Personalized Treatments for Functional Disorders of the Sphincter of Oddi: A Short Muscle with a Long History of Discussion and Controversies

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript provides a narrative overview of the anatomy, physiology, diagnostic approaches, and treatment options related to sphincter of Oddi (SO) disorders, with particular emphasis on functional dyskinesia and the long-standing controversies surrounding its diagnosis and management. Using selected literature and the authors’ personal clinical experience, it argues for an individualized, largely conservative approach to functional SO disorders, reserving invasive interventions for carefully selected cases. The review also revisits historical classifications and diagnostic tests, including manometry and pharmacologic provocation, to frame current clinical decision-making.

While the topic is important and clinically relevant, especially given the persistent confusion around SO dysfunction, the review in its current form feels dated and incomplete, reading more like a synthesis of debates from the 1990s and early 2000s than a truly contemporary “personalized” review. Major advances and paradigm shifts of the last decade are insufficiently integrated. In particular, the discussion of functional SO disorders remains heavily anchored in the Milwaukee classification and manometry-centered thinking, without adequately contextualizing how Rome IV criteria, post-EPISODE trial interpretations, and evolving concepts of functional biliary pain have reshaped real-world practice. The manuscript does not sufficiently engage with the growing skepticism regarding the clinical utility of SO dyskinesia as a distinct entity, nor does it critically reconcile older physiologic models with newer data suggesting overlap with functional gastrointestinal disorders and central pain modulation.

From a diagnostic standpoint, several key areas are either superficially addressed or essentially absent. Hepatobiliary scintigraphy is mentioned but not critically appraised in terms of sensitivity, specificity, reproducibility, or its declining role in modern algorithms. There is no meaningful discussion of bile analysis, bile microbiota, or bile acid composition, despite increasing evidence that these factors may contribute to post-cholecystectomy pain syndromes. Oddi dysfunction is discussed largely in isolation, without sufficient exploration of differential diagnoses such as functional biliary sphincter disorder versus papillary pathology, chronic pancreatitis mimics, or visceral hypersensitivity states. The role of secretin-enhanced MRCP is cited but not contrasted with endoscopic ultrasound (EUS), which in current practice is often central to excluding microlithiasis, subtle chronic pancreatitis, or papillary abnormalities before labeling a patient as having functional SO disease.

Importantly, papilitis is almost entirely neglected. Transient or persistent papillary inflammation or fibrosis secondary to microlithiasis or micro-stone passage is a clinically common scenario and could plausibly explain many cases historically labeled as “functional” dyskinesia. Closely related to this, the role of EUS in identifying papillary edema, scarring, small stones, or sludge is underdeveloped, despite EUS being one of the most relevant modern tools to guide management and avoid unnecessary ERCP. This omission significantly weakens the manuscript’s claim of offering a personalized approach.

Therapeutically, the review overemphasizes older pharmacologic strategies while underexploring newer concepts of multimodal management, including pain modulation strategies, careful patient phenotyping, and shared decision-making informed by contemporary risk–benefit data. The risks of ERCP and sphincterotomy are acknowledged, but the discussion lacks depth regarding long-term outcomes, quality of life, and patient-reported endpoints. Overall, the manuscript would benefit from a substantial update that integrates modern diagnostic pathways, clearer differentiation between papillary disease and functional pain syndromes, and a more critical appraisal of what SO dysfunction actually represents in 2025.

Author Response

This manuscript provides a narrative overview of the anatomy, physiology, diagnostic approaches, and treatment options related to sphincter of Oddi (SO) disorders, with particular emphasis on functional dyskinesia and the long-standing controversies surrounding its diagnosis and management. Using selected literature and the authors’ personal clinical experience, it argues for an individualized, largely conservative approach to functional SO disorders, reserving invasive interventions for carefully selected cases. The review also revisits historical classifications and diagnostic tests, including manometry and pharmacologic provocation, to frame current clinical decision-making.

