1.Drossman DA, Hasler WL. Rome IV -Functional GI Disorders ...
Chronic continuous abdominal pain: a large cohort-specific evaluation of diagnostic features, iatrogenesis and drug treatments.Kilgallon E 1, Vasant D.H. 2,3, Green D 4 Shields P.L. 5, Hamdy S1,2, Lal S 1,2, Paine P.A. 1,21 Gastroenterology, Salford Royal NHS Foundation Trust, Salford, United Kingdom2Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, United Kingdom3 Manchester University Foundation Trust, Wythenshawe Hospital, Manchester, United Kingdom4 Division of Cardiovascular Sciences, University of Manchester5 Lancashire Teaching Hospitals, Preston, United KingdomShort title : Chronic continuous abdominal painTotal word count (excluding abstract/summary): 4,554Grant Support: No external grant support was obtained for this study.Abbreviations: CCAP – chronic continuous or nearly continuous abdominal pain, CAPS – Centrally mediated abdominal pain syndrome, SD – Standard deviation, Abdominal Allodynia is short form for ‘cutaneous abdominal mechanical dynamic allodynia’.Correspondence: Dr Peter A Paine PhD MRCP, Gastroenterology Department, Salford Royal NHS Foundation Trust, Stott Lane, Salford, Greater Manchester, United Kingdom. E-mail: peter.paine@srft.nhs.uk, Telephone number: +44 (0)161 2064560 Disclosures: None of the authors have any relevant financial disclosures. Writing Assistance: No writing assistance was required. Author Contributions: EK gathered data and helped write the manuscript, DHV collected data, helped with data analysis and helped write the manuscript, DG helped with data analysis and helped write the manuscript, PLS SH and SL helped with study design and manuscript appraisal, PAP conceived the study, helped with data collection, analysis and manuscript writing.Summary:Background: Chronic continuous abdominal pain (CCAP) is characteristic of centrally mediated gastrointestinal pain disorders. It consumes significant healthcare resources yet is poorly understood, with minimal cohort-specific data in the literature. Aims: In a large cohort of CCAP patients, we examined; 1. diagnostic features, 2. iatrogenic impact of opioids and surgery. 3. drug treatment effects and tolerance.Methods: Consecutive tertiary CCAP referrals to a neurogastroenterology clinic (2009-2016) were reviewed for Rome IV and neuropathic pain criteria. Medical, surgical and drug histories, interventions and outcomes were correlated with clinical diagnosis and associated opioid use. Results: Of 103 CCAP patients (mean age 40±14, 85% female), 50% had physiological exacerbations precluding full Rome IV Centrally Mediated Abdominal Pain Syndrome criteria. However, there were no significant differences between patients who satisfied Rome IV criteria and those who didn’t. Overall, 81% had allodynia (light brush strokes evoking pain on abdominal examination). Opioid use was associated with allodynia (P=0.003). Prior surgery was associated with further operations post CCAP onset (p<0.001). Although 68% had undergone surgical interventions, surgery did not resolve pain in any patient and worsened pain in 35%. Whilst duloxetine was the most effective neuromodulator (P=0.003), combination therapy was superior to monotherapy (P=0.007). Conclusions: This currently largest cohort-specific CCAP dataset supports eliciting neuropathic features, including allodynia, for a positive clinical diagnosis, to guide treatment. Physiological exacerbation of CCAP may represent visceral allodynia, and need not preclude central origin. Use of centrally acting neuromodulators, and avoidance of detrimental opioids and surgical interventions appears to predict favourable outcomes.Keywords: neuropathic pain, allodynia, hyperalgesia, opioids, chronic abdominal pain, centrally acting neuromodulators, centrally mediated gastrointestinal painIntroductionSignificant advances have been made in understanding, classifying and diagnosing common episodic painful functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS) ADDIN EN.CITE <EndNote><Cite><Author>Drossman</Author><Year>2016</Year><RecNum>278</RecNum><record><rec-number>278</rec-number><foreign-keys><key app="EN" db-id="wr2rawvpewdx2neerws5v0fox0p9raapz09f">278</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Drossman, Douglas A.</author><author>Hasler, William L.