication use; prescription medication data was also accessed.

6.3.2 Study population and inclusion criteria

ALSA participants who participated in the 2003/04 data collection and who were living in the community were included in this study (n = 487). Participants who did not answer the question regarding constipation (n = 30) or who reported a colostomy (n = 3) were excluded from our analysis, as were participants who did not give consent for their prescription medication data to be 122

accessed (n = 140), leaving a total of 239 community-dwelling participants with complete constipation and medication use data who were included in this analysis.

6.3.3 Constipation

Constipation was both self-defined and self-reported. Participants were asked: “Do you have trouble with your bowels which makes you constipated?”. No definition of constipation was provided and no time frame was defined. Participants were also asked: “How often do you usually have a bowel movement?”. Bowel motion frequency has been used in the past as an indicator for constipation, with constipation generally considered to be associated with three or fewer bowel motions per week (Whitehead, et al., 1991).

6.3.4 Medication and laxative use

In this study both self-reported and administrative claims data were used to ensure capture of both prescribed and self-medicated medicines; this included laxatives since they are available both on prescription and over-the-counter.

Self-reported data: Participants were asked to name all medications purchased over-the-counter

(OTC) which they had taken in the last two weeks and to show the medicine container to the interviewer; they were also asked whether the OTC medicine had been prescribed or recommended by a doctor.

Administrative claims data: Prescription medicine data was obtained from the Pharmaceutical

Benefits Scheme (PBS) for the period from September 2003 to April 2004 (8 months). The PBS dataset contains records of all prescribed medicines, the costs of which have been reimbursed by the Australian government.

6.3.5 Potential risk factors for constipation

Potential risk factors for constipation were identified from the literature. These included medical conditions, medications and functional status as well as socio-demographic data. Medical conditions associated with constipation identified in the literature included heart conditions, haemorrhoids, and musculoskeletal problems (Chiarelli, et al., 2000; Wong, et al., 1999). Medications were 123

considered to have the potential to cause constipation if listed as an adverse effect in the Australian

Medicines Handbook (Rossi, 2013). An assessment of activities of daily living (ADL) was used as an indicator of physical function status.

6.3.6 Statistical analyses

Univariate analysis using Pearson’s chi-squared test for categorical data and t-test for continuous data was conducted to identify potential risk factors associated with constipation. Multifactorial logistic regression using the “enter” method was used to calculate adjusted odd ratios for all major risk factors which were associated with constipation on univariate analysis (those with p values below 0.15). For all analyses, p values of 0.05 or less were considered statistically significant. All statistical analysis was conducted using IBM SPSS Statistics (Version 21 IBM Corporation).

6.3.7 Ethics approval

Ethical approval for the ALSA study was obtained from the Clinical Investigation Committee of

Flinders Medical Centre (Minute 1462: Research Application 9/88 dated 22/3/88). All ALSA participants gave written informed consent prior to their inclusion in the study.

6.4 Results

6.4.1 Study population characteristics

Data from 239 community-dwelling older adults who had participated in the ALSA study and met the inclusion criteria for this study were included in this analysis. The majority of the cohort was female

(61%) and the mean age of participants was 84 years (Table 6.1). The majority of participants reported their health to be good, very good or excellent (68.6%) with a reported mean of 5 medical conditions and 11 medications per participant. A mean score of 0.8 for activities of daily living (ADL), an assessment of basic self-care tasks scored from 0 (independent) to 6 (completely dependent), indicated that tasks could be performed independently or with minor difficulty only for the majority of participants.

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Table 6.1: Cohort characteristics (n=239) Demographics

Mean age ± SD (years) 84.2 ± 4.4

Number of female participants 145 (60.7%)

Education

Left school at age 14 years or less 119 (49.8%)

Tertiary or other higher education 88 (36.8%)

Self-rated health

Poor or fair 75 (31.4%)

Good, very good or excellent 164 (68.6%)

Mean activities of daily living (ADL) ± SD 0.80 ± 1.4

Mean number of medical conditions ± SD 5.1 ± 2.7

Mean number of medications (including laxatives) 11.7 ± 6.5 ± SD

Constipation

Number of participants with self-reported 50 (20.9%) constipation

Number of females 35 (14.6%)

Number of males 15 (6.3%)

Number of participants reporting 3 or fewer bowel 10 (4.3%) motions per week†

Laxative use

Number of participants using any laxative 36 (15.1%)

Number of female laxative users 24 (16.6%)

Number of male laxative users 12 (12.8%)

Number of participants with self-reported 12 (35.3%) constipation AND using laxatives

Number of participants self-medicating with 19 (55.9%) laxatives*

Number of participants using prescribed laxatives* 19 (55.9%)

† Only 234 participants answered the question regarding bowel motion frequency

*2 participants reported using both self-medicated and prescribed laxatives

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6.4.2 Laxative use

Fifteen percent of the cohort had used a laxative as self-reported by participants in the interview. Of these, half reported self-medication, using non-prescribed laxatives, and half reported using laxatives that had been prescribed (Tables 6.1 and 6.2). Two participants reported using both self- medicated and doctor-prescribed laxatives. The prevalence of laxative use was higher in females than males (16.6% versus 12.8% (Table 6.1)) giving a female/male laxative use ratio of 1.30.

There was a marked difference between men and women with respect to self-medication with laxatives. Men were less likely to self-medicate with only 25% (n = 4/12) of male laxative users self- medicating compared to 62.5% (n = 15/26) of female laxative users. Approximately one quarter

(23.7%) of those reporting constipation also reported laxative use and only 33.3% of those using laxatives also reported constipation.

The main oral laxatives used were lactulose, senna, ispaghula and frangula combined with sterculia

(Table 6.2). Senna was the most popular laxative used for self-medication accounting for 36% of the self-medicated laxatives used, and lactulose was the most commonly prescribed laxative representing 58% of the prescribed laxatives used. Most participants used a single agent, however one participant reported using two different OTC laxatives and one participant reported using three different OTC laxatives.

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Table 6.2: Type of laxative used

Laxative Laxative class Number of participants using this laxative

Self-medicated Prescribed

Lactulose Osmotic 0 11

Senna Contact 8 0

Ispaghula Bulk-forming 4 0

Frangula & sterculia Contact & bulk- 2 2 forming

Docusate Softener 3 0

Bisacodyl Contact 1 1

Other oral laxative 4 0

Enema or suppository 0 5

Total number of 22 19 participants using laxatives

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6.4.3 Constipation prevalence and risk factors

Approximately one in five (20.1%) participants reported having experienced constipation. Females were more likely to report constipation than males (24.1%, n = 35 versus 16.0%, n = 15), giving a female/male ratio of 1.51 with respect to self-defined and self-reported constipation (Table 6.1).

In addition to self-reported constipation, participants were also asked about the number of bowel movements they experienced per week. The majority of participants who defined themselves as constipated, experienced more than three bowel movements per week (n = 43/50, 86%). Only ten participants who reported constipation (4.2%) reported having three or fewer bowel movements per week. Three participants (1.3%) reported fewer than three bowel movements per week but did not define themselves as constipated.

In this cohort, we found no association between previously reported socio-demographic risk factors and self-reported constipation on univariate analysis (Table 6.3). Only lower physical function status as evidenced by a higher activity of daily living (ADL) score and poorer self-reported health (SRH) status were associated with self-reported constipation. Although an increased number of medications and the use of medications with constipation potential were not associated with self- reported constipation, there was an association between an increased number of co-existing medical conditions as well as the presence of medical conditions with potential to cause constipation. Some specific medical conditions (haemorrhoids, heart conditions including angina, arthritis, osteoporosis and other muscular conditions) were significantly associated with constipation as were some specific medications (tricyclic antidepressants and clonidine).

On multivariate analysis, only lower levels of physical function and poorer self-reported health were found to be significant (Table 6.4). For every one unit increase in ADL score, the odds of reporting constipation increased by 40%. Similarly, the odds of reporting constipation increased by 70% for every one unit decrease in SRH.

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Table 6.3: Univariate analysis of potential risk factors for constipation

The number of participants answering each question (n) is indicated in brackets for each potential risk factor. Potential risk factors with a significant (p <0.05) relationship with constipation on univariate analysis are shown in bold.

Number of participants with Number of participants with p Potential risk factor self-reported constipation no self-reported (%) constipation (%)

Bowel movements per week <0.001 (n = 234): 3 or fewer 7(14.0) 3 (1.6)

More than 3 43 (86.0) 181 (98.4)

Gender (n = 239): 0.129

Males 15 (30.0) 79 (41.8)

Females 35 (70.0) 110 (58.2)

Mean age (years) (n = 239): 84.6 ± 4.6 84.1 ± 4.3 0.524

Annual income (n = 188): 0.401

Up to $20,000 21 (58.3) 100 (65.8)

Greater than $20,000 15 (41.7) 52 (34.2)

Education (n = 239): 0.146

Post-school qualification 14 (28.0) 74 (39.2)

No post-school qualification 36 (72.0) 115 (60.8)

Smoking (n = 239): 0.336

Smoker 2 (4.0) 15 (7.9)

Non-smoker 48 (96.0) 174 (92.1)

Alcohol use (n = 235): 0.535

Never 13 (27.1) 37 (19.8)

Infrequent 20 (41.7) 83 (44.4)

Daily 15 (31.3) 67 (35.8)

Mean activities of daily 1.60 ± 2.0 0.61 ± 1.2 0.004 living (ADL) score (n = 210):

Surgery (last 3 years) 0.261 (n = 235): Yes 20 (40.8) 60 (32.3)

No 29 (59.2) 126 (67.7)

Self-rated health (n = 239): 0.004

Poor or fair 24 (48.0) 51 (27.0)

Good, very good or excellent 26 (52.0) 138 (73.0)

Mean number of medical 6.64 ± 3.5 4.74 ± 2.9 <0.001 conditions (n = 239):

Medical conditions (n = 0.022 239):

Any medical condition with 47 (94.0) 152 (80.4) constipation potential

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No medical conditions with 3 (6.0) 37(19.6) constipation potential

Specific medical conditions (n = 239)#: Heart conditions/angina 26 (52.0) 58 (30.7) 0.005

Arthritis 36 (72.0) 100 (52.9) 0.015

Haemorrhoids 11 (22.0) 13 (6.9) 0.002

Osteoporosis 9 (18.0) 15 (7.9) 0.035

Other muscular conditions 12 (24.0) 21 (11.1) 0.019

Mean number of 12.70 ± 8.5 11.30 ± 5.7 0.274 medications excluding laxatives (n = 239): Laxative use (n = 239): 0.047

Any laxative 12 (24.0) 24 (12.7)

No laxatives used 38 (76.0) 165 (87.3)

Medications (n = 239): 0.827

Use of any medication with 26 (52.0) 95 (50.3) potential to cause constipation No medications with 24 (48.0) 94 (49.7) potential to cause constipation Specific medications (n = 239)#: Tricyclic antidepressants 12 (24.0) 24 (12.7) 0.047

Clonidine 2 (4.0) 0 (0) 0.006

Note. # Only those specific medical conditions & medicines where a significant relationship was found are shown

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Table 6.4: Risk factors associated with self-reported constipation on multifactorial analysis

Risk factor Odds ratio (95% confidence interval)

Female gender 1.82 (0.78 to 4.26)

No tertiary or post-school education 2.15 (0.92 to 5.00)

High activities of daily living (ADL) score 1.41 (1.11 to 1.8) (poorer functional status)

Poor or fair self-rated health (SRH) 1.76 (1.09 to 2.85)

Number of medical conditions 1.08 (0.93 to 1.25)

Presence of any medical condition with 3.4 0.63 to 15.93) constipating potential

Potential risk factors with a significant (p <0.05) relationship with constipation are shown in bold.

