key: cord-0876504-jlo8rlhz
authors: Ma, Christopher; Congly, Stephen E.; Novak, Kerri L.; Belletrutti, Paul J.; Raman, Maitreyi; Woo, Matthew; Andrews, Christopher N.; Nasser, Yasmin
title: Epidemiologic Burden and Treatment of Chronic Symptomatic Functional Bowel Disorders in the United States: A Nationwide Analysis
date: 2020-10-01
journal: Gastroenterology
DOI: 10.1053/j.gastro.2020.09.041
sha: d6cff4ed43a3ce63f2dabed203d839bb53bdcb5e
doc_id: 876504
cord_uid: jlo8rlhz

Background Functional bowel disorders (FBDs) are the most common gastrointestinal problems managed by physicians. We aimed to assess the burden of chronic symptomatic FBDs on ambulatory care delivery in the United States and evaluate patterns of treatment. Methods Data from the National Ambulatory Medical Care Survey were used to estimate annual rates and associated costs of ambulatory visits for symptomatic irritable bowel syndrome (IBS), chronic functional abdominal pain, constipation, or diarrhea. The weighted proportion of visits associated with pharmacologic and non-pharmacologic (stress/mental health, exercise, diet counseling) interventions were calculated, and predictors of treatment strategy were evaluated in multivariable multinomial logistic regression. Results From 2007-2015, ∼36.9 million [95% CI, 31.4-42.4] weighted visits in non-federal patients for chronic symptomatic FBDs were sampled. There was an annual weighted average of 2.7 million [95% CI, 2.3-3.2] visits for symptomatic IBS/chronic abdominal pain, 1.0 million [95% CI, 0.8-1.2] visits for chronic constipation, and 0.7 million [95% CI, 0.5-0.8] visits for chronic diarrhea. Pharmacologic therapies were prescribed in 49.7% [95% CI, 44.7%-54.8%] of visits, compared to non-pharmacologic interventions in 19.8% [95% CI, 16.0%-24.2%] of visits (P < .001). Combination treatment strategies were more likely to be implemented by primary care physicians and in patients with depression or obesity. The direct annual cost of ambulatory clinic visits alone for chronic symptomatic FBDs is ∼$358 million USD [95% CI, $233-482 million]. Conclusions The management of chronic symptomatic FBDs is associated with considerable health care resource utilization and cost. There may be an opportunity to improve comprehensive FBD management as fewer than 1 in 5 ambulatory visits include non-pharmacologic treatment strategies.

The functional bowel disorders (FBDs) represent a spectrum of chronic gastrointestinal (GI) conditions stemming from dysregulation of the gut-brain axis and are mediated by a complex interplay of abnormalities in gut motility, mucosal and immune function, intestinal microbiota diversity, central nervous system processing and visceral hypersensitivity. 1 The term FBD captures several conditions and the Rome IV criteria recognize five categories of FBDs: irritable bowel syndrome (IBS), functional constipation, functional diarrhea, abdominal bloating/distention, and unspecified FBD. 2 Importantly, all FBDs are characterized by chronic symptoms and absence of other explanatory anatomic or physiologic abnormalities. Over the past few decades, a conceptual framework for FBDs has evolved within an inclusive biopsychosocial model: this has resulted in advancements in both our understanding of the underlying pathophysiology as well as improved treatment options. [3] [4] [5] Nonetheless, FBDs remain the most common and often most challenging GI conditions to treat. [6] [7] [8] While the management of FBDs should be individualized for each patient, key tenets of treatment include establishing a strong therapeutic physician-patient relationship and comprehensively addressing the underlying cause of symptoms through both pharmacologic and non-pharmacologic approaches. For many patients, lifestyle changes represent a cornerstone in their treatment strategy. Several interventions have been studied in patients with chronic symptomatic FBDs, including increasing dietary fiber intake, limiting fermentable oligo-, di-, monosaccharides and polyols (FODMAPs), improving sleep hygiene, treating concomitant depression or anxiety, and increasing physical activity. Psychological interventions such as formal counseling regarding stress reduction, biofeedback techniques, cognitive behavioral or dynamic psychotherapy, and mind-body-breath interventions such as integrated yoga have also been studied. [9] [10] [11] [12] For patients with moderate-to-severe symptoms that impair quality of life, pharmacologic agents are often used adjunctively. Recently, several classes of advanced J o u r n a l P r e -p r o o f Ma et al.