</author></authors></contributors><titles><title>Rome IV -Functional GI Disorders: Disorders of Gut-Brain Interaction</title><secondary-title>Gastroenterology</secondary-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><pages>1257-1261</pages><volume>150</volume><number>6</number><dates><year>2016</year></dates><publisher>Elsevier</publisher><isbn>0016-5085</isbn><work-type>doi: 10.1053/j.gastro.2016.03.035</work-type><urls><related-urls><url>. However, less common chronic continuous abdominal pain (CCAP), with no clear underlying structural or metabolic cause, remains a challenging clinical entity for which very little is known to guide practice. Such patients may present repeatedly to secondary and tertiary services, with significant psychological co-morbidity, multiple repeated negative investigations and heavy socioeconomic costs including healthcare utilisation and the burden of loss of working days due to illness PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZWVmZXI8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 2-6. These patients may be subjected to futile or counter-productive treatments including opioid analgesia ADDIN EN.CITE <EndNote><Cite><Author>Szigethy</Author><Year>2018</Year><RecNum>279</RecNum><record><rec-number>279</rec-number><foreign-keys><key app="EN" db-id="wr2rawvpewdx2neerws5v0fox0p9raapz09f">279</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Szigethy, E.</author><author>Knisely, M.</author><author>Drossman, D.</author></authors></contributors><auth-address>Departments of Psychiatry and Medicine, University of Pittsburgh, 3708 Fifth Avenue, Pittsburgh, Pennsylvania 15213, USA.
School of Nursing, University of Pittsburgh, 3500 Victoria Street, Pittsburgh, Pennsylvania 15261, USA.
Center for Functional GI & Motility Disorders, University of North Carolina, Bioinformatics Building, 130 Mason Farm Road, Chapel Hill, North Carolina 27599, USA.
Drossman Gastroenterology PLLC, 901 Kings Mill Road, Chapel Hill, North Carolina 27517, USA.</auth-address><titles><title>Opioid misuse in gastroenterology and non-opioid management of abdominal pain</title><secondary-title>Nat Rev Gastroenterol Hepatol</secondary-title></titles><periodical><full-title>Nat Rev Gastroenterol Hepatol</full-title></periodical><pages>168-180</pages><volume>15</volume><number>3</number><edition>2017/11/16</edition><dates><year>2018</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1759-5053 (Electronic)
1759-5045 (Linking)</isbn><accession-num>29139482</accession-num><urls><related-urls><url> [pii]
10.1038/nrgastro.2017.141</electronic-resource-num><language>eng</language></record></Cite></EndNote>7. Indeed, the detrimental effects of opioids in this setting are increasingly being recognised and include nausea, vomiting, constipation, and the development of opioid-induced hyperalgesia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZWVmZXI8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 2. However, direct clinical evidence of how frequently these diagnostic criteria are present in a 'real world' CCAP cohort is currently lacking. Furthermore the nature of CCAP pathophysiological attribution and treatment recommendations, including a putative role of ‘neuropathic’ pain (i.e. pain arising from peripheral/central nerve dysfunction as opposed to normal ‘nociceptive’ pain provoked by tissue damage) remains speculative and derivative ADDIN EN.CITE <EndNote><Cite><Author>Clouse</Author><Year>2006</Year><RecNum>252</RecNum><record><rec-number>252</rec-number><foreign-keys><key app="EN" db-id="wr2rawvpewdx2neerws5v0fox0p9raapz09f">252</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Clouse, Ray E.</author><author>Mayer, Emeran A.</author><author>Aziz, Qasim</author><author>Drossman, Douglas A.</author><author>Dumitrascu, Dan L.</author><author>M?nnikes, Hubert</author><author>Naliboff, Bruce D.