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6.5 Discussion

This is the first Australian study to provide information on laxative use, constipation, and the risk factors for constipation in the community-dwelling elderly. The prevalence of laxative use in this population was found to be similar to that reported in US studies (Hanlon, et al, 2001). However, it is lower than that reported in the UK and New Zealand (Campbell, et al., 1993; Marfil, et al., 2005), but higher than that found in other Australian studies of community-dwelling elderly populations (Goh, et al., 2009; Australian Bureau of Statistics 1999). Differences in what is considered a laxative may be one factor accounting for this. Many studies exclude bulk-forming laxatives, such as ispaghula, from their analysis (Goh, et al., 2009), or do not define what was considered a laxative (Australian Bureau of Statistics 1999) whereas a strength of this study is that bulk-forming laxatives, over-the-counter laxatives and prescribed laxatives were all included in the analysis.

In this study only a quarter of those reporting constipation also reported laxative use. This result is much lower than that of other countries where, in subjects aged 60 years or older, it has been reported that 43 to 52% of those self-reporting constipation used laxatives (Wald, et al., 2008).

Further exploration of the management of constipation is needed to fully understand this difference but it may indicate under-treatment of constipation in the community dwelling population in

Australia. Our results also indicate that laxatives may be successfully managing constipation with two thirds of participants who used laxatives not reporting constipation.

Gender differences were noted both in the overall use of laxatives and in the use of laxatives as self- medication. In our cohort, more females used laxatives than males. Similar results have been reported internationally in the USA, UK, Germany and Brazil (Hanlon, et al, 2001; Heaton & Cripps,

1993; Wald, et al., 2008). Gender differences were also observed regarding the source of laxative. In our study, men were more likely to use prescribed laxatives, while women were more likely to self- medicate. Since similar results have been reported in other countries, this may be related to differences in healthcare seeking behaviour however further investigation of the reasons for these gender differences is needed. 132

Constipation can either be self-defined where an individual decides if they are constipated or not, or defined according to certain criteria such as the Rome criteria, or using the number of bowel movements in a certain time period to define constipation (Longstreth, et al., 2006). In the ALSA questionnaire, no definition of constipation was given and no time period was specified, however the prevalence of self-reported constipation in this elderly population was similar to the prevalence of self-reported constipation found in other elderly populations in Australia (Chiarelli, et al., 2000;

Pit, et al., 2008) and elsewhere (Campbell, et al., 1993; Chaplin, et al., 2000; Pare, et al., 2001; ;

Sandler, Jordan, & Shelton, 1990; Wald, et al., 2010; Wald, et al., 2008; Wong, et al., 1999). Self- reported and self-defined constipation is usually associated with a higher prevalence than bowel motion frequency defined constipation (Campbell, et al., 1993) and this has been confirmed in this study where it is clear that bowel motion frequency is not a good indicator of constipation.

Individuals do not define constipation solely in terms of bowel motion frequency and this is why the

Rome criteria incorporate other symptoms of constipation (Wald, et al., 2010). Prior to the introduction of the Rome criteria for defining gastrointestinal disorders in 1991, constipation was frequently defined as having a stool frequency of fewer than three bowel movements per week

(Whitehead, et al., 1991; Whitehead, at al., 1989). Use of such a narrow definition results in low prevalence rates being reported whereas studies using the Rome criteria, or some combination of symptoms such as straining, stool consistency, incomplete defecation as well as frequency, tend to report much higher prevalence rates. Studies using self-defined constipation where participants are free to define constipation themselves without any constraints usually report even higher prevalence rates (Wald, et al., 2010).

The high prevalence of constipation in elderly populations may partly be related to the large number of medical conditions with potential to cause constipation and the associated usage of medications with potential to cause constipation (Gallagher & O'Mahony, 2009). However, after adjusting for relationships between potential risk factors in this study, only lower levels of physical function (high

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ADL scores) and poor/fair self-reported health remained associated with self-reported constipation

(Table 6.4).

There are some limitations in this study. In the ALSA questionnaire, no definition of constipation was given; also, no time period was specified. Therefore, it is likely that the prevalence may have been different if a definition such as the Rome criteria had been used, or if a time period had been specified. This should be borne in mind when comparing the prevalence to that reported in other studies. However, the prevalence of self-reported constipation in this population was similar to that reported in comparable community-dwelling elderly populations both in Australia and internationally, and the female/male ratio of 1.51 was very similar to the figure of 1.48 calculated from New Zealand data (Campbell, et al., 1993). Also, in comparing studies of elderly populations, the average age is an important consideration; the average age of 84 years in this study is higher than that of most other published studies. Only one third of the laxative users reported no current constipation suggesting that these users may use laxatives for prevention rather than for treatment of constipation. Laxative use is therefore a potential confounder in assessing the prevalence of constipation. Conversely those suffering with constipation may not have been always treated with laxatives and may have used lifestyle measures such as increased physical activity, increased fluid intake or dietary modification to manage their constipation, none of which were captured in the data collection. Even though available laxative agents are largely unchanged in the time since ALSA data was collected, there is the potential that prescribing trends may have changed and products/brands may have changed over the years. A final limitation concerns the use of prescribed versus non-prescribed products; while participants were asked if their laxative had been prescribed by a doctor, they were not asked if it had ever been recommended by a healthcare professional.

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6.6 Conclusion

Health care professionals, including community nurses, need to be aware of the high prevalence of constipation in the community-dwelling elderly population. There is some indication that constipation is not being optimally managed with a relatively large proportion of the cohort reporting constipation but not using laxatives. Many older individuals, especially women, self- medicate with laxatives and involvement of health care professionals in the management of this condition appears to be limited.

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Campbell, A. J., Busby, W.J., & Horwath, C.C. (1993). Factors associated with constipation in a community based sample of people aged 70 years and over. Journal of Epidemiology and Community Health, 47(1), 23-26.

Chiarelli, P., Brown, W., & McElduff, P. (2000). Constipation in Australian women: prevalence and associated factors. International Urogynecology Journal, 11(2), 71-78.

Cusack, S., Day, M. R., Wills, T., & Coffey, A. (2012). Older people and laxative use: comparison between community and long-term care settings. British Journal of Nursing, 21(12), 711-717.

Dennison, C., Prasad, M., Lloyd, A., Bhattacharyya, S. K., Dhawan, R., & Coyne, K. (2005). The health- related quality of life and economic burden of constipation. Pharmacoeconomics, 23(5), 461- 476.

Gallagher, P., & O'Mahony, D. (2009). Constipation in old age. Best Practice & Research in Clinical Gastroenterology, 23(6), 875-887.

Gallegos-Orozco, J. F., Foxx-Orenstein, A. E., Sterler, S. M., & Stoa, J. M. (2012). Chronic constipation in the elderly. American Journal of Gastroenterology, 107(1), 18-25.

Hanlon, J. T., Fillenbaum, G. G., Ruby, C. M., Gray, S., & Bohannon, A. (2001). Epidemiology of over- the-counter drug use in community dwelling elderly: United States perspective. Drugs & Aging, 18(2), 123-131.

Heaton, K. W., & Cripps, H. A. (1993). Straining at stool and laxative taking in an English population. Digestive Diseases & Sciences, 38(6), 1004-1008.

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Longstreth, G. F., Thompson, W. G., Chey, W. D., Houghton, L. A., Mearin, F., & Spiller, R. C. (2006). Functional bowel disorders. Gastroenterology, 130(5), 1480-1491.

Luszcz, M. A., Giles, S., Eckermann, S., Edwards, P., Browne-Yung, K., & Hayles, C. (2007). The Australian Longitudinal Study of Ageing: 15 Years of Ageing in South Australia: Government of South Australia, Department for Families and Communities.

Marfil, C., Davies, G. J., & Dettmar, P. W. (2005). Laxative use and its relationship with straining in a London elderly population: free-living versus institutionalised. Journal of Nutrition Health & Aging, 9(3), 185-187.

Pinto Sanchez, M. I., & Bercik, P. (2011). Epidemiology and burden of chronic constipation. Canadian Journal of Gastroenterology, 25(Suppl B):11B-15B.

Rossi, S. (Ed.) (2013) Australian Medicines Handbook 2013 (Electronic edition). Retrieved from http://www.amh.net.au/online

Sandler, R. S., Jordan, M. C., & Shelton, B. J. (1990). Demographic and dietary determinants of constipation in the US population. American Journal of Public Health, 80(2), 185-189.

Schmidt, F. M. Q., & de Gouveia Santos, V. L. C. (2014). Prevalence of constipation in the general adult population: An integrative review. Journal of Wound, Ostomy & Continence Nursing, 41(1), 70-76.

Wald, A., Mueller-Lissner, S., Kamm, M. A., Hinkel, U., Richter, E., Schuijt, C., et al. (2010). Survey of laxative use by adults with self-defined constipation in South America and Asia: a comparison of six countries. Alimentary Pharmacology & Therapeutics, 31(2), 274-284.

Wald, A., Scarpignato, C., Kamm, M. A., Mueller-Lissner, S., Helfrich, I., Schuijt, C., et al. (2007). The burden of constipation on quality of life: results of a multinational survey. Alimentary Pharmacology & Therapeutics, 26(2), 227-236.

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Wald, A., Scarpignato, C., Mueller-Lissner, S., Kamm, M. A., Hinkel, U., Helfrich, I., et al. (2008). A multinational survey of prevalence and patterns of laxative use among adults with self- defined constipation. Alimentary Pharmacology & Therapeutics, 28(7), 917-930.

Whitehead, W. E., Chaussade, S., Corazziari, E., & Kumar, D. (1991). Report of an international workshop on management of constipation. Gastroenterology International, 4(3), 99-113.

Whitehead, W. E., Drinkwater, D., Cheskin, L.J., Heller, B.R., & Schuster, M.M. (1989). Constipation in the elderly living at home. Definition, prevalence, and relationship to lifestyle and health status. Journal of the American Geriatrics Society 37(5), 423-429.

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Chapter 7: A longitudinal study of constipation and laxative use in a community–dwelling elderly population

Werth, B.L., Williams, K.A. & Pont L.G. (2015). A longitudinal study of constipation and laxative use in a community-dwelling elderly population. Archives of Gerontology & Geriatrics 60, 418-424.

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7.1 Abstract

Background: Little is known about laxative use, the association of constipation with laxative use, risk factors for constipation and how each of these changes over time in the community-dwelling elderly.

Objective: The aim was to explore the prevalence of laxative use and of self-reported constipation, and identify risk factors (including age) associated with constipation, in a cohort of community- dwelling elderly residents.

Methods: Data from the Australian Longitudinal Study of Ageing (ALSA) was used to compare differences in constipation and laxative use in the community-dwelling elderly between 1992-93 and

2003-04.

Results: Relevant data was available for 239 ALSA participants. The prevalence of self-reported constipation increased from 14% in 1992-93 to 21% in 2003-04. There was a corresponding increase in the prevalence of laxative use from 6% to 15% over the same period. At both time points, females reported a higher prevalence of both constipation and laxative use however the female/male prevalence ratios decreased over time indicating higher increases in the prevalence of each among males. Persistent chronic constipation occurred in 9% of the cohort. The association between laxative use and self-reported constipation was poor and laxative use was associated with self- reported constipation in less than a third of cases.

Conclusion: The prevalence of both constipation and laxative use increases with age in the elderly, and these increases are greater for males than for females. Discrepancies between self-reported constipation and laxative use may suggest sub-optimal management of constipation in the community-dwelling elderly and further work is needed to fully understand this.

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7.2 Introduction

Like most developed countries, the Australian population is ageing with the majority of the elderly population residing in the community (Luszcz et al., 2007). Constipation is a relatively common condition which is particularly prevalent in the elderly and usually self-managed with laxatives

(Gallagher & O'Mahony, 2009; McCrea, Miaskowski, Stotts, Macera, & Varma, 2009). Over $100 million is spent annually in Australia on laxatives but this is only one cost consequence of constipation. The costs of doctor consultations, hospitalisations and lost productivity due to constipation represent a significant additional economic burden (Dennison et al., 2005; Locke,

Pemberton, & Phillips, 2000; Sonnenberg & Koch, 1989a, 1989b). In addition to the financial costs associated with constipation, the impact on the quality of life of those who suffer with constipation is a further consequence which cannot be ignored (Belsey, Greenfield, Candy, & Geraint, 2010;

Dennison et al., 2005; Johanson & Kralstein, 2007; Talley, 2004; Wald et al., 2007).