treatments have been demonstrated to be effective and obtained approval for FBD indications in the US, including selective chloride channel activators, guanylate cyclase C agonists, nonabsorbable antibiotics, peripheral µ-opioid receptor agonists, and high affinity 5hydroxytryptamine receptor-4 agonists. 13, 14 As the number of treatment options in the therapeutic armamentarium for FBDs increases, so does the complexity of managing these patients in day-to-day practice. Most patients with FBDs are seen in the ambulatory outpatient setting where tight time constraints and pressures to increase high throughput efficiency are potential barriers to treating complex, multifactorial diseases. A detailed evaluation of current treatment practices and patterns for FBDs is therefore needed to identify potential therapeutic gaps and areas where the delivery and quality of comprehensive care can be improved. Furthermore, the impact of changes in treatment on the epidemiologic burden of FBDs has not been well studied. Although functional disorders are known to be the most common GI problem presenting to medical attention, estimates of the prevalence and cost associated with managing FBDs vary widely, depending on the study design, cohort definitions, geographic region, and sampling time frame. [15] [16] [17] [18] Understanding trends in health care resource utilization for FBDs will be critical for informing future resource allocation.

Therefore, we aimed to determine nationally representative and generalizable rates of ambulatory care utilization, estimate costs for outpatient clinic visits, and evaluate patterns of pharmacologic and non-pharmacologic treatment for FBDs in the US.

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We analyzed data collected in the National Ambulatory Medical Care Survey (NAMCS). NAMCS is a national, cross-sectional survey of non-federally employed office-based physicians primarily engaged in patient care, administered by the National Center for Health Statistics (NCHS).

Visits are sampled using a three-stage clustered probability sampling design, based on geographic region, physician specialty, and visits within individual physician practices. Data collection from a systematic random sample of visits to each clinic occurs over a one-week reporting period and is completed using a standardized patient record form. Patient record forms may be completed by physicians, medical office personnel, or by trained Census Bureau staff based on the medical chart. NAMCS collects data on patient demographics, reasons for the visit (up to three), physician diagnoses coded using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), investigations ordered, and both pharmacologic and non-pharmacologic interventions. Medications for each patient include those that were ordered, supplied, administered, or continued during the visit. Data from NAMCS between 2007 and 2015 was pooled to add power to our analyses.

The study population of interest was adult patients (≥18 years) presenting to ambulatory outpatient clinics with: 1) a provider diagnosis of a chronic FBD and; 2) active, chronic GI symptoms. To identify relevant encounters, we applied: 1) provider diagnostic codes used previously in analyses of NAMCS data and; 2) patient-reported symptom codes. 15 J o u r n a l P r e -p r o o f diarrhea 15950). Patients were categorized as having either 1) IBS/chronic abdominal pain; 2) chronic constipation; or 3) chronic diarrhea. If multiple diagnoses were coded (for example, a patient with IBS as the primary diagnosis and chronic constipation as a secondary diagnosis), we assigned the category by the highest-ranking diagnostic position (in this example, IBS).

Recognizing that the ICD-9-CM diagnostic coding for FBDs lacks specificity, we excluded patients with established GI pathology (abdominal hernias, colorectal cancer, diverticular disease, Crohn's disease, ulcerative colitis, cholelithiasis, pancreatitis, appendicitis, and Celiac disease). Both new consultations and follow-up visits for chronic GI symptoms were included.

However, to further improve the specificity of our study population for chronic FBDs, we excluded all visits for patients presenting with a new GI complaint (<3 months), because some of these patients may be diagnosed with non-functional pathology on future investigations that would not be captured in a cross-sectional study design. Furthermore, the diagnostic criteria for FBD requires chronicity in symptoms. To ensure the consistency of our findings, we conducted a sensitivity analysis including patients with a provider diagnosis of FBD but without active coded GI symptomatology at the time of the visit.