</author></authors></contributors><titles><title>Functional Abdominal Pain Syndrome</title><secondary-title>Gastroenterology</secondary-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><pages>1492-1497</pages><volume>130</volume><number>5</number><dates><year>2006</year></dates><publisher>Elsevier</publisher><isbn>0016-5085</isbn><work-type>doi: 10.1053/j.gastro.2005.11.062</work-type><urls><related-urls><url>. In CAPS, it is notable that the clinical features, postulated pathophysiology of central sensitisation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXllcjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 11-12 and recommended centrally acting neuromodulator therapy significantly overlap that of neuropathic pain ADDIN EN.CITE <EndNote><Cite><Author>Searle</Author><Year>2012</Year><RecNum>205</RecNum><record><rec-number>205</rec-number><foreign-keys><key app="EN" db-id="wr2rawvpewdx2neerws5v0fox0p9raapz09f">205</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Searle, R. D.</author><author>Howell, S. J.</author><author>Bennett, M. I.</author></authors></contributors><auth-address>The Pain Clinic, Royal Cornwall Hospital NHS Trust, Truro, Cornwall TR1 3LJ, UK. robert.searle@rcht.cornwall.nhs.uk</auth-address><titles><title>Diagnosing postoperative neuropathic pain: a Delphi survey</title><secondary-title>Br J Anaesth</secondary-title></titles><periodical><full-title>Br J Anaesth</full-title></periodical><pages>240-4</pages><volume>109</volume><number>2</number><edition>2012/06/01</edition><keywords><keyword>Acute Disease</keyword><keyword>Delphi Technique</keyword><keyword>Humans</keyword><keyword>Neuralgia/*diagnosis/etiology</keyword><keyword>Pain Measurement/methods</keyword><keyword>Pain, Postoperative/*diagnosis</keyword></keywords><dates><year>2012</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1471-6771 (Electronic)
0007-0912 (Linking)</isbn><accession-num>22649184</accession-num><urls><related-urls><url> [pii]
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ADDIN EN.CITE.DATA 2, 14-15. Moreover, key clinical diagnostic features of neuropathic pain, including allodynia (a non-painful stimulus evoking pain sensation) and hyperalgesia (pain experienced as more painful for a given stimulus), have recently been defined by a consensus study using a Delphi approach ADDIN EN.CITE <EndNote><Cite><Author>Searle</Author><Year>2012</Year><RecNum>205</RecNum><record><rec-number>205</rec-number><foreign-keys><key app="EN" db-id="wr2rawvpewdx2neerws5v0fox0p9raapz09f">205</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Searle, R. D.</author><author>Howell, S. J.</author><author>Bennett, M. I.</author></authors></contributors><auth-address>The Pain Clinic, Royal Cornwall Hospital NHS Trust, Truro, Cornwall TR1 3LJ, UK. robert.searle@rcht.cornwall.nhs.uk</auth-address><titles><title>Diagnosing postoperative neuropathic pain: a Delphi survey</title><secondary-title>Br J Anaesth</secondary-title></titles><periodical><full-title>Br J Anaesth</full-title></periodical><pages>240-4</pages><volume>109</volume><number>2</number><edition>2012/06/01</edition><keywords><keyword>Acute Disease</keyword><keyword>Delphi Technique</keyword><keyword>Humans</keyword><keyword>Neuralgia/*diagnosis/etiology</keyword><keyword>Pain Measurement/methods</keyword><keyword>Pain, Postoperative/*diagnosis</keyword></keywords><dates><year>2012</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1471-6771 (Electronic)
0007-0912 (Linking)</isbn><accession-num>22649184</accession-num><urls><related-urls><url> [pii]
10.1093/bja/aes147</electronic-resource-num><language>eng</language></record></Cite></EndNote>13. Additionally, lower abdominal cutaneous electrical pain thresholds as a quantitative measure of allodynia have been shown to be predictive of response to centrally acting neuromodulators in CCAP secondary to chronic pancreatitis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PbGVzZW48L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 16. As an alternative to electrical pain thresholds, mechanical dynamic allodynia is a more readily elicited physical sign in the clinic setting using simple gentle brush strokes over the skin, and is attributed to central sensitisation in patients with neuropathic pain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJvbjwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 20-21, but its effects in CCAP are currently unknown and were therefore evaluated in this study. This study has therefore sought to address these evidence gaps by reviewing a large CCAP patient dataset. In particular, this study had three main aims;1. To elicit clinical diagnostic and putative pathophysiological features in CCAP patients, vis-à-vis both current Rome IV Centrally Mediated and also Delphi consensus Neuropathic Pain criteria. 