International studies have reported a wide range in the prevalence of constipation in community- dwelling elderly populations (Campbell, Busby, & Horwath, 1993; Chaplin, Curless, Thomson, &

Barton, 2000; Hammond, 1964; Wong, Wee, Pin, Gan, & Ye, 1999). Depending on the definition of constipation used, prevalence rates between 11 to 55% have been reported. Studies using self- defined constipation where participants are free to define constipation themselves without any constraints usually report higher prevalence rates than those using a specified definition or criteria

(Wald et al., 2008). A recent US longitudinal study of the general adult population over a period of

20 years investigated the prevalence of persistent chronic constipation and found that 3% had persistent chronic constipation (Choung et al., 2012) but no longitudinal studies focussed on elderly populations have been published to date.

A number of factors associated with an increased risk of constipation have been reported in the general population and one of these risk factors is age. An increase in the prevalence of constipation with age in those older than 60 years has been well documented internationally (Chaplin et al.,

2000; Hammond, 1964; Harari, Gurwitz, Avorn, Bohn, & Minaker, 1996; Lu, Chang, Chen, Luo, & Lee, 141

2006; Nakaji et al., 2002; Wong et al., 1999) with some studies indicating that the largest increases occur after 70 to 75 years of age (McCrea et al., 2009; Talley, Jones, Nuyts, & Dubois, 2003). In addition to increasing age, other risk factors for constipation identified include gender, co-morbidity and medications. In most studies, females are more likely to report constipation than males

(Campbell et al., 1993; Stewart, Moore, Marks, & Hale, 1992b; Talley et al., 1996a). Other risk factors which have been reported in elderly populations include low levels of physical activity (Brown,

Mishra, Lee, & Bauman, 2000), medical conditions such as stress, stroke, heart conditions (Wong et al., 1999) and haemorrhoids (Chiarelli, Brown, & McElduff, 2000), and medications such as diuretics, calcium channel blockers, antidepressants and hypnotics (Campbell et al., 1993; Chiarelli et al., 2000;

Wong et al., 1999).

Whilst some international studies have reported the prevalence of constipation and risk factors in community-dwelling elderly populations, less is known about the management of constipation and the use of laxatives. Several international studies have reported the prevalence of laxative use in the community-dwelling elderly ranging from 10% to 25% (Campbell et al., 1993; Chaplin et al., 2000;

Marfil, Davies, & Dettmar, 2005; May, 1982; Pahor, Guralnik, Chrischilles, & Wallace, 1994; Ruby,

Fillenbaum, Kuchibhatla, & Hanlon, 2003; Stoehr, Ganguli, Seaberg, Echement, & Belle, 1997; Stoller,

1988; W. E. Whitehead, Drinkwater, Cheskin, Heller, & Schuster, 1989). The reported prevalence may vary according to the definition of laxative used, and whether the laxative was prescribed or non-prescribed. U.S. studies have found laxative use to be higher in females than males (May, 1982;

Stoehr et al., 1997), laxative usage increases with age (Stoehr et al., 1997) and, with the exception of lactulose, all laxative products were over-the-counter (OTC) medicines with few prescribed by doctors (Ruby et al., 2003). However there have been few Australian studies of constipation and laxative use in the community dwelling elderly, and no published Australian study has investigated the association of laxative use with constipation in any population. In fact, the prevalence of laxative use and its association with constipation in the community-dwelling elderly has not been extensively

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studied either in Australia or internationally, nor have these issues been examined on a longitudinal basis.

The aim of our study was to determine the impact of ageing on the prevalence of constipation and laxative use in a cohort of community-dwelling elderly residents. We also aimed to explore changes in various risk factors associated with constipation over time.

7.3 Methods

7.3.1 Data source

The Australian Longitudinal Study of Ageing (ALSA) is a longitudinal cohort study of ageing in the community (Luszcz et al., 2007). The study was conducted in Adelaide, South Australia and commenced in 1992 with 2,087 participants aged 65 years or older. Participants were interviewed and data collected at eight different time points over the next 14 years. The number of participants was reduced over this time due to a variety of reasons including refusal to participate further, ill health, death or being un-contactable. The detailed ALSA methodology has been published previously (Luszcz et al., 2007).

At baseline in 1992-93, face-to-face interviews were conducted at the place of residence of each participant to elicit answers to a wide range of questions regarding their health and welfare. Data on all medical conditions were recorded, including self-reported constipation, as well as data for both prescribed and non-prescribed medications. Interviews and collection of data were repeated in

2003-04.

7.3.2 Study population

Of the original 2,087 participants from 1992-93, 487 participated in 2003-04, of whom 412 were living in the community and eligible for inclusion in this analysis. For this study, participants must have had complete constipation and medication use data recorded at both the 1992-93 and 2003-04 time points. Participants who did not answer the question regarding constipation (n = 30) or who reported a colostomy (n = 3) were excluded from our analysis, as were participants who did not give

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consent for medication data to be accessed (n = 140), leaving a total of 239 community-dwelling participants with complete constipation and medication use data in both 1992-93 and 2003-04.

7.3.3 Self-reported constipation

At both time points, participants were asked to report on constipation. In 1992-93, the question was: “Do you often have trouble with your bowels which makes you constipated?” and in 2003-04 participants were asked a slightly different question: “Do you have trouble with your bowels which makes you constipated?”. Also, at both time points, the participants were asked about bowel movement frequency: “How often do you usually have a bowel movement?”.

7.3.4 Medication use

Two sources of medication use data were used. In 1992-93, participants were asked to name all medications (both prescribed and purchased over-the-counter) which had been taken in the previous two weeks. Participants were also asked to show the medicine container to the interviewer.

In 2003-04, the same methodology was used for OTC medications but the participants were also asked whether the OTC medicine was prescribed by a doctor since many OTC medicines are available for reimbursement if prescribed by a doctor for elderly patients. In addition, medicine reimbursement data was obtained for all prescription medicines which had been subsidised by the

Australian government. Both reimbursed and OTC medications included a number of laxative agents.

7.3.5 Potential risk factors for constipation

Potential risk factors for constipation were identified from the literature. These included medical conditions, medications and level of physical activity as well as socio-demographic data. Medications were considered to have the potential to cause constipation if listed as an adverse effect in published reviews of the subject (Branch & Butt, 2009; Toney, Wallace, Sekhon & Agrawal, 2008).

Medical conditions associated with constipation identified in the literature included conditions affecting the heart, lower gastrointestinal system (e.g. haemorrhoids), and musculoskeletal system

(Chiarelli et al 2000; Fosnes, Lydersen & Farup, 2011; Talley et al, 2003; Wong et al, 1999). 144

7.3.6 Analysis

Analysis of data was done using IBM SPSS Statistics version 21 (IBM Corporation). For unifactorial analyses of potential risk factors, Pearson’s chi-squared test, Kruskal-Wallis test and t-test

(independent and paired) were used as appropriate. Prevalence at each time point was compared using McNemar’s test. P values of 0.05 or less were considered to be statistically significant.

7.4 Results

7.4.1 Study population

The majority of the cohort was female (61%) and the mean age of the cohort increased from 73 in

1992-93 to 84 years in 2003-04 (Table 7.1). Half of the cohort had left school by the age of 14 years and a third had some form of higher education. Although the number of medical conditions reported by each participant did not change greatly over the period, the number of medications taken by each participant increased dramatically over time. Physical activity (functional status) as indicated by the activities of daily living (an assessment of basic self-care tasks) declined over the study period as did levels of self-rated health.

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Table 7.1: Participant characteristics, including self-reported constipation (SRC), bowel motions (BM) and laxative use (LU) (n=239)

Characteristic 1992-93 2003-04 p Mean age (years) 73.2 84.2

Age range (years) 65-90 75-102 Females, n (% of total) 145 (60.7)

Age left school (<14 yrs), n (% of total) 119 (49.8)

Post-school qualification, n (% of total) 88 (36.8) Self -rated health – poor or fair, n (% of 41 (17.2) 75 (31.4) <0.001 total) Activities of daily living (mean ADL score) 0.15 0.80 <0.001 Mean no. of medical conditions 5.0 5.1 0.513 Mean no. of medications 2.4 11.7 <0.001 Self-reported constipation (SRC), n (% of 33 (13.8) 50 (20.9) 0.012 Laxativetotal) use (LU), n (% of total) 15 (6.3) 36 (15.1) 0.002 3 or fewer BM/week, n (% of total) 7 (2.9) 10 (4.2) 0.607 Males reporting constipation, n (% of males) 7 (7.4) 15 (16.0) 0.04

Females reporting constipation, n (% of 26 (17.9) 35 (24.1) 0.14 females)

Males reporting laxative use, n (% of males) 2 (2.1) 12 (12.8) 0.04

Females reporting laxative use, n (% of 13 (9.0) 24 (16.6) 0.04 females)

Males using Rx laxatives, n (% of males) Unknown 8 (8.5) Females using Rx laxatives, n (% of females) Unknown 11 (7.6) n (% of SRC/LU) n (% of SRC/LU) n (% of total) Reported constipation AND 3 or fewer 4 (12.1) 7 (14.0) BM/week

Reported constipation AND laxative use 10 (30.3) 12 (24.0)

SRC at both time points (persistent) 21 (63.6) 21 (42.0) 21 (8.8)

SRC at one time point only (non-persistent) 21 (36.4) 29 (58.0) 41 (17.2)

LU at both time points (persistent) 4 (26.7) 4 (11.1) 4 (1.7)

LU at one time point only (non-persistent) 11 (73.3) 32 (88.9) 43 (18.0)

Note. Total number of participants = 239. In the table for each characteristic, n = number of participants. Rx laxatives = prescribed laxatives.

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7.4.2 Constipation

A statistically significant increase in the prevalence of constipation was seen between 1992-93

(13.8%) and 2003-04 (20.9%) (Table 7.1). More females than males reported constipation at both time points however the ratio of females to males declined in 2003-04 (1.51) compared to

1992-93 (2.42). The change in the female/male prevalence ratio may be attributed to a doubling in the prevalence of constipation in males over the time.

Looking at changes over time for individual participants, 64% (n = 21/33) of participants who reported constipation in 1992-93 also reported constipation in 2003-04 (Table 7.1). These individuals can be classified as persistent sufferers, representing 9% of the total cohort whereas non-persistent cases, those reporting constipation at one time point only, represented 18% of the total cohort with 73% not reporting constipation at either time point.

The frequency of bowel motions did not correlate with self-reported constipation at either time point. Only 12% (n = 4/33) of those reporting constipation in 1992-93 also reported 3 or fewer bowel motions per week, and in 2003-04 this figure was 14% (n = 7/50). There was no significant difference in bowel motion frequency between the two-time points.

Potential risk factors varied between the 1992-93 and 2003-04 time periods (Table 7.2). Risk factors which were significantly associated with self-reported constipation at both time points included the level of physical activity/functional status, as measured by the activities of daily living (ADL), and the number of medical conditions reported by participants. Also, those who reported their health as poor or fair were more likely to report constipation at both time points.

In 1992-93, participants with a tertiary or higher education were less likely to report constipation and the age at which participants left school was also significant but neither of these factors remained significant in 2003-04.

Certain medical conditions have been reported in the literature as being frequently associated with constipation and these were investigated (Table 7.2). No significant differences were found in 1992-93 with regard to constipation and specified co-morbidities with the exception of

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osteoporosis, however this changed over time. In the 2003-04 data, heart conditions (including angina), arthritis, haemorrhoids, osteoporosis and muscular complaints were all significant risk factors for constipation.

Medication use varied over time. The number of medications used was significantly associated with self-reported constipation in 1992-93, however despite the number of medications per participant increasing over time, no association between number of medications and self- reported constipation was observed at the second-time point (Table 7.2). Tricyclic antidepressants were the only drugs significantly associated with constipation at both times; other drugs significantly associated with constipation at one time point were diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, anti-parkinsonism drugs and clonidine.

