Does central sensitization help explain idiopathic overactive bladder?

The existing clinical and experimental evidence of a role of central sensitization in OAB might be limited, although an additional line of argument centres on the relationship between OAB and IC/BPS. Although generally distinguished from IC/BPS owing to the absence of pain, considerable overlap, in terms of the lower urinary tract symptoms and bladder hypersensitivity exists between OAB and IC/BPS 7 , 29 – 31 . Urinary urgency is a common symptom of both conditions 131 and many patients with OAB will describe their symptoms as being uncomfortable or even painful 7 , 31 . The majority of patients with IC/BPS (87%) will describe their urinary urgency as being caused by pain, pressure, or discomfort, while 40% of those with OAB will describe their urinary urgency similarly, as opposed to attributing it to fear of incontinence 31 , 132 , which is how urgency owing to OAB is classically described 133 . The existence of overlap between these two conditions has encouraged some to consider OAB and IC/BPS as spectrum diseases that are united by an underlying, common pathophysiology 7 , 29 – 31 , which, according to the proposed argument, might reflect the presence of central sensitization. As proposed by Yukio Homma 8 , when classified together under the rubric of Hypersensitive Bladder, OAB and IC/BPS are both manifestations of an underlying disorder of hyperactivity of sensory nerves with differing features of pain and incontinence. Interstitial cystitis is a further subdesignation in patients with specific bladder pathology. Similarly, J. Quentin Clemens 7 classifies OAB and IC/BPS primarily as genitourinary sensory disorders with an underlying dysfunction of the afferent nervous system, referring to them as afferent urological and/or pelvic disorders 7 . Others disagree and maintain that IC/BPS and OAB are separate conditions, distinguished primarily by the presence of pain with bladder filling in patients with IC/BPS and the generally episodic nature of urinary urgency (relatively fast onset and/or disappearance) in patients with OAB compared with the progressive build-up of bladder pain and discomfort with bladder filling in paatients with IC/BPS 133 , 134 , while acknowledging that the two conditions can also occur in the same patient. Diagnostic criteria and clinical definitions of IC/BPS have undergone considerable revisions in the past decade, but the ongoing lack of agreement or uniformity in how these conditions are defined certainly adds to the confusion in understanding the underlying contributory mechanisms. IC/BPS has been considered a central sensitization syndrome for many years and exhibits many of the clinical characteristics that define these syndromes 11 , 28 , 135 . On psychophysical testing, individuals with IC/BPS have impaired inhibition of descending pain pathways that might be a result of central sensitization 102 , including hyperalgesia 51 , 99 – 101 and hypersensitivity (including increased startle reflexes) in responses to acoustic stimuli 136 , 137 . However, most of these studies only include small numbers of patients and employ a variety of psychophysical techniques, thus limiting the generalizability of the reported findings. Brain imaging data published in 2015 from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain project indicate that women with IC/BPS have white matter abnormalities that are consistent with those observed in the brains of patients with other chronic pain conditions, thus reinforcing the suggested mechanistic commonality of these disorders 138 . Women with IC/BPS also demonstrate susceptibility to comorbid central sensitization syndromes, and frequently report the co-occurrence of IC/BPS with fibromyalgia, chronic fatigue syndrome, IBS, TMJD, chronic pelvic pain, migraine, lower-back pain, and vulvodynia 33 , 36 , 139 , 140 . In addition, evidence suggests that the increased number of comorbid syndromes is associated with a greater risk of IC/BPS 140 – 145 . In fact, many of these comorbid conditions seem to predate the onset of IC/BPS, suggesting the existence of an underlying predisposition 33 , 139 , 142 , 144 , 146 – 149 . Evidence published in 2014 on temporal relationships in women with IC/BPS also suggests that urinary symptoms such as those associated with OAB might predate the onset of IC/BPS. In a case–control study comparing women with IC/BPS to those without, women with a history of nonbladder pelvic pain with urinary features, urinary frequency and/or prior episodes of bladder pain before diagnosis (prodrome symptoms) were more likely to develop IC/BPS 142 . Furthermore, women with prodrome symptoms were more likely to have antecedent nonbladder syndromes that might reflect underlying central sensitization, such as chronic fatigue syndrome, IBS, and fibromyalgia, before the onset of IC/BPS. Although these findings might be limited owing to major flaws in the study design, these results suggest the possibility that central sensitization might explain progression from nonpainful lower urinary tract symptoms (such as an increased urinary frequency) in some women to painful IC/BPS and hint that some of the urinary symptoms of OAB might reflect the presence of central sensitization as an underlying mechanism. If this is indeed the case, early identification and treatment of OAB might help prevent worsening of the condition and progression to IC/BPS.