2. To solicit any iatrogenic effects of opioids and surgery in CCAP patients. 3. To determine the responses to drug treatments in CCAP patients. Materials and MethodsWe conducted a retrospective review of the electronic medical records of all patients who attended a regional tertiary functional gastrointestinal clinic in the North West of England between 1 January 2009 and 31 May 2016. Ethics approval was not required for this study, since this was a service evaluation of existing practice compared with Rome guidelines.Definition of CCAPAll CCAP patients included met the same chronic continuous pain definition as used in Rome IV - that the pain should be “continuous or nearly continuous” “with pain occurring more or less every day” and should have been present for at least the preceding 3 months and onset at least 6 months before diagnosis. Questionnaires were not used, but all patients were asked the same questions in clinic as to the frequency and duration of their pain. These were documented in the patients’ case notes and retrospectively elicited from all patients’ charts.Patient population:Patients with unexplained CCAP were identified from a prospectively maintained database of tertiary clinic referrals. Patients whose symptoms were attributable to an alternative active primary structural or metabolic diagnosis were excluded. In line with Rome IV CAPS criteria, patients with previous surgery, adhesions or inactive organic diagnosis were included. Patients with the anterior cutaneous nerve entrapment syndrome were excluded on the basis of a positive Carnett’s sign and very focal cutaneous allodynia along the rectus sheath ADDIN EN.CITE <EndNote><Cite><Author>Glissen Brown</Author><Year>2016</Year><RecNum>212</RecNum><record><rec-number>212</rec-number><foreign-keys><key app="EN" db-id="wr2rawvpewdx2neerws5v0fox0p9raapz09f">212</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Glissen Brown, J. R.</author><author>Bernstein, G. R.</author><author>Friedenberg, F. K.</author><author>Ehrlich, A. C.</author></authors></contributors><auth-address>Department of Medicine, Section of Gastroenterology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA.</auth-address><titles><title>Chronic Abdominal Wall Pain: An Under-Recognized Diagnosis Leading to Unnecessary Testing</title><secondary-title>J Clin Gastroenterol</secondary-title></titles><periodical><full-title>J Clin Gastroenterol</full-title></periodical><pages>828-835</pages><volume>50</volume><number>10</number><edition>2016/08/23</edition><dates><year>2016</year><pub-dates><date>Nov/Dec</date></pub-dates></dates><isbn>1539-2031 (Electronic)
0192-0790 (Linking)</isbn><accession-num>27548731</accession-num><urls><related-urls><url>. Data collection:Data collected for each patient from case note review included: age, gender, clinical diagnoses; relationship of pain to physiological events including menses, bowel habit, stool frequency and consistency and relationship with meals; presence of additional gastrointestinal symptoms; details of previous surgical interventions; co-existing gastrointestinal, functional or chronic pain diagnoses; use of motility drugs, opioid analgesics and patient reported response to centrally acting neuromodulators (amitriptyline, nortriptyline, gabapentin, pregabalin, duloxetine) and linaclotide. It was recorded as to whether the patient had indicated that the drug had helped their pain, whether it had not helped their pain and whether they had needed to stop due to intolerance of side effects. These were standard questions asked about drug efficacy and tolerance to all patients in clinic.All patients initiated on neuromodulators received the same advice, together with their GP, to start at a low dose and up-titrate according to tolerance and response and to use for a minimum of two to three months before concluding there was no effect.Whilst we were unable to systematically capture the data on dose and duration, the standard dosing advice for these drugs from the clinic was as follows:For amitriptyline to start at 20mg nocte and up-titrate in 10mg increments per week to a dose between 30-50mg according to tolerance and response. Higher doses up to 