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Table 7.2: Potential risk factors for self-reported constipation (SRC)

Potential risk factor 1992-93 1992-93 2003 -04 SRC 2003-04 p No SRC p SRC No SRC n (%) n (%) n (%) n (%) or mean or mean or mean or mean

Number of participants: 33 206 50 189

Education:

Age left school: 14 years or younger 24 (72.7) 95 (46.1) 0.015 27 (54.0) 92 (48.7) 0.645

Post-school qualification 7 (21.2) 81 (39.3) 0.045 14 (28.0) 74 (39.2) 0.146

Physical activity/functional status:

Mean ADL score* 0.55 0.08 0.028 1.60 0.61 0.004

Self-rated health: 0.001 0.004

Poor or fair 11 (33.3) 26 (12.6) 34 (68.0) 51 (27.0)

Good/very good/excellent 22 (66.6) 180 (87.4) 16 (32.0) 138 (73.0)

Medical conditions:

Mean no. of medical conditions 6.45 4.78 0.001 6.64 4.74 <0.001

Medical condition with potential for constipation:

Heart condition/angina 8 (24.2) 37 (18.0) 0.392 26 (52.0) 58 (30.7) 0.005

Arthritis 18 (54.5) 99 (48.1) 0.489 36 (72.0) 100 (52.9) 0.015

Haemorrhoids 0 3 (1.5) 0.485 11 (22.0) 13 (6.9) 0.002

Osteoporosis 4 (12.1) 5 (2.4) 0.007 9 (18.0) 15 (7.9) 0.035

Other muscular 0 7 (3.4) 0.282 12 (24.0) 21 (11.1) 0.019

Medications:

Mean no. of medications 4.42 2.10 <0.001 12.70 11.30 0.274

Medication with potential for constipation:

Diuretic 10 (30.3) 30 (14.6) 0.025 22 (44.0) 86 (45.5) 0.849

NSAID 10 (30.3) 29 (14.1) 0.019 8 (16.0) 26 (13.8) 0.686

Tricyclic antidepressant 5 (15.2) 10 (4.9) 0.024 12 (24.0) 24 (12.7) 0.047

Opioid analgesic 4 (12.1) 8 (3.9) 0.044 14 (28.0) 44 (23.3) 0.489

Clonidine 0 1 (0.5) 0.688 2 (4.0) 0 0.006

Anti-Parkinson 1 (3.0) 0 0.012 1 (2.0) 2 (1.1) 0.595

Total number of participants = 239. In 1992-93, 33 participants reported constipation and in 2003-04, 50 participants reported constipation. In the table for each potential risk factor, n = number of participants and means are presented in italics. Only those specific medical conditions and medicines where a significant relationship was found are shown. *Missing data for 29 participants in 2003-04.

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7.4.3 Laxative use

The prevalence of laxative use in the cohort increased significantly from 6.3% in 1992-93 to

15.1% in 2003-04 (Table 7.1). Despite 35% of the cohort reporting constipation at one or more time points, the majority of the cohort did not use laxatives at either time point (80%). In 1992-

93, 2% of males reported laxative use compared to 9% of females, but the difference was much less in 2003-04 with 13% of males and 17% of females reporting laxative use (Table 7.1). Non- persistent users were defined as those reporting laxative use at one time point only and comprised 18% of the cohort. Only 4 participants (2%) reported using laxatives at both time points.

A variety of laxative agents were reported at both time points (Figure 7.1). In 1992-93, ispaghula was the most popular and lactulose was the most popular in 2003-04. Usage of senna was similar at both time points and was the second most popular laxative agent each time. In the

2003-04 data, the use of prescribed versus self-initiated laxatives could be explored. In 2003-04, just over half of all laxatives used were not prescribed (52%). One participant reported using three different non-prescribed laxative products and two participants used both prescribed and non-prescribed laxatives. Men were more likely to report use of prescription laxatives (67% of male laxative users) while women were more likely to use non-prescription products (54% of female laxative users).

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Laxatives used 30

25 20 15 10

% of laxatives of % 5 1992-93 0 2003-04

Other oral laxatives included herbal products with various active ingredients.

Figure 7.1: Choice of laxatives used

7.4.4 Constipation and laxative use

It was found that laxative use was not strongly associated with self-reported constipation. Only 30%

(n = 10/33) of those reporting constipation in 1992-93 used laxatives whereas in 2003-04 the comparable figure was only 24% (n = 12/50) (Table 1). This is also the case for those with persistent constipation with only 43% (n = 9/21) of those reporting constipation in both 1992-93 and 2003-04 reporting laxative use in 2003-04.

7.5 Discussion

The prevalence of both self-reported constipation and laxative use in this community-dwelling elderly population increased significantly over the study period.

7.5.1 Constipation

The prevalence of constipation in 2003-04 of 21% is comparable to that reported in other Australian studies. One study reported the prevalence of constipation to be 22% in those aged 65 years or more (Pit, Byles, & Cockburn, 2008) and another reported a prevalence of 28% in women aged 70 to

75 years (Chiarelli et al., 2000). The mean age of the cohort increased from 73 years in 1992-03 to 84 years in 2003-04 and a corresponding increase in the prevalence of constipation was also observed. 151

The increased prevalence of constipation observed in this cohort over time confirms what has been reported elsewhere: that the largest increases in prevalence occur after the age of 70 years (McCrea et al., 2009) and that the risk of constipation increases markedly above 75 years (Talley et al., 2003).

A number of risk factors for constipation in the community-dwelling elderly were evident in this analysis. Females were more likely to report constipation than males throughout the study, although there was a greater increase in the number of males reporting constipation over time as evident in the decreasing female/male ratio. The female/male ratio of 1.51 in 2003-04 is comparable to that reported in elderly populations in other western countries where the ratio ranged from 1.48 to 1.75

(Campbell et al., 1993; Stewart, Moore, Marks, & Hale, 1992a; Talley et al., 1996b). At both time points, those who rated themselves to be in poorer health were also more likely to report constipation; this may also have been a consequence of constipation itself. Other risk factors identified in this study included lower levels of education, co-morbid medical conditions, number of medications and low daily activity levels. However, the importance of individual risk factors appears to change over time, with only number of medical conditions and low daily activity levels significant risk factors at both time points.

The number of medications taken would be expected to increase in an elderly group whose mean age increased from 73 to 84 years, and polypharmacy seemed common throughout the cohort in

2003-04 with a mean of 11.7 medications per participant. This high level of polypharmacy probably explains why the number of medications was not significantly associated with constipation at this time point. Tricyclic antidepressants which are well known for their anticholinergic effects on bowel function were the only medication class consistently identified as a risk factor for constipation.

In 64% of those reporting constipation, constipation was reported both at baseline and again eleven years later. This indicates that it may have become a persistent, chronic condition in these cases.

Expressed as a percentage of the total cohort, this result was three times higher than that reported in a recent US adult population study for a population which was not solely elderly, although comparable results were found for non-persistent cases (Choung et al., 2012). This indicates that

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persistent chronic constipation may be up to three times higher in elderly populations. As reported in numerous other studies including those in elderly populations (Campbell et al., 1993), the prevalence of self-reported and self-defined constipation was found to be much higher than that indicated by bowel motion frequency. Individuals do not define constipation solely in terms of bowel motion frequency (Annells & Koch, 2002) and this is why the Rome criteria incorporates other symptoms of constipation (Longstreth et al., 2006). Prior to the introduction of the Rome criteria for defining gastrointestinal disorders in 1991, constipation was frequently defined as having a stool frequency of fewer than three bowel movements per week (Whitehead, Chaussade, Corazziari, &

Kumar., 1991; Whitehead et al., 1989). Use of such a narrow definition results in low prevalence rates being reported whereas studies using the Rome criteria, or some combination of symptoms such as straining, stool consistency and incomplete defaecation, as well as frequency, tend to report much higher prevalence rates. Studies using self-defined constipation, such as this analysis, where participants are free to define constipation themselves without any constraints usually report even higher prevalence rates (Wald et al., 2008).

7.5.2 Laxative use

This study found a higher prevalence of laxative use than that previously reported in the Australian literature (Goh, Vitry, Semple, Esterman, & Luszcz, 2009; McLennan, 1999). One considerable difference between these studies is the way in which laxatives were defined, with both earlier studies excluding fibre products such as ispaghula husk and sterculia/frangula, both of which are commonly used over-the-counter products and included in this analysis (Goh et al., 2009; McLennan,

1999).

The increased prevalence of laxative use in 2003-04 clearly correlates with an increased prevalence of constipation (Table 7.1). The percentage of males using laxatives in 2003-04 was much higher than at baseline and the female/male prevalence ratio decreased from 4.28 to 1.30, a level that is similar to results obtained for the elderly in the UK (1.37) and Germany (1.39) (Wald et al., 2008) and also comparable to the ratio of 1.57 reported in the Australian 1995 National Health Survey for

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those aged 65 years or more (McLennan, 1999). However there seemed to be a reluctance of males to self-medicate with the majority using doctor-prescribed laxatives. Previous Australian research in a predominantly female elderly sample indicated a strong desire for self-management of constipation (Annells & Koch, 2002) and this seems to have been confirmed in our data. Lactulose was the most commonly prescribed laxative in 2003-04 but it was not reported at all in 1992-93 even though it was available at this time. This change in the mix of laxative agents used over the period probably reflects dissatisfaction with the efficacy of laxatives and a continuing need by both doctors and sufferers to search for new and better treatments, as reported in a recent European survey (Muller-Lissner, Tack, Feng, Schenck, & Specht Gryp, 2013). Any changes in product availability, e.g. changes in medicine reimbursement or changes in prescribing trends, during this time may also have influenced the mix.

At both time points, the relationship between self-reported constipation and laxative use was low.

Only 24 to 30% of those reporting constipation also reported laxative use suggesting that over 70% of those reporting constipation may not have used laxatives to treat the condition since they did not report laxative use in the two weeks or eight months prior to the interview. Conversely it suggests that others may be using laxatives successfully to prevent constipation with 5 subjects in 1992-93 and 22 subjects in 2003-04 reporting laxative use but not reporting constipation. In comparison, it has been reported that 43-52% of those self-reporting constipation in subjects aged 60 years or older in other countries also reported using laxatives (Wald et al., 2008).

7.5.3 Limitations

One limitation of this study was slight differences in the collection of medication use data. At both time points, self-reported medication use was used and like all self-reported data the validity of this may be limited by the recall ability of the participants. In 1992-93, participants were asked about medications used during the preceding two weeks however in 2003-04, prescription reimbursement data for an 8 months period was used in conjunction with this same question for any non-prescribed products that were used. As a result, more medications were reported in 2003-04 and this may have

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affected some of the comparative analyses of medication data although it is unlikely to have resulted in any large differences in medication use over the two time points. Furthermore, no distinction was made between regular use of medications and ad hoc use; this difference may also influence outcomes regarding both laxative use and medications as a risk factor.

Also, the constipation question asked in 1992-93 was slightly different to the question asked in

2003-04 and this may have resulted in a different response by some participants thereby affecting constipation prevalence rates; neither question was validated. Much of the variability in prevalence rates in studies of constipation and laxative use is because of how these are defined. In the ALSA questionnaire, no definition of constipation was given; also, no time period was specified. Therefore, it is likely that the prevalence may have been different if a definition such as the Rome criteria had been used, or if a time period (e.g. in the last 12 months) had been specified. This should be borne in mind when comparing the prevalence at either time point to that reported in other studies.

However, the prevalence in 2003-04 seems comparable to that reported in the previous two

Australian studies of elderly populations where constipation was also self-reported but for defined periods of time (Chiarelli et al., 2000; Pit et al., 2008). Also, the time period for use of medications

(including laxatives) was defined at each time point whereas this was not the case for constipation so this may have affected any correlations between self-reported constipation and medication use.

A final limitation is the fact that laxative use is a potential confounder in determining the prevalence of constipation and bowel motion frequency.