Currently no methods of direct assessment of mechanisms of central sensitization are available in humans. However, clinical manifestation of central sensitization can be indexed using a group of psychophysical laboratory techniques known as quantitative sensory testing (QST) 40 . QST enables perceptual responses to be systematically applied and quantifiable sensory stimuli to be assessed, for the purpose of characterizing somatosensory function or dysfunction 41 ( BOX 2 ). QST is often used in the context of chronic pain research in order to understand possible contributory mechanisms related to enhanced responses to painful stimuli, including central sensitization. Depending on the QST modality and target tissues, a variety of different peripheral afferents can be activated, and their function tested, with some degree of specificity. For example, contact thermal and mechanical methods have been shown to reliably assess the function of C-fibres and Aδ-fibres or Aβ-fibres, respectively 41 . Despite the inherently subjective nature of sensory perception of even highly standardized stimuli, data from a multicentre study investigating QST has demonstrated acceptable test–retest reliability 42 . QST methods can be used to accurately assess dynamic activity in pain processing pathways, including facilitation and inhibition of sensory responses that might relate to central sensitization. For example, quantifying the extent of temporal summation provides information regarding facilitatory mechanisms that are believed to be related to central sensitization and contribute to enhanced nociceptive processing in chronic pain conditions. Temporal summation refers to an increase in pain perception in response to application of a repetitive series of brief noxious stimuli delivered at constant intensity, and at a frequency that elicits C-fibre firing and activation of second-order spinal neurons (termed ‘wind-up’) ( FIG. 2 ). Temporal summation is presumed to be the psychophysical manifestation of central sensitization 41 , 43 and is the most widely accepted index for measurement of central sensitization in the context of pain available in the published literature 43 . QST is frequently used for clinical assessment and phenotyping of patients with chronic conditions such as functional abdominal pain 44 – 46 , IBS 47 , TMJD 48 , fibromyalgia 49 , 50 , IC/BPS 51 , and lower-back pain 44 . Other than QST, few established objective measures or markers of central sensitization are available. Several studies, using various neuroimaging techniques, have reported changes in brain morphology and function in patients with central sensitization conditions compared with the brain morphology of healthy individuals 37 , 38 , 52 , 53 . Unfortunately, heterogeneity in study designs and imaging protocols often makes drawing definitive conclusions across studies difficult. Thus, attributing changes in brain morphology specifically to mechanisms of central sensitization is challenging. Furthermore, the cross-sectional design of these studies limits the interpretation of the causal relationship between brain alterations and clinical symptoms related to central sensitization. As yet, no molecular biomarker has emerged that is specific to the pathophysiology of central sensitization. Some attempts have been made to develop patient-reported questionnaires designed to tap into pathophysiological mechanisms that might relate to central sensitization. The Central Sensitization Index 54 – 56 is a psychometrically-validated questionnaire that differentiates between patients with and without central sensitization syndromes that presumably reflects the underlying mechanisms of central sensitization. The Patient Health Questionnaire-15 ( REFS 57 , 58 ) and short-form Somatic Symptom Scale-8 ( REF. 57 ), although not specifically designed to assess central sensitization, have nevertheless been used successfully to quantify the degree of somatization (such as reports of excessive sensation) in many populations of individuals with, and without central sensitization syndromes 57 , including fibromyalgia 59 , IBS 60 and chronic prostatitis/chronic pelvic pain syndrome 61 . However, the specificity of such psychometric instruments for spinal mechanisms of central sensitization remains untested.