Comment 1: While the topic is important and clinically relevant, especially given the persistent confusion around SO dysfunction, the review in its current form feels dated and incomplete, reading more like a synthesis of debates from the 1990s and early 2000s than a truly contemporary “personalized” review. Major advances and paradigm shifts of the last decade are insufficiently integrated. In particular, the discussion of functional SO disorders remains heavily anchored in the Milwaukee classification and manometry-centered thinking, without adequately contextualizing how Rome IV criteria, post-EPISODE trial interpretations, and evolving concepts of functional biliary pain have reshaped real-world practice. The manuscript does not sufficiently engage with the growing skepticism regarding the clinical utility of SO dyskinesia as a distinct entity, nor does it critically reconcile older physiologic models with newer data suggesting overlap with functional gastrointestinal disorders and central pain modulation.

Response 1: Thank You for the comment and criticism. 

We conducted a new literature search and added 32 papers to the reference list. However, we could not meet a specific percentage for more recent literature, as the basic research pertaining to the physiology and pathophysiology of the Oddi sphincter is older, and these works are of paramount importance.

We continue to reference the Milwaukee classification, in line with the majority of current literature. However, we further emphasize that the only functional disorder of the Oddi sphincter is class II. We believe that our viewpoint aligns with most publications, including the Rome IV criteria. It is crucial for future research to distinguish organic diseases of the papilla from SOD and to conduct new studies exploring therapeutic options for these patients.

 Our suggestions are not "manometry-centered." Indeed, OS manometry was performed by one of us (ZB) and has been largely abandoned for several years. The primary reason for this decision – beside the risk of pancreatitis - was the minimal impact of manometry results on our therapeutic decisions. We advocate for conservative treatment as the first therapeutic approach. Nevertheless, well-designed studies are necessary, particularly those focusing exclusively on patients with functional (class II) SOD, to more definitively address this question.

Comment 2: From a diagnostic standpoint, several key areas are either superficially addressed or essentially absent. Hepatobiliary scintigraphy is mentioned but not critically appraised in terms of sensitivity, specificity, reproducibility, or its declining role in modern algorithms.

Response 2: We have included two original figures of hepatobiliary scintigraphy, previously published in a book (Endoscopia biliopancreática. Una visión interamericana. IKU Santiago, Chile 2023. Ed: Rodrigo Mansilla Vivar), along with the editor’s permission (in Spanish). We added literature about the value of hepatobiliary scintigraphy. While we agree that it is not an optimal method, our opinion is that it is one the best non-invasive methods, particularly when combined with provocation tests. 

There is no meaningful discussion of bile analysis, bile microbiota, or bile acid composition, despite increasing evidence that these factors may contribute to post-cholecystectomy pain syndromes. Oddi dysfunction is discussed largely in isolation, without sufficient exploration of differential diagnoses such as functional biliary sphincter disorder versus papillary pathology, chronic pancreatitis mimics, or visceral hypersensitivity states. The role of secretin-enhanced MRCP is cited but not contrasted with endoscopic ultrasound (EUS), which in current practice is often central to excluding microlithiasis, subtle chronic pancreatitis, or papillary abnormalities before labeling a patient as having functional SO disease.

Response 2: We have added new subchapter discussing the relationship between postcholecystectomy syndrome and dysfunction of the Oddi sphincter. While our primary focus is the Oddi sphincter, we have also included information about the role of gut microbiota and visceral hypersensitivity in postcholecystectomy syndrome.

Comment 3: Importantly, papilitis is almost entirely neglected. Transient or persistent papillary inflammation or fibrosis secondary to microlithiasis or micro-stone passage is a clinically common scenario and could plausibly explain many cases historically labeled as “functional” dyskinesia. Closely related to this, the role of EUS in identifying papillary edema, scarring, small stones, or sludge is underdeveloped, despite EUS being one of the most relevant modern tools to guide management and avoid unnecessary ERCP. This omission significantly weakens the manuscript’s claim of offering a personalized approach.

Response 3: Thank You for Your comment. We agree that the exclusion of organic diseases is the condition which permits to speak about the possibility of a functional disorder. We emphasized the importance of EUS in this process, being the most sensitive way to detect microlithiasis, early chronic pancreatitis and alterations of the papilla.

Comment 4: Therapeutically, the review overemphasizes older pharmacologic strategies while underexploring newer concepts of multimodal management, including pain modulation strategies, careful patient phenotyping, and shared decision-making informed by contemporary risk–benefit data. The risks of ERCP and sphincterotomy are acknowledged, but the discussion lacks depth
regarding long-term outcomes, quality of life, and patient-reported endpoints. Overall, the manuscript would benefit from a substantial update that integrates modern diagnostic pathways, clearer differentiation between papillary disease and functional pain syndromes, and a more critical appraisal of what SO dysfunction actually represents in 2025.