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7.6 Conclusion

This analysis provides insight into age-related changes in the prevalence of constipation and laxative use over time in the community-dwelling elderly. Self-reported constipation and laxative use in the cohort increased significantly over the 11-year period and, although both were more prevalent in females than males, the proportion of males was much higher 11 years later. Advancing age and several associated risk factors appear to be the major reasons for these outcomes. Persistent chronic constipation was found in almost two thirds of those with constipation, the prevalence of which was three times that of the general adult population. Less than one third of all those reporting constipation used laxatives at either time point so it may be possible that laxatives are being used more for prevention, rather than for treatment, of constipation.

With the increase in life expectancy and the increases in medical conditions, medications and other risk factors in old age, the prevalence of constipation in the elderly is likely to increase in the future.

Health care professionals need to be aware of these issues and the needs of the community- dwelling elderly to ensure optimal outcomes in the management of constipation and use of laxatives in this population.

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7.7 References

Australian Bureau of Statistics (ABS) (1999) 1995 National Health Survey Use of Medications Australia. Cat No. 4377.0. Canberra: ABS.

Annells, M., & Koch, T. (2002). Older people seeking solutions to constipation: the laxative mire. Journal of Clinical Nursing, 11(5), 603-612.

Branch, R., & Butt, T.F. (2009). Drug-induced constipation. Adverse Drug Reaction Bulletin, 257, 987- 990.

Chiarelli, P., Brown, W., & McElduff, P. (2000). Constipation in Australian women: prevalence and associated factors. International Urogynecology Journal, 11(2), 71-78.

Dennison, C., Prasad, M., Lloyd, A., Bhattacharyya, S. K., Dhawan, R., & Coyne, K. (2005). The health- related quality of life and economic burden of constipation. Pharmacoeconomics, 23(5), 461- 476.

Fosnes, G.S., Lydersen, S., & Farup, P.G. (2011). Constipation and diarrhoea – common adverse drug reactions? A cross-sectional study in the general population. BMC Pharmacology and Toxicology, 11.

Gallagher, P., & O'Mahony, D. (2009). Constipation in old age. Best Practice & Research in Clinical Gastroenterology, 23(6), 875-887.

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Hammond, E. C. (1964). Some preliminary findings on physical complaints from a prospective study of 1,064,004 men and women. American Journal of Public Health & the Nation's Health, 54, 11-23.

Johanson, J. F., & Kralstein, J. (2007). Chronic constipation: a survey of the patient perspective. Alimentary Pharmacology & Therapeutics, 25(5), 599-608.

Locke, G. R., 3rd, Pemberton, J. H., & Phillips, S. F. (2000). AGA technical review on constipation. American Gastroenterological Association. Gastroenterology, 119(6), 1766-1778.

Longstreth, G. F., Thompson, W. G., Chey, W. D., Houghton, L. A., Mearin, F., & Spiller, R. C. (2006). Functional bowel disorders. Gastroenterology, 130(5), 1480-1491.

Luszcz, M. A., Giles,S., Eckermann,S., Edwards, P., Browne-Yung, K., Hayles C. (2007). The Australian Longitudinal Study of Ageing: 15 Years of Ageing in South Australia: Government of South Australia, Department for Families and Communities.

May, F. E., Stewart, R.B., Hale, W.E., & Marks, R.G. . (1982). Prescribed and nonprescribed drug use in an ambulatory elderly population. Southern Medical Journal, 75(5), 522-528.

Nakaji, S., Tokunaga, S., Sakamoto, J., Todate, M., Shimoyama, T., Umeda, T., & Sugawara, K. (2002). Relationship between lifestyle factors and defecation in a Japanese population. European Journal of Nutrition, 41(6), 244-248.

Pahor, M., Guralnik, J. M., Chrischilles, E. A., & Wallace, R. B. (1994). Use of laxative medication in older persons and associations with low serum albumin. Journal of the American Geriatrics Society, 42(1), 50-56.

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Ruby, C. M., Fillenbaum, G. G., Kuchibhatla, M. N., & Hanlon, J. T. (2003). Laxative use in the community-dwelling elderly. American Journal of Geriatric Pharmacotherapy, 1(1), 11-17.

Sonnenberg, A., & Koch, T. R. (1989a). Epidemiology of constipation in the United States. Diseases of the Colon & Rectum, 32(1), 1-8.

Sonnenberg, A., & Koch, T. R. (1989b). Physician visits in the United States for constipation: 1958 to 1986. Digestive Diseases and Sciences, 34(4), 606-611.

Stewart, R. B., Moore, M. T., Marks, R. G., & Hale, W. E. (1992a). Correlates of constipation in an ambulatory elderly population. American Journal of Gastroenterology, 87(7), 859-864.

Stoehr, G. P., Ganguli, M., Seaberg, E. C., Echement, D. A., & Belle, S. (1997). Over-the-counter medication use in an older rural community: the MoVIES Project. Journal of the American Geriatrics Society, 45(2), 158-165.

Stoller, E. P. (1988). Prescribed and over-the-counter medicine use by the ambulatory elderly. Medical Care, 26(12), 1149-1157.

Talley, N. J. (2004). Definitions, epidemiology, and impact of chronic constipation. Reviews in Gastroenterological Disorders, 4 (Suppl 2), S3-S10.

Talley, N. J., Fleming, K. C., Evans, J. M., O'Keefe, E. A., Weaver, A. L., Zinsmeister, A. R., & Melton, L. J., 3rd. (1996b). Constipation in an elderly community: a study of prevalence and potential risk factors. American Journal of Gastroenterology, 91(1), 19-25.

Talley, N. J., Jones, M., Nuyts, G., & Dubois, D. (2003). Risk factors for chronic constipation based on a general practice sample. American Journal of Gastroenterology, 98(5), 1107-1111.

Toney, R.C., Wallace, D., Sekhon, S., & Agrawal, R.M. (2008). Medication induced constipation and diarrhea. Practical Gastroenterology, 32(5), 12-28.

Wald, A., Scarpignato, C., Kamm, M. A., Mueller-Lissner, S., Helfrich, I., Schuijt, C., . . . Petrini, O. (2007). The burden of constipation on quality of life: results of a multinational survey. Alimentary Pharmacology & Therapeutics, 26(2), 227-236.

Whitehead, W. E., Chaussade, S., Corazziari, E., & Kumar, D. (1991). Report of an international workshop on management of constipation. Gastroenterology International, 4(3), 99-113.

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Chapter 8: Discussion, Conclusion and Future Directions

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8.1 Discussion

8.1.1 The prevalence of constipation and laxative use

This research shows that both constipation and the use of laxatives occur commonly in community- dwelling adults in Australia. A quarter of the adult population experience chronic constipation and over a third of the population use laxatives in a year.

Knowing the national prevalence of constipation is important to healthcare professionals and policy makers (Mugie, Benninga, & Di Lorenzo, 2011) for planning health interventions and developing public health programs (Schmidt & Santos, 2014). This research has found that the national prevalence of chronic constipation is 24%. Although constipation prevalence in Australia has been reported previously, there was such wide variation in prevalence estimates that the true prevalence was unclear. Previous Australian studies used a variety of constipation definitions and none were national surveys which is problematic because constipation prevalence may vary in different regional areas within the same country (Chu et al., 2014; Ebling et al., 2014; Rey, Balboa, & Mearin,

2014; Sandler, Jordan, & Shelton, 1990). When different definitions were employed in the national survey in this thesis, the prevalence of constipation varied six-fold. This partly explains the wide variation of prevalence estimates reported in the literature when different definitions are used in different studies. The use of different definitions creates difficulties when pooling and comparing results from different countries so standard definitions are required for these purposes (Grant &

Booth, 2009). Any standard definition needs to incorporate all constipation symptoms and this is the basis of the Rome criteria (Rao, 2007). Definitions of constipation based on bowel motion frequency alone are not adequate because a bowel motion frequency of fewer than three per week is one of the least prevalent symptoms as reported in this thesis research and others (Lee et al., 2014;

Patimah, Lee, & Dariah, 2017). Although it is the most complex definition, this research shows that the Rome III criteria (now Rome IV) are the best for defining chronic constipation.

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This research found that constipation occurs commonly in Australian adults and judging if the prevalence is high or low typically requires international comparisons to be made (Mugie, Benninga,

& Di Lorenzo, 2011; Schmidt & Santos, 2014). To make valid comparisons of the Australian constipation prevalence to that of other countries, studies must have used the same definition and data collection method (Grant & Booth, 2009). The prevalence of chronic constipation in the

Australian general adult population (24.0 %) appears to be comparable with that of the Netherlands

(24.5%) and Japan (28.0%) in studies where Rome III definitions and online surveys were also used

(Meinds, van Meegdenburg, Trzpis, & Broens, 2017; Tamura et al., 2016). Similarly, in Australian older adults, the prevalence of any constipation (13.8%) was comparable with that of the UK (13.8%) and Indonesia (16.5%) in studies where self-reported constipation with no specified time period and face-to-face interviews were used (Chaplin, Curless, Thomson, & Barton, 2000; Suyasa, Paterson,

Xiao, & Lynn, 2011).

In the Australian general adult population, this research shows that 40% of those with any constipation and 14% of those with chronic constipation do not use laxatives to manage the condition. In older adults, the usage of laxatives is less with three quarters of those reporting constipation not using laxatives. Similar results have been reported elsewhere (Lee et al., 2014). This indicates that either non-laxative methods are used to manage constipation or constipation is under-treated in the community. Conversely, not all laxative users appear to have constipation. In the general population, 15% of laxative users did not report constipation and in elderly adults, two thirds of laxative users did not report constipation. Up to 7% of laxative users not reporting constipation has been noted elsewhere (Galvez et al., 2006; Heaton & Cripps, 1993; Suyasa et al.,

2011). Although it is possible in these cases that laxatives may be used sometimes for purposes other than prevention of constipation e.g. weight loss, this is unlikely to be the case in the elderly where it assumed that laxatives are being used successfully for prevention. It has been acknowledged that the prevalence of constipation in the community may be higher if not for the

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prophylactic use of laxatives (Bosshard, Dreher, Schnegg, & Bula, 2004; Talley, 2004) which acts as a potential confounder in determining the true prevalence in the community.

If the prevalence of laxative use in the community is unknown, healthcare professionals and policy makers will be unaware of the extent of laxative usage and will be unable to effectively plan improved interventions and public health programs. This may result in more appropriate use of laxatives with better health outcomes and reduced financial burden. This research shows that, in the

Australian general adult population, the national prevalence of laxative use in the community is 37%.

This is the first study in Australia to report the prevalence of laxative use and the first study globally to use an internationally accepted laxative definition such as the ATC definition, a specified recall time period, and a nationally representative sample of appropriate size. The few international studies reporting prevalence of laxative use in the community have shown that prevalence estimates range widely. One possible explanation for these wide ranges is that in the majority of studies laxatives have been either poorly defined or not defined by investigators. In the latter case, this means that laxatives are entirely self-defined by study participants. This makes it difficult to determine what agents are included or excluded in each study. An important consideration is the inclusion or exclusion of fibre products and bulk-forming laxatives in any definition. Also, some studies have excluded suppositories and enemas. Because a standard definition has not been used, any comparisons or pooling of different studies are challenging (Grant & Booth, 2009). However, the central issue is that, without a proper laxative definition, it is not at all clear what the actual prevalence of laxative use is in the community. The prevalence of laxative use in Australia as reported in this research might appear to be much higher than that reported in other countries but valid comparisons cannot be made because other studies have lacked laxative definitions and had different study designs. However, comparisons are possible in the older adult population. Using the same age range, data collection method and similar laxative definition, US studies have reported the prevalence in the community to be 10% (Ruby, Fillenbaum, Kuchibhatla, & Hanlon, 2003; Stoehr,

Ganguli, Seaberg, Echement, & Belle, 1997) which is comparable to the 6% prevalence (which 164

increased to 15% over 11 years) reported here. Therefore, whilst laxative usage in Australian older adults may be similar to US older adults, it is not possible to determine how laxative usage in the general adult population compares internationally.