Healthy bladder function is under the coordinated control of afferent and efferent nerves, and is integrated at multiple levels, including locally within the bladder, peripherally in the ganglia and centrally in the spinal cord and brain 62 . Onuf’s nucleus in the spinal cord and the pontine micturition centre in the brain both serve as centres for the control of micturition function, mediating ascending and descending autonomic and somatic signals. Afferent nerves innervating the bladder are predominantly small-calibre, myelinated Aδ fibres that are responsible for sensing bladder volume and the contractile state of the detrusor 63 . These mechanosensitive nerves consist of a combination of low-threshold and high-threshold fibres that are responsive to changes in intravesical pressure and bladder volumes, respectively, and are important for normal physiological filling as they continually gauge the degree of bladder wall distension 64 . These Aδ-fibres convey sensations of bladder fullness to the spinal cord and have their cell bodies in the dorsal root ganglia at the S2–S4 and T11–L2 spinal segments 62 , 65 . Projections from Aδ-fibres synapse with spinal neurons that project to the higher brain centres. Large-calibre unmyelinated C-fibres are also present and usually only respond to high-intensity activation (such as extreme distension, cold, heat or chemical irritation) and are thus termed ‘silent’, as they do not participate in normal physiological bladder function 63 , 65 . However, in animal models of pathological bladder states such as OAB, these ‘silent’ C-fibres can become spontaneously active and hypersensitive to low intensity input 66 , 67 , and these changes are mediated by second-order neurons in the spinal cord 68 , 69 . Similar enhancement in C-fibre activity is also observed in the context of central sensitization 10 , 13 . Several potential mechanisms might contribute to OAB pathophysiology; these can be broadly characterized as abnormally increased afferent signals from the bladder; or decreased capacity to modulate afferent signals in the CNS 65 . Even in a nonpathological state, continuous bladder afferent activity during the micturition cycle delivers a myriad of signals conveying pain, mechanosensation, chemical sensitivity and motor and/or sensory function to the CNS for processing 70 . Aptly named ‘afferent noise’, only a fraction of these signals generate sensations, although most components contribute to reflexes coordinating bladder filling, sphincter function and voiding. The CNS is responsible for modulating these signals to suppress unnecessary and/or unconscious bladder sensations and to facilitate afferent signals necessary for homeostasis. Evidence from investigations of CNS function suggests a prominent role of the CNS in the development of OAB 65 . Increased afferent signalling from the bladder to the spinal cord and brain results in part from inherent dysfunction of the bladder urothelium and/or detrusor smooth muscle 65 . According to hypotheses regarding the role of the urothelium in OAB 63 , 71 the urothelium actively responds to local mechanical, osmotic, inflammatory and chemical stimuli with alterations in expression and/or sensitivity of cell membrane receptors and channels and with release of chemical mediators that act on adjacent afferent neurons, effectively transducing stimulating signals to the afferent nervous system. This increased afferent activity then augments the afferent stimulation produced by bladder fullness to produce urinary urgency and activate the micturition reflex. According to the myogenic hypothesis, detrusor smooth muscle fibres become hyperexcitable, possibly through upregulation or activation of Ca 2+ channels and/or downregulation of K + channel expression and/or activity, so that physiological detrusor micromotions become synchronized into an active, coordinated contraction that stimulates urgency and activates the micturition reflex 72 . The causes of this hyperexcitable state and increased afferent signalling are not fully understood; however, in both situations, which could hypothetically occur concurrently in the same individual, increased afferent signalling to the spinal cord and higher levels of the CNS ensues. Bladder overactivity also can result from stimulating signals that arise separate from the bladder, but act on the bladder through common afferent pathways 64 , 65 , 73 . Emerging evidence highlights the interrelatedness of pelvic organ function through overlapping neural pathways that converge in the CNS at the level of the dorsal root ganglia, the spinal cord or the brain, in the pontine micturition centre 22 , 73 , 74 . Viscero-visceral hyperalgesia can occur between any two visceral organs with common innervation arising from sensory projections with overlapping or common origins in the spinal cord 75 ; visceral organ crosstalk involving the bladder is best described relative to activation of the bowel, which shares sensory innervation in regions of the thoracic and sacral spinal cord with the bladder. Convergent neural mechanisms of activation of the bladder and the bowel, in particular, explain the reproducible interactions demonstrated in experimental models (known as pelvic organ crosstalk) 73 , 76 , 77 . For instance, in animal studies, rectal stimulation either through distension 78 , 79 or inflammation 80 precipitates detrusor inhibition and/or overactivity that is mediated by activation of convergent bladder and bowel C-fibre afferent nerves in the spinal cord 78 . Similarly, in animal models of pelvic pain or cystitis, colonic stimulation increases pain responses attributed to bladder inflammation 81 . Clinical studies that document overlap between