Response 4: We added literature data about the early adverse effects and late response to EST in SOD and about the late effect of EST on the OS function, independently from its original indication.

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript is a review of sphincter of Oddi dysfunction (SOD), addressing its physiology, etiology, diagnostic approach, and management strategies. While the topic is clinically relevant, several major revisions are recommended, as outlined below:

1. The anatomy and anatomical location of the sphincter of Oddi should be clearly described in the Introduction. Inclusion of a schematic or anatomical figure illustrating the sphincter’s location and surrounding structures would enhance reader understanding.
2. The epidemiology of SOD should be expanded. Specifically, the authors should discuss the prevalence and incidence of SOD, the proportion of patients presenting with SOD-like symptoms who ultimately do not meet diagnostic criteria after formal testing, and reported treatment failure rates among patients with suspected or confirmed SOD.
3. Typical symptoms and clinical features of patients with SOD should be summarized in the Introduction to provide appropriate clinical context.
4. The discussion of SOD etiology should be broadened. In particular, the potential role of the brain–gut axis and functional gastrointestinal mechanisms should be addressed.
5. Figure 1 is overly simplistic and requires revision. The figure should clearly specify relevant laboratory abnormalities, define ductal dilation thresholds, and illustrate how these findings guide subsequent diagnostic or management steps.

Author Response

This manuscript is a review of sphincter of Oddi dysfunction (SOD), addressing its physiology, etiology, diagnostic approach, and management strategies. While the topic is clinically relevant, several major revisions are recommended, as outlined below:
1. The anatomy and anatomical location of the sphincter of Oddi should be clearly described in the Introduction. Inclusion of a schematic or anatomical figure illustrating the sphincter’s location and surrounding structures would enhance reader understanding.

Response 1:  Thank You for Your suggestion. Unfortunately, we have no access to a good figure about the anatomy of Oddi sphincter, which is no protected by copyright. We added a short description of the anatomy of Oddi sphincter.

2. The epidemiology of SOD should be expanded. Specifically, the authors should discuss the prevalence and incidence of SOD, the proportion of patients presenting with SOD-like symptoms who ultimately do not meet diagnostic criteria after formal testing, and reported treatment failure rates among patients with suspected or confirmed SOD.

Response 2:Thank You for Your commentary. We added a subchapter on the postcholecystectomy syndrome and the diagnostic difficulties of SOD in this context. We tried to emphasize better the diagnostic difficulties of this functional disordee.

3. Typical symptoms and clinical features of patients with SOD should be summarized in the Introduction to provide appropriate clinical context.

Response 3:

Thank You. We added the Rome IV criteria in the diagnosis of biliary type abdominal pain.

4. The discussion of SOD etiology should be broadened. In particular, the potential role of the brain–gut axis and functional gastrointestinal mechanisms should be addressed.

Response 4: Thank You, we agree regarding the importance of psychosocial factor in all of functional gastrointestinal disorders, including postcholecystectomy syndrome and SOD. We added new literature about this topic.

5. Figure 1 is overly simplistic and requires revision. The figure should clearly specify relevant laboratory abnormalities, define ductal dilation thresholds, and illustrate how these findings guide subsequent diagnostic or management steps.

Response 5: Thank You, the figure was modified, accepting Your suggestions.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

While the revision adds references and acknowledges several contemporary concepts, further substantive improvements are still required to align the manuscript with current clinical practice. Most importantly, papillitis and papillary inflammatory/fibrotic disease must be elevated from a peripheral mention to a central diagnostic alternative, as this entity likely explains a substantial proportion of cases historically labeled as “functional” sphincter of Oddi dysfunction. The manuscript should explicitly reframe the diagnostic pathway to prioritize exclusion of papillary pathology using EUS as a core step, rather than treating it as an ancillary consideration. In parallel, older diagnostic constructs (provocation tests, scintigraphy, Milwaukee-era physiology) should be critically contextualized rather than presented as ongoing practical tools, with clearer alignment to Rome IV concepts, post-EPISOD practice, and functional pain frameworks. Finally, the therapeutic section would benefit from a more modern, multimodal perspective that integrates patient phenotyping, pain modulation strategies, and long-term quality-of-life outcomes, rather than focusing predominantly on legacy pharmacologic or endoscopic interventions. Addressing these points would substantially strengthen the manuscript’s claim of offering a truly personalized and contemporary approach.