The primary outcome of interest in our study population was the treatment intervention, categorized as medications alone, non-pharmacologic intervention alone, combination pharmacologic and non-pharmacologic treatment, and no therapy. Medications (up to eight) are recorded and classified in NAMCS using the Lexicon Plus® Cerner Multum, Inc. database (Supplemental Table 1 ). We considered the following classes of relevant therapies for chronic symptomatic FBDs: laxatives, anti-diarrheal medications, tricyclic antidepressants, selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, benzodiazepines, anti-cholinergic antispasmodics, probiotics, rifaximin, non-steroidal antiinflammatory drugs (NSAIDs), and opioid analgesics. Bile acid binders were considered as anti-J o u r n a l P r e -p r o o f diarrheal medications; guanylate cyclase-C agonists and chloride channel activators were categorized as laxatives. Rifaximin, a semisynthetic rifamycin-based non-systemic antibiotic, is classified in the Multum database as a "miscellaneous antibiotic"; therefore, we used the NCHSassigned 5-digit drug code to identify rifaximin use. Treatments for FBDs approved for use after 2015 (e.g. eluxadoline, plecanatide, prucalopride) were not included.

Non-pharmacologic interventions of interest included: 1) dietary and nutrition counseling; 2) exercise (including physical therapy) or weight reduction counseling; 3) stress reduction and mental health counseling (including psychotherapy); and 4) complementary alternative medicine (CAM). Detailed descriptions of each intervention are provided in Supplemental Table 1 .

Briefly, diet/nutrition counseling included providing patient education relating to consumed foods and beverages, dietary restrictions/guidelines, or a referral to a dietician or nutritionist. Exercise and weight reduction counseling included covering topics relating to the patient's physical condition or fitness and includes referrals to health and fitness professionals. Mental health counseling included provision of advice about psychological issues, stress reduction, biofeedback, or yoga. CAM described interventions such as acupuncture, chiropractic, homeopathy, massage, or herbal therapies. Given that weight reduction counseling alone may not be considered an appropriate treatment for FBDs, we conducted a sensitivity analysis excluding weight reduction as a non-pharmacologic intervention. If the patient was seen by a specialist in referral, recommendations provided specifically for the primary care provider may not be captured if they were not also discussed with the patient. 

NAMCS data is derived from a complex clustered probability stratified sample, with deliberate oversampling of certain subgroups. Therefore, to ensure that estimates are representative of the national population, sampling weights were applied in a multistage estimation procedure as recommended by the NCHS. These sampling weights adjust for sampling probability, survey non-response, ratio adjustment within specialty groups, and weight smoothing to ensure that an individual provider does not overcontribute to the total sample. Sampling weights were applied for all analyses and to extrapolate unweighted direct observations to weighted estimates reflective of the national population. Baseline demographic characteristics are presented using J o u r n a l P r e -p r o o f was stable over time with no significant changes in patient age, sex, race, primary method of payment, or comorbidity burden.

Treatment patterns for chronic symptomatic FBDs are described in Table 2 Despite this substantial economic burden and the high rate of repeated visits among symptomatic patients, we identify a potential gap in comprehensive FBD care as most patients in this study population did not receive non-pharmacologic treatment advice on diet, exercise, stress reduction, mental health counseling or mind-body interventions. Furthermore, the likelihood of receiving a combined medication and non-pharmacologic approach for managing chronic symptomatic FBDs varies by provider, geographic region, and patient profile. Taken together, these findings highlight an opportunity to improve the quality of care for FBDs in the US.

Our data demonstrate that patients with chronic symptomatic FBDs are predominantly treated using pharmacologic therapies. However, several considerations should be factored into the interpretation of these findings. Importantly, this was a cross-sectional analysis rather than a longitudinal cohort study. Therefore, it is possible that patients may have previously already tried and failed non-pharmacologic therapies, particularly among patients being referred to specialist care. However, we did not find a significant difference in treatment strategy use when we compared patients who were evaluated as new consultations vs. follow-up visits. Second, we were unable adjust for patient preference for pharmacologic vs. non-pharmacologic J o u r n a l P r e -p r o o f interventions in this type of survey study and treatment decisions may have been dictated by complex patient-provider conversations in a shared decision-making model that is not easily captured with binary data points.