bladder and bowel function 82 – 85 support these experimental findings from animal models. For example, rectal distension results in changes in bladder capacity, bladder sensation and detrusor overactivity 86 , 87 , while straining to defecate and constipation can both impair bladder emptying and increase the severity of voiding and storage symptoms 84 , 85 , 88 – 92 . Central sensitization might contribute to several aspects of the pathophysiology of OAB ( FIG. 3 ). The data summarized above indicates that central sensitization can lead to hypersensitivity of both Aδ and C-fibre afferent pathways, both of which are involved in the generation of OAB-related sensations in the bladder. Both central sensitization and OAB are mediated or induced by activation of C-fibre afferent nerves, which generally transmit signals derived from more intense or nociceptive stimulation. Repetitive C-fibre activitation, in conjunction with continued stimulation of low-threshold (Aδ) fibres, results in sensitization of second order neurons in the spinal cord. In OAB, this latter type of stimulation could be provided by mechanoreceptor input from normal bladder cycling or inherent aspects of urothelial or detrusor function described above (such as afferent noise, urothelial signalling, and/or bladder micromotions). In addition, a facilitated ability of low-threshold impulses to activate central neural circuits at the level of the spinal cord, as seen with central sensitization, would explain bladder hypersensitivity, whereby greater sensations of bladder fullness, such as urinary urgency, occur at reduced bladder volumes 93 . Additional sensory mechanisms also contribute to OAB symptoms as neural pathways of pelvic-organ crosstalk could enable sensitization across separate organs. For example, central sensitization initiated by dysfunction of organs that are neurologically related to the bladder through overlapping or convergent neural pathways in the spinal cord, such as the bowel as described above, could extend to incorporate regions of the spinal cord innervating the bladder and result in concomitant bladder dysfunction or OAB, as is proposed for the overlap between OAB and IBS 94 . Variously termed ‘visceral organ crosstalk’ and ‘pelvic-organ cross-sensitization,’ this phenomenon is, in fact, attributed to central sensitization, and can also be observed in other examples of visceral pain conditions, such as heartburn, renal colic, IBS and dysmenorrhea 22 . In this scenario, the primary dysfunction arises from the bowel, but the bladder becomes affected secondarily owing to the ability of central sensitization syndromes to spread to different organs 13 . The absence of obvious bladder pathology or injury in OAB also fits with the concept of central sensitization, as the actual source of the conditioning C-fibre stimulus might be anatomically or even temporally remote. Few published data on inciting events for OAB are available, but some investigators suggest a role for UTI, urinary retention or other precipitating events, which could provide the requisite high-threshold stimulation for the ‘silent’ bladder C-fibre activation needed for induction of central sensitization 95 – 98 . The mechanisms of pelvic organ crosstalk described above also suggest that an inciting event might be produced by separate, but physiologically related, organ systems such as the bowel. Such precipitating events in related organs would likely be difficult to recognize.

Despite this potential overlap in mechanisms between central sensitization and OAB, current experimental data provide only indirect evidence for this association. QST techniques are frequently applied in the study of chronic pain conditions and central sensitization syndromes to identify underlying pathophysiological mechanisms and to phenotype patients, although their use in urological conditions is limited mostly to IC/BPS 51 , 99 – 101 . Women with IC/BPS typically demonstrate hyperalgesia in response to mechanical cutaneous pressure 51 and bladder filling 99 as well as a decreased thermal pain threshold and decreased pain tolerance levels compared with women without IC/BPS 102 . Interestingly, no reports of QST specifically assessing temporal summation in patients with IC/BPS are currently available, even though this would be the most convincing evidence of central sensitization in patients with this disorder 28 . For OAB, a few investigators 103 – 107 have examined urethral electrical current perception thresholds that, in theory, can be used to assess firing thresholds of specific subtypes of afferent fibres. However, results of these studies have been inconsistent and difficult to interpret 103 – 107 . Peripheral QST with either mechanical or heat stimuli in patients with OAB has not been reported; therefore, it remains unknown if patients with OAB have the more generalized hyperaesthesia, allodynia or hyperalgesia to evoked pain stimuli on psychophysical testing reported in some other patients with central sensitization-related disorders 44 , 47 , 49 , 50 . Currently, to our knowledge, no published reports are available regarding temporal summation of evoked painful stimuli in patients with OAB, which might provide quantitative information on the existence or extent of central sensitization in this population. Evidence of urinary biomarkers of bladder dysfunction might support a role of central sensitization in OAB. Investigators in a number of studies have examined NGF and BDNF specifically as potential markers of OAB, both of which have important roles in nociception and central sensitization. Data from animal studies demonstrate that BDNF is involved in maintaining bladder function at the spinal cord level through