With the aging population in Australia and elsewhere, an understanding of the extent of constipation and laxative use in older adults is important for planning future health programs. This subpopulation contributes more to the financial burden (Bosshard et al., 2004) and also is affected more in terms of quality of life (Wald et al., 2007) and physical consequences (Dennison et al., 2005;

Gallagher, O'Mahony, & Quigley, 2008). Although the national survey shows the prevalence of chronic constipation and laxative use in older adults is lower than younger age groups, both any constipation and laxative use increase over time in older adults. It is hypothesised that the increased prevalence of constipation with age in older populations, particularly above 80 years, may be more related to secondary causes (comorbid conditions and medications) than anything else (Gallagher &

O'Mahony, 2009).

An understanding of the prevalence of constipation and the prevalence of laxative use using standard definitions would allow more meaningful comparisons between countries and may also provide the ability to pool results, both of which would provide an indication of how public health programs impact prevalence and of how prevalent constipation and laxative use is worldwide. This in turn may lead to improvements in management and improved health outcomes.

8.1.2 Factors associated with constipation in the community

There are many factors that could potentially be associated with constipation and elucidation of the key factors would provide assistance for healthcare professionals in the diagnosis and treatment of constipation. Apart from female gender and some health-related factors, it is unclear whether most other factors are associated with constipation because of insufficient evidence or conflicting data

(Leung, 2007; Muller-Lissner, Kamm, Scarpignato, & Wald, 2005). The research presented in this

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thesis provides some clarification of the importance of each factor in both general adult and older adult populations. It is the first study to investigate a wide range of associated factors in the same general adult population sample using multivariate analysis. The study provides further evidence for factors previously reported in population-based studies to be associated with chronic constipation in adults as well finding evidence for some factors not previously reported. Despite widely held beliefs about factors such as physical activity and fluid intake being associated with constipation, no association was found for these in this research. In elderly adults, only two factors, poor self-rated health and a higher need for assistance with activities of daily living, were associated with any constipation.

This research also found that increasing age is not associated with chronic constipation in the general adult population. In fact, chronic constipation is less prevalent in older age groups (55 years and above) compared to younger age groups. Similar results have been reported previously in

Australia (Howell, Quine, & Talley, 2006) and elsewhere (Jun et al., 2006; Wald et al., 2010). It has been hypothesised that this might be the result of increased laxative use in older adults (Bosshard et al., 2004). However, the current research shows this is not the case as there is a lower prevalence of laxative use in older adults compared to younger age groups in the general population which suggests that older adults may be using laxatives more efficiently after years of trial and error (Selby

& Corte, 2010). Whilst chronic constipation is less prevalent in older adults compared to younger age groups, longitudinal data in older Australian adults indicates that constipation prevalence increases with age beyond 75 years confirming results reported elsewhere (McCrea, Miaskowski, Stotts,

Macera, & Varma, 2009; Mugie et al., 2011).

There are many complexities involved when identifying factors associated with constipation in population-based studies. Some factors identified as being associated with constipation could be potential risk factors, or they could be caused by constipation or both (e.g. poor self-rated health, haemorrhoids, depression) (Nellesen et al., 2013). For comorbid conditions, it is possible that

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medications being used as treatment may be contributing to the constipation. In conditions such as depression, musculoskeletal disorders and cardiovascular diseases, constipation is a known side effect of many medications used for treatment (Branch, 2009). Also, differences in constipation definitions, population samples, study designs, data collection methods and analyses may contribute to the different results obtained in population-based studies. Published cross-sectional studies investigating factors associated with constipation have tended to focus on a small number of factors of interest, ignoring other confounding variables. In addition, many early studies have assessed factors only on univariate analysis, not multivariate, and have therefore not taken all confounding variables into account.

8.1.3 Characterisation of laxative use in the community

Laxative utilisation in the community has been rarely researched and it is unknown how today’s laxatives are chosen and used. Without this information it is not possible to consider the development of improved management guidelines (World Health Organisation, 2003). This thesis provides valuable information on OTC laxative choice and use by adults in Australia.

In this research it was found that all OTC laxative classes are used for both prevention and treatment of constipation. Different laxatives have different onsets of action and certain laxatives such as contact laxatives are not always considered suitable for long term use (Selby & Corte, 2010; Tytgat et al., 2003), therefore some are better suited for treatment than prevention and vice versa. This research indicates that laxatives are being chosen and used inappropriately with or without the advice of healthcare professionals (pharmacists, doctors, nurses). This may be because algorithms for managing constipation by healthcare professionals are empirically based i.e. based on consensus based experience rather than evidence based i.e. based on controlled clinical trials (Eoff & Lembo,

2008) and do not take into account the use of laxatives for prevention. All laxative agents may have side effects (Xing & Soffer, 2001), some have precautions for use and some are contraindicated in certain situations (Tytgat et al., 2003). There are many different OTC laxative products available and

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choice of the appropriate laxative can be daunting for the consumer (Shibata et al., 2016) and may also pose difficulties for the healthcare professional. Selection of the appropriate laxative will depend on the situation and purpose of use. This research indicates that behavioural change is warranted for both consumers and healthcare professionals regarding appropriate use of laxatives and this may require re-education. Healthcare professional education needs to incorporate, for each laxative agent, an understanding of the modes of action, onsets of action and potential for use as a preventative or treatment as well as evidence –based research on safety and effectiveness. Current thinking on these issues should be provided in continuing professional education (CPD) programs.

For consumers, information on constipation and management with laxatives can be provided by healthcare professionals or directly via information leaflets, magazine articles or online from unbiased websites. It is challenging however for consumers not to be influenced by product advertising.

This is the first study to investigate the choice and use of laxatives for prevention and treatment of constipation although international studies have previously reported laxative classes chosen for the overall management of constipation (Harris, Horn, Kissous-Hunt, Magnus, & Quigley, 2017; Irvine,

Ferrazzi, Pare, Thompson, & Rance, 2002; Motola et al., 2002; Muller-Lissner, Tack, Feng, Schenck, &

Specht Gryp, 2013). Prior to this thesis research, the sources influencing laxative choices were largely unknown, particularly the involvement of healthcare professionals in recommending appropriate laxative agents for the intended purpose i.e. prevention or treatment of constipation.

Healthcare professional involvement occurs in 56% of laxatives chosen to manage constipation in the general adult population with a variety of other sources influencing the choice of laxative. In elderly adults, half of the laxatives used are prescribed by a doctor which might be expected because of the higher prevalence of comorbidities and prescribed medication (Song, 2012; Talley et al.,

1996). The wide availability and variety of OTC laxative products, and different sources of information, make it challenging for a consumer to choose the most appropriate laxative (Shibata et al., 2016). Since almost 60% of laxatives are purchased in a pharmacy, there is an opportunity for 168

pharmacists to make recommendations to ensure appropriate choice and use (Shibata et al., 2016;

Tytgat et al., 2003). However, evidence from this research and a study conducted in USA, UK and

Germany (Kamm et al., 2008) indicates that pharmacists may need to improve their knowledge of constipation and laxatives to ensure provision of appropriate advice to consumers.

OTC laxatives are widely available in many outlets in Australia and it is not known if consumers are always satisfied with laxative performance. Although more research into the effectiveness of methods for preventing and treating constipation may be needed (Petticrew, Watt, & Sheldon,

1997), knowing how effective laxatives are in practice is critical to understanding how to optimize laxative use (World Health Organisation, 2003). Regardless of whether laxatives are used for prevention or treatment of constipation, this research shows that they are perceived by consumers to be effective in only half of the uses. Usage of multiple laxatives in both general adult and elderly populations is a further indication of the dissatisfaction level with the performance of individual laxatives. Research conducted in healthcare professionals also shows dissatisfaction with laxatives

(Harris et al., 2017). Dissatisfaction with effectiveness may be the result of inappropriate laxative choice and inappropriate use for the intended purpose. Whilst there is a paucity of clinical trials of

OTC laxatives in treating constipation (Nelson et al., 2016; Pare & Fedorak, 2014) and very few in preventing constipation (Petticrew et al., 1997), laxatives may still be used effectively if appropriate choices are made. New prescription laxatives have not shown any better efficacy than OTC laxatives to date (Ford & Suares, 2011; Nelson et al., 2016) so more judicious use of OTC laxatives may be necessary to increase effectiveness and improve constipation management in the community.

Appropriate laxative use, which may involve revising current management guidelines to incorporate laxative use for prevention as well as treatment, along with better educated healthcare professionals and in turn better informed consumers, should result in beneficial consequences in terms of improved outcomes, improved quality of life and reduced financial burden.

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8.2 Strengths and limitations

There were a number of strengths of this research. Data was sourced from two large surveys of the

Australian adult population. One survey was conducted in a large, nationally representative sample of the Australian general adult population. This national survey was supplemented with data from the ALSA survey of the older adult population. Analysis of the ALSA data, which preceded the national survey, revealed that laxatives were possibly being used for prevention of constipation so questions regarding laxative use for prevention as well as treatment were then included in the questionnaire used in the national survey.

Also, some limitations of the research need to be acknowledged. There is the possibility of some selection or avidity bias because, in both the national survey and the ALSA survey, those with an interest in constipation might have been more likely to complete the questionnaires but this is no different to that of most other surveys. Although all age groups in the national survey closely matched census data at the time of the survey, the elderly as defined as 75 years and older (Orimo,

2006) represented only 15% of the group aged 65 years and older. However, analysis of the ALSA survey data compensated for this. In the ALSA survey, no definition of constipation was provided but it should be noted that the baseline ALSA data was collected in 1992/93 which preceded publication of the Rome I criteria in 1994. In analysing both the national survey and the ALSA data, any non- laxative measures used to manage constipation have not been taken into account. This includes lifestyle changes, dietary changes and other non-pharmacological interventions such as acupuncture, all of which may have occurred concurrently with laxative use. As with any studies of this kind, much depends on the recall ability of participants. For medications in the national survey, the provision of an extensive list of laxative products in the questionnaire as well as non-prescription medications served to improve product recall (Gama, Correia, & Lunet, 2009). In the ALSA survey, participants were required to show medications to the interviewer and this was supplemented with prescription medication data.

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8.3 Conclusion

The research presented in this thesis contributes new knowledge about adult constipation and OTC laxative use in the community and provides insights hitherto unknown which could be used in the future to assist in developing improved management guidelines. Adult constipation and OTC laxative use in Australia are common occurrences with a quarter of the population reporting chronic constipation and a third of the population reporting laxative use. Since definitions used for both constipation and laxatives may impact prevalence estimates, standard definitions are needed to enable valid comparisons and to determine true prevalence. The identification of various factors associated with constipation may assist in diagnosis and management of the condition. The possibility of both under usage and over usage of OTC laxatives is indicated by the lack of correlation between constipation and laxative use. All OTC laxatives are used to treat and to prevent constipation but they are often perceived to be ineffective and healthcare professionals are not always involved in the choice of laxatives. To ensure better outcomes with OTC laxatives, it seems that healthcare professionals, particularly pharmacists, need to be more involved with product selection to ensure that appropriate products are selected and used appropriately for the intended purpose i.e. treatment or prevention of constipation. Furthermore, constipation management guidelines may need to be revised to differentiate between the use of OTC laxatives for treatment and prevention of constipation in order to optimize management with laxatives in the community.

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8.4 Recommendations for future research

The results of the research presented in this thesis suggest several opportunities for further research. Although this quantitative research clearly shows the utilisation of laxatives for both treatment and prevention of constipation, some qualitative research could be undertaken in a mixed method approach to provide some further insights which may help to refine proposed revisions to management guidelines. Such research could be conducted with consumers but it may be more informative if conducted with healthcare professionals to uncover current thinking as to why certain laxatives are chosen for prevention versus treatment. The main outcome from this thesis research is that current guidelines for the management of constipation do not reflect the usage of laxatives for prevention and treatment. It is proposed that new guidelines based on this research outcome should be developed and then trialled in clinical practice by doctors and pharmacists. If successful in improving constipation management, the new guidelines should be published and then instituted with education of both healthcare professionals and consumers. The lack of correlation between constipation and OTC laxative use in adults is another area for further research which could investigate the apparent under usage and over usage of laxatives, particularly over usage of laxatives for prevention when non-pharmacological methods may be more appropriate.