Nevertheless, non-pharmacologic interventions may be better suited for addressing the multifactorial biological, psychological, and social framework in which functional GI symptoms develop. 4 We found that stress and mental health counselling were underutilized in this patient population, despite the established association with mood and somatization disorders. 4, 20, 21 Central factors such as psychologic distress substantially impact patient-reported outcomes 22, 23 and are more predictive of impaired quality of life in IBS patients than GI symptoms alone. 24 A recent meta-analysis demonstrated that centrally-directed therapies such as CBT, relaxation therapy, gut-directed hypnotherapy, and dynamic psychotherapy are safe and effective for the treatment of FBDs with a number needed to treat of 4-5. 25 The benefits from these modalities are durable and home-based/remote delivery of therapy has also been shown to be effective, a consideration which is particularly relevant given the current coronavirus pandemic. [26] [27] [28] [29] [30] Although a combined pharmacologic and non-pharmacologic multidisciplinary approach has been suggested as the optimal method for treating chronic symptomatic FBDs, 4, 31, 32 several factors likely contribute to the limited utilization of combination therapy. First, not all physicians will be comfortable recommending non-pharmacologic interventions. For example, psychologic therapies require specialized training and while an experienced physician may have knowledge about effective dietary treatments, a skilled dietitian is likely more adept at identifying and managing nutritional deficiencies and orthorexia. 4, 28, 30 Second, there may be extra costs associated with psychological counseling, mind-body interventions, and dietary approaches, particularly if these strategies are not covered by insurance plans or require a substantial copayment. Third, in addition to financial costs, lifestyle intervention resources are often not co-J o u r n a l P r e -p r o o f located with medical clinics requiring patient time for additional appointments and away from work. Fourth, there may be less awareness of the effectiveness of non-pharmacologic interventions compared to medications for chronic symptomatic FBDs. This is compounded by the relative ease of either writing a prescription or taking a pill to relieve GI symptoms compared to the substantial time and effort that must be invested by both clinicians and patients to optimize lifestyle therapies.

We identified that primary care providers were more likely than medical specialists (predominantly internal medicine specialists) to prescribe combination non-pharmacologic and pharmacologic interventions, potentially reflecting increased time spent with patients, a more established long-term patient-physician relationship, better awareness of an individual patient's complex biopsychosocial background, or better access or comfort with a multidisciplinary strategy. 33 There is of course, a selection bias towards more severe cases being referred to gastroenterologists, and it should be acknowledged that not all patients with chronic symptomatic FBDs necessarily require a multidisciplinary approach, particularly if the severity is low. However, using the number of medical visits in the past year to the same provider as a surrogate for disease severity, our findings suggest that non-pharmacologic treatments are underutilized even on the severe end of the FBD spectrum: while medication use significantly increased among patients with frequent clinic visits, non-pharmacologic interventions were no more likely to be implemented.

Determining the precise epidemiologic and economic burden of chronic symptomatic FBDs is challenging for several reasons. First, because FBDs are clinical diagnoses based predominantly on symptomatic criteria, heterogeneity can be introduced by the study definitions alone. Second, only a subset of symptomatic patients seek out medical care so the total burden of disease is typically underestimated. 34, 35 Third, patients presenting with GI symptoms at the J o u r n a l P r e -p r o o f index visit are often difficult to appropriately classify pending additional investigations.

Recognizing these limitations, we purposively sampled a highly restricted study population to maximize our diagnostic specificity, including only patients with both a provider diagnosis of FBD and active, chronic GI symptomatology at the time of the clinic visit. Therefore, while our estimate of ~4 million annual visits for chronic symptomatic FBDs in the US represents a substantial utilization of health care resources, it is also highly conservative compared to previous studies. 15, 19, 36, 37 Accordingly, our cost estimates for chronic symptomatic FBDs in the US almost certainly underestimate the true economic impact of this disorder. Importantly, we only estimated the direct ambulatory clinic costs associated with the visit encounter and did not account for costs of referrals to other specialists, additional investigations such as cross-sectional imaging or endoscopy, or recurrent follow-up visits for the same patient. Specialized tests that are for new office visits we used in our analysis as a replacement. 38 Our estimates do not include the cost of insurance premiums and copayments that represent a substantial out-of-pocket expense that patients pay for their care. Third, clinic costs only account for a small fraction of the total cost of FBDs. The costing analysis does not include the high cost of pharmaceuticals nor indirect costs to society such as decreased productivity and increased workplace J o u r n a l P r e -p r o o f absenteeism as well as reduced quality of life for both patients and their partners, which are known to be substantial. 34, 35, [39] [40] [41] [42] Overall, the total cost of FBDs to society is enormous.

Our study has some important strengths. We used national survey data that is geographically diverse, includes all payer types, and captures a broad range of both patients and physicians.

Applying survey weights allowed us to report generalizable findings that reflect national level practice patterns. Although only ~2% of the total unweighted sample visits within NAMCS were for FBDs, NAMCS is not GI-specific but broadly captures ambulatory care delivery in the US.