modulation of glutamate receptor activation (see Song et al. 2014 ( REF. 108 ) for a recent review). Clinically, elevated levels of BDNF and NGF have been found in the urine of individuals with OAB and of those with IC/BPS 109 . Data from several studies have revealed significantly increased urinary NGF levels from women with OAB compared with those without 110 – 113 . Furthermore, treatment with antimuscarinic agents 111 or onabotulinum toxin injections 112 results in decreased urinary NGF levels, but not in nonresponders to therapy 113 . Similarly, results suggest that patients with OAB have elevated urinary levels of BDNF compared with those without OAB 114 , 115 and that conservative treatments can decrease urinary BDNF levels in those with OAB 115 . Urinary BDNF levels were also increased in women with IC/BPS and decreased following successful treatment of overactive bladder symptoms with intravesical injections of onabotulinum toxin A 116 . The lack of specificity of these, or indeed any, biomarkers of OAB remains a major limitation 109 . As with research on central sensitization syndromes, CNS imaging — specifically regarding brain morphology and functionality — has increasingly been employed to elucidate the mechanisms of OAB, many of which appear to parallel those of other syndromes. For instance, Griffiths et al. 110 demonstrated increased activation of the anterior cingulate cortex on functional MRI associated with perception of urgency in women with urge incontinence compared with women with no symptoms of urinary urgency 117 , findings that were further confirmed in 2011 by Komesu et al. 118 This activation is attributed to the fear of leakage associated with urinary urgency in patients with OAB 119 . Interestingly, activation of the anterior cingulate cortex also seems to be a hallmark of IBS 37 , 52 and fibromyalgia 53 . The presence of these common findings is certainly not conclusive or specific to the presence of central sensitization, although they do reinforce the hypothesis that similar neural mechanisms might contribute to OAB as to other central sensitization syndromes that are more typically associated with pain-related symptoms. Comorbidity with, or clustering of, central sensitization syndromes is proposed as a hallmark of the presence of central sensitization. Indeed, the overlap observed between OAB and IBS might reflect the existence of a common pathophysiology 83 , 94 , although the nature of the underlying mechanisms has not been examined. Various reports in the literature suggest the existence of overlap between OAB and some of the more commonly recognized central sensitization syndromes 36 , 41 , including IBS 77 , 92 , 94 , 120 , 121 , fibromyalgia 122 – 126 , and idiopathic back pain 127 . According to population data, over one-third of Japanese women with OAB have concomitant IBS, as defined by Rome criteria 128 , whereas American women are more likely to report a diagnosis of IBS if they have more severe storage-type lower urinary tract symptoms 120 . Women with IBS are also more likely to report storage-type lower urinary tract symptoms of greater severity than those without IBS 82 . In a case–control study, women with fibromyalgia were more likely to report urge urinary incontinence and urinary frequency and more likely to have detrusor overactivity, as observed on urodynamics, than women with urinary tract symptoms without fibromyalgia 122 . In China, 40% of community dwelling women with fibromyalgia also have OAB compared with 12% without fibromyalgia (OR 3.39; 95% CI 1.82–6.31) 123 . In a self-report, questionnaire-based study, 20% of women with back pain reported the presence of urge and mixed urinary incontinence 127 , and elsewhere, associations between urinary incontinence and back pain have been demonstrated to be reciprocal, in that women with back pain have a higher risk of urinary incontinence and women with urinary incontinence have a higher risk of back pain 129 , 130 . Data also suggest that urinary incontinence, allergies, bowel symptoms, and back pain appear in ‘clusters’, meaning that they all occur more frequently in certain women with one or more of these symptoms 129 . Clustering of central sensitization syndromes in individuals with OAB has rarely been systematically examined and all the aforementioned studies are limited regarding the specificity of diagnoses (such as an over-reliance on patient self-reported or nonvalidated measures) or in the generalizability of the findings (for example, owing to the small sample sizes).

OAB remains a clinical enigma in many patients owing to the existence of a disconnect between our understanding of the clinical features and of the pathophysiology. While a number of mechanisms have previously been proposed that might contribute to the symptoms of OAB, central sensitization provides an explanation that also appears likely to contribute to the underlying pathophysiology of OAB, at least in a subgroup of patients. In addition, a role of central sensitization in OAB might explain the comorbid occurrence of this syndrome with many central-sensitization-related syndromes. How central-sensitization-related factors affect the experience of individuals with OAB or their therapy outcomes remains unknown. Nonetheless, evaluating patients with OAB for evidence of central sensitization and the comorbid occurrence of other central sensitization syndromes affords the potential opportunity for directed management based upon pathophysiological profiling, and represents an important initial step towards personalized medicine in the management of OAB. Additional research specifically evaluating the hypothesized role of central sensitization in OAB seems to be warranted.