“The scientific man does not aim at an immediate result. He does not expect that his advanced ideas will be readily taken up. His work is like that of the planter—for the future. His duty is to lay the foundation for those who are to come, and point the way.”

Nikola Tesla (1856-1943)

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Patimah, A. W., Lee, Y. Y., & Dariah, M. Y. (2017). Frequency patterns of core constipation symptoms among the Asian adults: A systematic review. BMC Gastroenterology, 17 (1),115.

Petticrew, M., Watt, I., & Sheldon, T. (1997). Systematic review of the effectiveness of laxatives in the elderly. Health Technology Assessment, 1(13), i-iv, 1-52.

Rao, S. S. C. (2007). Constipation: Evaluation and Treatment of Colonic and Anorectal Motility Disorders. Gastroenterology Clinics of North America, 36(3), 687-711.

Ruby, C. M., Fillenbaum, G. G., Kuchibhatla, M. N., & Hanlon, J. T. (2003). Laxative use in the community-dwelling elderly. American Journal of Geriatric Pharmacotherapy, 1(1), 11-17.

Sandler, R. S., Jordan, M. C., & Shelton, B. J. (1990). Demographic and dietary determinants of constipation in the US population. American Journal of Public Health, 80(2), 185-189.

Schmidt, F. M. Q., & Santos, V. L. C. d. G. (2014). Prevalence of constipation in the general adult population: an integrative review. Journal of Wound, Ostomy, & Continence Nursing, 41(1), 70-76.

Selby, W., & Corte, C. (2010). Managing constipation in adults. Australian Prescriber, 33(4), 116 -119

Song, H. J. (2012). Constipation in community-dwelling elders: Prevalence and associated factors. Journal of Wound, Ostomy and Continence Nursing, 39(6), 640-645.

Suyasa, I. G. P. D., Paterson, J. B., Xiao, L. D., & Lynn, P. A. (2011). Prevalence of constipation in community dwelling older people in Indonesia. Journal of Gastroenterology and Hepatology, 4), 84.

Talley, N. J. (2004). Definitions, epidemiology, and impact of chronic constipation. Reviews in Gastroenterological Disorders, 4(Suppl. 2), S3-S10.

Tytgat, G. N., Heading, R. C., Muller-Lissner, S., Kamm, M. A., Scholmerich, J., Berstad, A., . . . Briggs, A. (2003). Contemporary understanding and management of reflux and constipation in the general population and pregnancy: a consensus meeting. Alimentary Pharmacology & Therapeutics, 18(3), 291-301.

World Health Organisation. (2003). Introduction to Drug Utilization Research. Oslo: World Health Organisation.

Xing, J. H., & Soffer, E. E. (2001). Adverse effects of laxatives. Diseases of the Colon & Rectum, 44(8), 1201-1209.

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Appendix 1:

Survey Questionnaire

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This survey is being done to provide a better understanding of constipation and its treatment in the community. Please answer ALL questions. To answer, please place a tick in the relevant circle, or circle the relevant word, or write in the space provided. Please answer all questions honestly. If you are uncertain, please record your best guess. All responses will be treated anonymously and all information provided will be kept strictly confidential.

You have consented to participate in this survey as you have consented to participate in any surveys conducted by this market research agency by your enrolment in the agency’s database. However, if you do not wish to participate in this particular survey then you should not proceed to answer any questions. Please confirm that you have read the Participant Information Statement and that you wish to proceed:

o I have read the Participant Information Statement and I wish to proceed to answer the survey questions.

o I do not wish to proceed to answer the survey questions.

1. Gender: o Male o Female

2. Age (years):______

3. Residence: What is your residential postcode?______

4. Education: Which one of the following best describes the highest qualification that you have completed? o Left school before completing high school (year 12) o Completed high school (Year 12) o Bachelor degree, masters degree or doctorate

5. Income: Before tax is taken out, which of the following best describes your household’s total income over the last 12 months? o Less than $50,000 o $50,000 to $100,000 o More than $100,000

6. Work status: Which of the following best describes your current work status? o Working full time o Working part time o Not working

Please think about your bowel motion experiences over the last 3 months (since ……….) in answering Questions 7 to 14.

7. Do you often have fewer than 3 bowel movements each week?

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(Note: When we say “often”, we mean more than 25% or a quarter of the time in the last 3 months.) o Yes o No

8. Do you often strain to have a bowel movement? o Yes o No

9. Are your stools often hard? o Yes o No

10. After finishing a bowel movement, do you often feel that there is still stool which needs to be passed? o Yes o No

11. Do you often feel a blockage in the bowel which makes it difficult to pass the stool? o Yes o No

12. Do you often need to press your finger in or around the anus or vagina in order to complete a bowel movement? o Yes o No

13. If you answered yes to any of questions 7 to 12, did any of these symptoms begin more than 9 months ago? o Yes o No

14. If you did not take any laxative products, do you think you would ever have loose stools? o Yes o No o Don’t know

15. Have you often felt constipated during the last 3 months? o Yes o No Please think about your bowel motion experiences over the last 12 months (since ……….) in answering the remaining questions (unless stated otherwise).

16. Have you felt constipated at any time during the last 12 months? o Yes

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o No (Go to Question 19)

17. For how long has constipation been a problem for you? o Up to 3 years o 3 to 10 years o More than 10 years o Constipation is usually not a problem for me . 18. When you are constipated, do you experience any of the following symptoms? Please tick all that apply. o Bloating o Abdominal pain or cramps o Flatulence or gas o Nausea or vomiting o Heartburn or reflux o Cold hands and feet o Other (please specify) ______o None of these

19. In the last 12 months, how many bowel movements did you usually have each week? o 1 or none o 2 o 3 to 4 o 5 to 8 o 9 to 14 o More than 14

20. Have you ever been diagnosed by a doctor as having irritable bowel syndrome (IBS)? o Yes o No You may have taken certain actions (including using laxative products) to prevent or treat constipation during the last 12 months. Firstly we will ask questions about treating constipation, then we will ask questions about prevention of constipation.

If you have experienced constipation in the last 12 months (answered “yes” to Question 16), please answer the following questions regarding treatment. If not, please go to Question 37.

“Treatment” means that when constipation is experienced, a laxative product or some other means is used to try to treat or fix the problem i.e. to relieve the symptoms of constipation):

21. Which laxative products do you usually use to treat constipation? Please circle brands used.

Metamucil/Fybogel/Agiofibe/Psyllium Normafibe Coloxyl with senna/Soflax Coloxyl tablets/ Coloxyl drops 180

Agarol/Parachoc Senokot/Sennetabs/Laxettes/Ford tablets/Nu-Lax/Prunelax Dulcolax tablets/Bisalax tablets/Lax-Tab Dulcolax SP drops Dulcolax suppositories/Fleet suppositories/Glycerol suppositories/Petrus Bisacodyl suppositories Bisalax enema/Fleet enema Microlax enema/Micolette enema Fleet Phospho Soda liquid Epsom salts Sorbilax liquid Duphalac/Actilax/Genlac/Lac-dol/Lactocur/GenRx Lactulose Movicol/Movicol Half/Osmolax/Medi Health Clear Lax Nucolox/Agiolax/Normacol Plus Peritone Other (please name products used): ______Not applicable (I don’t use laxatives to treat constipation, either because I don’t treat my constipation, or I use other means to treat constipation): (Go to Question 30)

For each laxative product circled above, please write the name in the space provided on the top of the next page and then answer the questions which follow:

[Please copy this page if required for additional products]

Product name (laxative for treatment of constipation): ______

22. How frequently do you use the laxative product? o Every day or most days o At least once a month o Only when required

23. For how long have you used this laxative product? o Up to 3 years o 3 to 10 years o More than 10 years

24. Why did you choose this laxative product? o Prescribed by doctor (Go to Question 26) o Recommended by doctor (Go to Question 26) o Recommended by pharmacist (Go to Question 26) o Recommended by pharmacy staff (Go to Question 26) o Recommended by relative or friend (Go to Question 26) o Selected by myself o Other (please specify):______(Go to Question 26)

25. If you selected the product yourself, what influenced your selection? o Advertising for the product o Information published in magazines or newspapers o Information on the Internet o Other (please specify):______

26. From where do you usually purchase the laxative product? 181

o Pharmacy o Supermarket o Health food store o Other (please specify):______

27. Are you satisfied that the laxative product is effective in treating your constipation? (Note: When we say “effective”, we mean successful treatment of most of your constipation symptoms.) o Yes o No o Sometimes but not always effective o Effective only when used in combination with other treatments

28. Do you think that the laxative product might have caused any side effects? o Yes o Maybe (not sure) o No (Go to Question 30)

29. You think the laxative product might have caused side effects, what side effects have you noticed? o Bloating o Wind o Abdominal pain o Diarrhoea o Other (please specify):______

Other treatments for constipation:

30. Apart from laxatives, have you tried any other treatments for constipation? See the next question for a list of various other treatments. o Yes o No (Go to Question 37)

31. You said that you have tried other treatments for constipation apart from laxatives, which other treatments have you tried? o Eating foods containing high fibre o Eating specific foods which have a laxative effect e.g. prunes, figs, liquorice, rhubarb o Avoiding certain foods which may be constipating e.g. bananas, chocolate o Drinking more fluids o Increasing exercise and physical activity o Changing medications or adjusting the dose of medications (excluding laxative products) o Acupuncture o Other (please specify):______

For each action circled above, please write the action in the space provided on the top of the next page and then answer the questions which follow:

[Please copy this page if required for additional treatments]

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Other treatment of constipation: ______

32. Why did you choose it? o Prescribed by doctor o Recommended by doctor o Recommended by pharmacist o Recommended by pharmacy staff o Recommended by relative or friend o Information published in magazines or newspapers o Information on the Internet o Other (please specify):______

33. For how long have you used this treatment? o Up to 3 years o 3 to 10 years o More than 10 years

34. Are you satisfied that it is effective in treating your constipation? (Note: When we say “effective”, we mean successful treatment of most of your constipation symptoms.) o Yes o No o Sometimes but not always effective o Effective only when used in combination with other treatments

35. Do you think that it might have caused any side effects? o Yes o Maybe o No (Go to Question 37)

36. You think it might have caused side effects, what side effects have you noticed? o Bloating o Wind o Abdominal pain o Diarrhoea o Other (please specify):______

We will now ask about what actions you may have taken to prevent constipation. “Prevention” means that some action is taken to prevent constipation occurring.