Author Response

While the revision adds references and acknowledges several contemporary concepts, further substantive improvements are still required to align the manuscript with current clinical practice. Most importantly, papillitis and papillary inflammatory/fibrotic disease must be elevated from a peripheral mention to a central diagnostic alternative, as this entity likely explains a substantial proportion of cases historically labeled as “functional” sphincter of Oddi dysfunction. The manuscript should explicitly reframe the diagnostic pathway to prioritize exclusion of papillary pathology using EUS as a core step, rather than treating it as an ancillary consideration.

Response: 

Thank You. We agree and we included the following in the new version, using the reviewer’s concept and even some of his own words (asking his permission):

While endoscopic suspicion of papillitis is not infrequent, the diagnostic accuracy of EUS is superior: sensitivity was 92.3% and specificity 73.2% in a publication [51]. This is particularly important because papillitis was likely responsible for a substantial proportion of cases historically labeled as functional SOD. Indeed, Ponchon et al reported already in 1995 that 30 of their 69 patients presented varying degree of fibrosis and inflammatory infiltration in papillary biopsies taken 10 days after EST performed to treat SOD [52]. While this seems probable, there is no evidence of a sequence micolithiasis -repeated stone passage – papillitis – stenosing papillitis – obstructive stenosis of the papilla, which represent an organic disease rather than  a  functional disorder.

Reviewer: In parallel, older diagnostic constructs (provocation tests, scintigraphy, Milwaukee-era physiology) should be critically contextualized rather than presented as ongoing practical tools, with clearer alignment to Rome IV concepts, post-EPISOD practice, and functional pain frameworks.

Response: 

Thank You for this criticism. However, our opinion is somewhat different regarding the diagnostic possibilities of SOD. We think that the consequence of Rome IV concepts that the group with suspected SOD became considerably reduced. Currently we do not find better non-invasive methods in the literature than the old, previously abandoned provocation tests, scintigraphy and more modern secretin-MRCP to demonstrate the involvement of the OS in the symptoms presented by the patient. Our experience that the hepatobiliary scintigraphy - or the MRCP (without secretin) in case of recurrent pancreatitis- performed during the provocation test can be a suitable way to distinguish SOD and other functional GI disorder.

The following was included in the new version of manuscript:

As mentioned above, the specificity and sensitivity of these older diagnostic methods have been repeatedly questioned. However, we believe that with the Rome IV criteria and the EPISOD studies the suspected SOD has been limited to a considerably smaller group. Mild bile duct dilatation after a cholecystectomy or slight elevations of transaminases in an overweight individual do not prove OS involvement. In our opinion it is necessary to reconsider the provocation tests and hepatobiliary scintigraphy or MRCP, particularly when performed simultaneously.

Reviewer:

Finally, the therapeutic section would benefit from a more modern, multimodal perspective that integrates patient phenotyping, pain modulation strategies, and long-term quality-of-life outcomes, rather than focusing predominantly on legacy pharmacologic or endoscopic interventions. Addressing these points would substantially strengthen the manuscript’s claim of offering a truly personalized and contemporary approach.

Response: 

Thank You, we included life-style modifications and mind-body methods, used in the treatment of other functional GI disorders. However, we have no personal experience with these methods and we did not find bibliography about the use of these methods specifically in SOD. The following was included in the new version:

The treatment should always include recommendations for life-style changes, stress management and the use of all available methods for treating other functional gastrointestinal disorders, such as mindfulness, yoga [95] and even acupuncture [96]. These mind-body interventions have proven to be an effective complement to more traditional therapies [97]. There are some extreme cases reported where spinal cord stimulation resulted in long-lasting pain-relief and return to normal daily life in patients whose disabling pain was refractory to all medical treatment attempts [98].

Reviewer 2 Report

Comments and Suggestions for Authors

The authors response all the comments with modification of the manuscript. 

Author Response

Thank You for Your work in revision of our paper. We appreciate Your suggestions.