The presence of central sensitization in patients with OAB, if this hypothesis is confirmed, and how this relates to patient management might be an important consideration for future treatment approaches. Few therapies exist that have demonstrated direct effects on any aspects of central sensitization. Clinical and preclinical evidence regarding ketamine 150 , 151 , gabapentanoids (such as gabapentin, pregabalin, and agents with effects on γ-aminobutyric acid signalling, such as carbamazepine) 152 – 155 and certain antidepressants (such as duloxetine) 156 indicate reversed or diminished central sensitization and decreased allodynia and hyperalgaesia upon treatment 10 . Research published in 2005 has shown that gabapentin and carbamazepine reduce the intensity of temporal summation-induced pain, consistent with an ameliorating effect of these agents on central sensitization 157 . Interestingly, gapapentin 158 and pregabalin 159 have both been investigated as treatments of OAB in studies with small cohort sizes, but with encouraging results. Treatment with duloxetine, compared with placebo, also improves the outcomes of patients with OAB 160 , but these results have not been confirmed in other clinical trials. Data published in 2012 also suggest that duloxetine might have a beneficial role as a treatment of OAB in women with multiple sclerosis 161 . In general, only a few attempts to tailor OAB treatment approaches based on pathophysiological profiling or on a mechanistic approach have been made, despite the availability of a large body of scientific and experimental evidence on pathophysiology. In a systematic review published in 2014, only 48 of 239 (20%) of published randomized controlled trials on OAB profiled participants regarding the underlying pathophysiology of their disease and only 20 (8%) reported the efficacy of OAB treatment based on pathophysiological disease subtype 162 . This might, in large part, reflect a lack of translational opportunities or techniques for assessing the relevant pathophysiological features of OAB in vivo in the context of clinical trials. However, established methods for assessing manifestations of central sensitization in other conditions are available (using temporal summation assessment in particular), and considering OAB within the broader construct of central sensitization provides an opportunity to directly measure the role of central sensitization in the context of OAB using these techniques. In addition, owing to the clustering of central sensitization syndromes having presumed central sensitization-related mechanisms, phenotyping patients with OAB based upon comorbidity with these other syndromes might help identify subgroups with underlying central sensitization in a clinically pragmatic way. Presently, comorbidities that increase the risk of OAB are acknowledged to be a knowledge gap that is relevant to OAB therapy 163 . In other conditions, such as IBS 34 , 164 , the presence and number of comorbid functional somatic syndromes seems to differentiate individuals into subgroups that vary by symptom severity, quality of life, and treatment outcomes. Examinations of the clustering of central sensitization syndromes in individuals with OAB might help to identify certain phenotypes of OAB subgroups that reflect specific pathophysiological mechanisms (such as central sensitization), and these phenotypes might have implications for the prognosis and treatment of patients with this disease. Such a mechanistic approach to OAB management would represent a positive initial step towards personalized treatment of OAB. A number of widely-used treatments of OAB also have effects on other organ systems and, as such, many treatments commonly employed for OAB might also be effective as treatments of comorbid central sensitization syndromes. First-line therapies for OAB include lifestyle modifications, such as fluid intake and dietary management 165 , and use of psychological therapies (such as cognitive behavioural therapy; CBT) 166 , 167 . Both are also effective as treatments of IBS, and CBT in particular is an important treatment modality 168 . Antimuscarinic agents, which are widely used treatments of OAB, are known to act on the bowel, and, in fact, constipation is considered an adverse effect, occurring in up to 15% of patients receiving these drugs 121 . However, this ‘adverse effect’ could also be considered advantageous in the setting of overactive bowel or functional diarrhoeal states, and possibly even in IBS. Antidepressants (including duloxetine, imipramine and amitriptyline) have a long history of clinical use in the management of OAB and urinary incontinence 169 and afford an opportunity to concurrently treat OAB and certain central sensitization syndromes in carefully selected patients, such as those with fibromyalgia 170 or IBS 168 . Finally, sacral neuromodulation has direct effects on bladder and bowel function and is indicated for the treatment of faecal incontinence, in addition to OAB 171 . Neuromodulation certainly has a role as a treatment of dual incontinence (such as urinary and faecal incontinence) 172 . However, given emerging reports of efficacy in patients with additional bowel conditions, such as constipation 173 , functional anal pain 174 , IBS 175 , and pelvic conditions 175 such as IC/BPS 176 – 178 , sacral neuromodulation might have a role in individuals with multiple pelvic comorbidities. Additional research into how patients with comorbidities such as those described above respond to OAB therapies is needed 163 .