For comparison, all hypertension-related visits in the US only accounted for 1.6% of the NAMCS sample in 2015. Given that we included adult patients from a wide range of ages and ethnicities, seen by different types of care providers, sampled from across the US and over a nine year study period, with data analysis by application of appropriate sample weights, we believe the results are nationally representative. Data collection within NAMCS is robust, data quality is routinely monitored, and we used a range of statistical methodologies to capture the scope of both the epidemiologic burden and treatment of FBDs. Our estimates of pharmacotherapy use are aligned with recent studies conducted using other methodologies: for example, in a prospective population-based survey, Oh et al. estimated that 47.8% of patients used medications to manage chronic constipation, which is almost identical to our estimate of 47.4%. 43 However, there may be important underreporting of behavioral non-pharmacologic counseling in the NAMCS survey, particularly as patient report forms can be completed by medical office personnel or Census Bureau staff reviewing the medical chart. In these circumstances, complex discussions and shared decision-making processes between providers and patients may not always be extracted. Gilchrist et al. compared NAMCS reporting with direct visit observations by trained research nurses in primary care, demonstrating a 9.6% difference in coding for dietary counseling and 7.7% difference in coding for exercise counseling. 44 However, the specificity of NAMCS coding for non-pharmacologic interventions J o u r n a l P r e -p r o o f was high (90-93%). Furthermore, even accounting for a possible 10% underreporting difference, fewer than 1 in 3 patients with chronic symptomatic FBDs receives non-pharmacologic treatment.

We also acknowledge some other important limitations. First, all administrative database studies are susceptible to potential misclassification errors in identifying the patient population, exposures, and outcomes. To mitigate this, we have used previously established ICD-9-CM coding and applied restrictive exclusion criteria to improve the specificity for identifying patients with chronically symptomatic FBDs. Validation of ICD coding for functional GI conditions is an area of research need; some previous work has shown high sensitivity and specificity for IBS although robust validation of coding for individual FBD subtypes has not been performed. 45 There is no specific ICD-9-CM classification for functional abdominal distention/bloating, although this may be evaluated in future studies as US databases migrate to ICD-10. Direct validation of our coding against medical records is impossible because all data within NAMCS is de-identified for public use. The highest risk of misclassification is in patients with non-specific chronic abdominal pain as there may be other diagnoses associated with pain symptoms.

However, we believe the likelihood of this is low as we excluded patients with other causes of non-functional pain, recognizing that there is no direct method within NAMCS to determine timing of concurrent conditions. Additionally, we used the 2015 dataset to check if any patients in our study had associated upper GI or genitourinary causes of abdominal pain. No patients from our study sample had concurrent ICD-9-CM coding for dyspepsia, peptic ulcer disease, ovarian cysts, endometriosis, or ovarian/fallopian tube/uterine cancer.

A second limitation is that data from NAMCS is captured at the level of the clinic visit, rather than the individual patient so more granular details such as disease duration, severity, and previous treatments are not available. As previously identified, it is likely that some patients may have tried other therapies in the past that cannot be captured in this cross-sectional survey design. However, patients identified in this study who remain chronically symptomatic and seek Exercise education includes any topics related to the patient's physical conditioning or fitness. Examples include information aimed at general health promotion and disease prevention and information given to the patient to treat or control a specific medical condition. It includes referrals to other health and fitness professionals, but excludes referrals for physical therapy Physical therapy PT Physical therapy includes treatments using heat, light, sound, or physical pressure or movement (e.g., ultrasonic, ultraviolet, infrared, whirlpool, diathermy, cold or manipulative therapy). Weight reduction WTREDUC Education on weight reduction refers to Information given to the patient to assist in the goal of weight reduction. It includes referrals to other health professionals for the purpose of weight reduction.

Stress management counseling refers to information intended to help patients reduce stress through exercise, biofeedback, yoga, etc. It includes referrals to other health professionals for the purpose of coping with stress. Mental health counseling MENTAL Mental health counseling includes general advice and counseling about mental health issues and education about mental disorders. It includes referrals to other mental health professionals for mental health counseling but excludes psychotherapy. Psychotherapy PSYCHOTH Psychotherapy includes all treatment involving the intentional use of verbal techniques to explore or alter the patient's emotional life in order to effect symptom reduction or behavior change. Complementary alternative medicine CAM Complementary alternative medicine (CAM) includes medical interventions neither widely taught in

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