37. Which laxative products do you usually use to prevent constipation? Please circle all brands used.

Metamucil/Fybogel/Agiofibe/Psyllium Normafibe Coloxyl with senna/Soflax Coloxyl tablets/ Coloxyl drops Agarol/Parachoc Senokot/Sennetabs/Laxettes/Ford tablets/Nu-Lax Dulcolax tablets/Bisalax tablets/Lax-Tab Dulcolax SP drops Dulcolax suppositories/Fleet suppositories/Glycerol suppositories/Petrus Bisacodyl suppositories Bisalax enema/Fleet enema

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Microlax enema/Micolette enema Fleet Phospho Soda liquid Epsom salts Sorbilax liquid Duphalac/Actilax/Genlac/Lac-dol/Lactocur/GenRx Lactulose Movicol/Movicol Half/Osmolax/Medi Health Clear Lax Nucolox/Agiolax/Normacol Plus Peritone Other (please name products used): ______Not applicable (I don’t use laxatives to prevent constipation, either because I don’t try to prevent my constipation, or I use other means to prevent constipation): (Go to Question 46)

For each laxative product circled above, please write the name in the space provided on the next page and then answer the questions which follow:

[Please copy this page if required for additional products]

Product name (laxative for prevention of constipation): ______

38. How frequently do you use the laxative product? o Every day or most days o At least once a month o Only when required

39. For how long have you used this laxative product? o Up to 3 years o 3 to 10 years o More than 10 years

40. Why did you choose this laxative product? o Prescribed by doctor (Go to Question 42) o Recommended by doctor (Go to Question 42) o Recommended by pharmacist (Go to Question 42) o Recommended by relative or friend (Go to Question 42) o Selected by myself o Other (please specify):______(Go to Question 42)

41. If you selected the product yourself, what influenced your selection? o Advertising for the product o Information published in magazines or newspapers o Information on the internet o Other (please specify):______

42. From where do you usually purchase the laxative product? o Pharmacy o Supermarket o Health food store o Other (please specify):______

43. Are you satisfied that the laxative product is effective? (Note: When we say “effective”, we mean successful prevention of most of your constipation symptoms.) o Yes o No o Sometimes but not always effective o Effective only when used in combination with other means of prevention 184

44. Do you think that the laxative product might have caused any side effects? o Yes o Maybe (not sure) o No (Go to Question 46)

45. You think the laxative product might have caused side effects, what side effects have you noticed? o Bloating o Wind o Abdominal pain o Diarrhoea o Other (please specify):______

Other ways to prevent constipation:

46. Apart from laxatives, have you ever tried any other means to prevent constipation? See the next question for a list of various other ways to prevent constipation. o Yes o No (Go to Question 53)

47. You said you have tried other means to prevent constipation apart from laxatives, which other things have you tried? o Eating foods containing high fibre o Eating specific foods which have a laxative effect e.g. prunes, figs, liquorice, rhubarb o Avoiding certain foods which may be constipating e.g. bananas, chocolate o Drinking more fluids o Increasing exercise and physical activity o Changing or adjusting the dose of medications (excluding laxative products) o Other (please specify):______

For each action above, please write the name in the space provided on the next page and then answer the questions which follow:

[Please copy this page if required for additional means of prevention]

Other means to prevent constipation: ______

48. Why did you choose it? o Prescribed by doctor o Recommended by doctor o Recommended by pharmacist o Recommended by pharmacy staff o Recommended by relative or friend o Information published in magazines or newspapers o Information on the Internet o Other (please specify):______

49. For how long have you used this means of prevention? 185

o Up to 3 years o 3 to 10 years o More than 10 years

50. Are you satisfied that it is effective? (Note: When we say “effective”, we mean successful prevention of most of your constipation symptoms.) o Yes o No o Sometimes but not always effective o Effective only when used in combination with other means of prevention

51. Do you think that it might have caused any side effects? o Yes o Maybe (not sure) o No (Go to Question 53)

52. You think it might have caused side effects, what side effects have you noticed? o Bloating o Wind o Abdominal pain o Diarrhoea o Other (please specify):______

53. Have you felt constipated at any time during the last 2 weeks? o Yes o No

Please recall any medications (excluding laxative products) prescribed by a doctor which you have used in the last 2 weeks. Also please recall any medications (excluding laxative products) which were not prescribed by a doctor that you have used in the last 2 weeks.

54. Which medicines that were prescribed by a doctor did you use in the last 2 weeks?

If you did not use any prescription medicines in the last 2 weeks, go to Question 58.

List all prescribed medicines here: ______

For each prescription medicine above, please write the name in the space provided on the next page and then answer the questions which follow:

[Please copy this page if required for additional prescription medicines]

Name of prescription medicine: ______

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55. How often did you take or use it? o Frequently (most days and/or nights) o Only when required

------Name of prescription medicine: ______

56. How often did you take or use it? o Frequently (most days and/or nights) o Only when required ------Name of prescription medicine: ______

57. How often did you take or use it? o Frequently (most days and/or nights) o Only when required

58. Which medicines that you have obtained without a prescription did you use in the last 2 weeks? Please circle products/brands used.

Aspirin Ibuprofen (Nurofen or other brand) Diclofenac (Voltaren or other brand) Paracetamol (Panadol/Panamax or other brand) Codeine (Panadeine or other brand) Antihistamines (Telfast/Claratyne/Zyrtec/Polaramine/Phenergan or other) Antacids (Mylanta, Gastrogel,Gaviscon or other) Antidiarrhoeals (Imodium, Gastro-Stop, Diareze, Lomotil, Lofenoxal or other) Cough & cold products (Codral, Dimetapp or other) Hyoscine (Kwells, Travacalm,Buscopan, Donnatab or other) Peppermint oil (Mintec or other) Iron (Ferrogradumet, FGF,Ferrograd C or other) Calcium (Caltrate, Calcia, Citracal, Cal-Sup, Ostelin Calcium, Ostevit-D & Calcium or other) Other (please name products used; include any herbal medicines and vitamin or mineral supplements): ______

If you did not use any non-prescription medicines or vitamin/mineral products in the last 2 weeks, go to Question 62.

For each non-prescription medicine circled above, please write the name in the space provided on the next page and then answer the questions which follow:

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[Please copy this page if required for additional non-prescription medicines]

Name of non-prescription medicine: ______

59. How often did you take or use it? o Frequently (most days and/or nights) o Only when required

------Name of non-prescription medicine: ______

60. How often did you take or use it? o Frequently (most days and/or nights) o Only when required ------Name of non-prescription medicine: ______

61. How often did you take or use it? o Frequently (most days and/or nights) o Only when required

62. Do you have any of the following long-term health conditions (conditions that have lasted or are likely to last for 6 months or more)? Tick all that apply.

o Diabetes

o Multiple sclerosis

o Parkinson’s disease

o Thyroid disease

o Dementia

o Angina pectoris or other heart conditions

o High blood pressure (hypertension)

o Urinary incontinence

o Depression

o Haemorrhoids

o Arthritis

o Epilepsy

o Hayfever

o Anaemia

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o Osteoporosis

o Cancer

o Obesity

o Varicose veins

o Other (please specify): ______

o None of the above

63. Have you been pregnant during the last 12 months? o Yes o No

64. Have you had any surgery or operations in a hospital in the last 12 months? o Yes o No (Go to Question 66)

65. What were the operations or surgery that you had? ______

66. Were you a regular smoker (at least once a day) during the last 12 months? o Yes o No

67. On average, how many standard alcoholic drinks have you had per week in the last 12 months? One standard drink = 1 small bottle (stubbie) of full strength beer, or one glass of wine, or one shot of spirits

o None o 1 or 2 drinks o 3 to 6 drinks o 7 to 10 drinks o More than 10 drinks

68. Did you regularly (at least once a day) drink any of the following beverages in the last 12 months? Tick all that apply.

o Tea (other than herbal, green, Chinese or Japanese teas) o Herbal or green tea o Chinese or Japanese tea

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o Coffee o Cola soft drinks (e.g. Coca Cola) o Water o Juice o Other (please specify): ______

69. Approximately how many cups or glasses for each of these beverages do you normally drink each day?

Beverage: ______

o None o 1 cup or glass per day o 2 cups or glasses per day o 3 cups or glasses per day o 4 cups or glasses per day o 5 or more cups or glasses per day

70. Did you engage in any regular vigorous exercise in the last 12 months? (Vigorous exercise is exercise which causes a large increase in heart rate or breathing, for example playing tennis or jogging. Regular means at least two times per week.)

o Yes (Go to Question 73) o No

71. If “no”, did you engage in any regular moderate exercise in the last 12 months? (Moderate exercise is exercise which causes a little or moderate increase in heart rate or breathing, for example swimming or walking briskly. Regular means at least two times per week.) o Yes (Go to Question 73) o No

72. If “no”, did you ever get any limited exercise such as walking to shops or similar activity during the last 12 months? o Yes o No (unable to exercise at all)

73. During the last 12 months, have you travelled away from home (e.g. holiday or business trip) or experienced any other significant change in your home environment? o Yes, I have travelled during this time o Yes, my home environment changed significantly during this time o No, I have not travelled and there have been no significant changes in my home environment

74. How would you rate your overall health during the last 12 months? 190

o Excellent o Very good o Good o Fair o Poor

75. Have you ever sought the help of a health care professional (doctor, pharmacist etc) for constipation during the last 12 months? o Yes o No

76. If you answered “Yes”, which health care professional did you consult? o Doctor o Pharmacist o Other (please specify) ______

Thank you for your participation in this survey. Your contribution to our research is greatly appreciated. Please note: If you have been troubled with constipation for a long time which has not been satisfactorily treated, or if you have used frequent or large amounts of laxatives (with or without success), it is recommended that you should consult your doctor for advice.

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Appendix 2: Ethics approval letter

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Appendix 3:

Participant information statement

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Constipation and laxative use in the community

PARTICIPANT INFORMATION STATEMENT

(1) What is this study about?

You are invited to take part in a research study to investigate the prevalence of constipation and of laxative use in the Australian community.

This Participant Information Statement tells you about the research study. Knowing what is involved will help you decide if you want to take part in the research. Please read this sheet carefully and ask questions about anything that you don’t understand or want to know more about.

Participation in this research study is voluntary. So it’s up to you whether you wish to take part or not.

By giving your consent to take part in this study you are telling us that you:  Understand what you have read  Agree to take part in the research study as outlined below  Agree to the use of your personal information as described.

You will be given a copy of this Participant Information Statement to keep.

(2) Who is running the study?

The study is being carried out by the following researchers:  Dr Lisa Pont and Mr Barry Werth, Sydney Nursing School, University of Sydney  Assoc Prof Kylie Williams, Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney.

(3) What will the study involve for me?

If you agree to participate in this study, you will be asked to complete an online questionnaire concerning your bowel habits and your use of medications including laxative agents (and other ways of managing constipation) as well as other questions regarding your general health and wellbeing.

(4) How much of my time will the study take?

The questionnaire should take about 30 minutes to complete.

(5) Who can take part in the study?

If you are 18 years or older you can participate in the study provided that you are living in the community either in your own home or in rented premises. You cannot participate if you are living in a residential care facility such as a nursing home.

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(6) Do I have to be in the study? Can I withdraw from the study once I've started?

Being in this study is completely voluntary and you do not have to take part. Submitting your completed questionnaire is an indication of your consent to participate in the study. You can withdraw your responses any time before you have submitted the questionnaire. Once you have submitted it, your responses cannot be withdrawn because they are anonymous and therefore we will not be able to tell which one is yours.

(7) Are there any risks or costs associated with being in the study?

Aside from giving up your time, we do not expect that there will be any risks or costs associated with taking part in this study.

(8) Are there any benefits associated with being in the study?

You will be reimbursed for your time if you complete the entire questionnaire. The broader community may benefit from this study because it may provide a better understanding of constipation and its treatment, and this may lead to better management of constipation by healthcare professionals in the community.

(9) What will happen to information about me that is collected during the study?

By providing your consent, you are agreeing to us collecting personal information about you for the purposes of this research study. Your information will only be used for the purposes outlined in this Participant Information Statement, unless you consent otherwise.

Your information will be stored securely and your identity/information will be kept strictly confidential, except as required by law. Only the investigators named above will have access to information provided by you but in any case this information is provided anonomously. Study findings may be published, but you will not be individually identifiable in these publications.

(10) Can I tell other people about the study?

Yes, you are welcome to tell other people about the study.

(11) What if I would like further information about the study?

When you have read this information, Mr Barry Werth will be available to discuss it with you further and answer any questions you may have. If you would like to know more at any stage during the study, please feel free to contact Mr Barry Werth (Email: [email protected], phone: 0401 697 972) or Dr Lisa Pont (Phone: 9351 0563).

(12) Will I be told the results of the study?

It will not be possible to provide you with any feedback about the overall results of this study. This is because all of the responses to the questionnaire will be anonymous.

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(13) What if I have a complaint or any concerns about the study?

Research involving humans in Australia is reviewed by an independent group of people called a Human Research Ethics Committee (HREC). The ethical aspects of this study have been approved by the HREC of the University of Sydney [INSERT protocol number once approval is obtained]. As part of this process, we have agreed to carry out the study according to the National Statement on Ethical Conduct in Human Research (2007). This statement has been developed to protect people who agree to take part in research studies.

If you are concerned about the way this study is being conducted or you wish to make a complaint to someone independent from the study, please contact the university using the details outlined below. Please quote the study title and protocol number.

The Manager, Ethics Administration, University of Sydney:  Telephone: +61 2 8627 8176  Email: [email protected]  Fax: +61 2 8627 8177 (Facsimile)

This information sheet is for you to keep

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