100mg nocte were permitted. If limiting daytime somnolence side effects were encountered then the recommendation was made to switch to an equivalent dose of nortriptyline.For duloxetine 30mg once daily was recommended as the starting dose, up-titrating to 30mg twice daily if required.For gabapentin, a 300mg three times daily starting dose was recommended, up-titrating in 100mg three times daily increments per week according to tolerance and response to a maximum dose of 1.2g three times daily. It was recommended that most patients would likely need between 600mg to 900mg three times daily to get some meaningful response. If side effects were encountered at the 300mg three times daily starting dose, then it was suggested to re-start at 100mg three times daily and up-titrate.For pregabalin it was recommended to start at 75mg twice daily and up-titrate in 75mg twice daily weekly increments to a maximum dose of 300mg twice daily.Data were also collected on investigations performed and details of engagement with nutrition, chronic pain and psychology services. Background pain scores were recorded which had been physician recorded from verbal patient report, of the level of constant background pain, with the patients given a reference range by the physician of zero (no pain) to ten (worst pain ever). Outcome measuresDiagnostic criteria: Case notes were reviewed retrospectively, by investigators not involved in the patients care, for the following diagnostic criteria: Rome IV the CAPS criteria and the neuropathic pain criteria described by Searle et al ADDIN EN.CITE <EndNote><Cite><Author>Searle</Author><Year>2012</Year><RecNum>205</RecNum><record><rec-number>205</rec-number><foreign-keys><key app="EN" db-id="wr2rawvpewdx2neerws5v0fox0p9raapz09f">205</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Searle, R. D.</author><author>Howell, S. J.</author><author>Bennett, M. I.</author></authors></contributors><auth-address>The Pain Clinic, Royal Cornwall Hospital NHS Trust, Truro, Cornwall TR1 3LJ, UK. robert.searle@rcht.cornwall.nhs.uk</auth-address><titles><title>Diagnosing postoperative neuropathic pain: a Delphi survey</title><secondary-title>Br J Anaesth</secondary-title></titles><periodical><full-title>Br J Anaesth</full-title></periodical><pages>240-4</pages><volume>109</volume><number>2</number><edition>2012/06/01</edition><keywords><keyword>Acute Disease</keyword><keyword>Delphi Technique</keyword><keyword>Humans</keyword><keyword>Neuralgia/*diagnosis/etiology</keyword><keyword>Pain Measurement/methods</keyword><keyword>Pain, Postoperative/*diagnosis</keyword></keywords><dates><year>2012</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1471-6771 (Electronic)
0007-0912 (Linking)</isbn><accession-num>22649184</accession-num><urls><related-urls><url> [pii]
10.1093/bja/aes147</electronic-resource-num><language>eng</language></record></Cite></EndNote>13 (Table 1). Definition and examination for “abdominal allodynia”: “Allodynia” is defined as a non-painful innocuous stimulus evoking a painful sensation. It is a characteristic feature and biomarker of neuropathic pain (i.e. pain due to nerve dysfunction). There are different types of allodynia including mechanical dynamic allodynia, mechanical static allodynia, cold allodynia and heat allodynia that reflect different types of nerve dysfunction 17. In particular, dynamic mechanical allodynia on physical examination refers to gentle/light brush strokes over the skin evoking pain (using either a brush or cotton swab), which is due to the central sensitisation component of neuropathic pain 17. This has previously been used for abdominal and pelvic skin examination ADDIN EN.CITE <EndNote><Cite><Author>Jarrell</Author><Year>2009</Year><RecNum>268</RecNum><record><rec-number>268</rec-number><foreign-keys><key app="EN" db-id="wr2rawvpewdx2neerws5v0fox0p9raapz09f">268</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jarrell, John</author></authors></contributors><titles><title>Demonstration of Cutaneous Allodynia in Association with Chronic Pelvic Pain</title><secondary-title>Journal of Visualized Experiments : JoVE</secondary-title></titles><periodical><full-title>Journal of Visualized Experiments : JoVE</full-title></periodical><pages>1232</pages><number>28</number><dates><year>2009</year></dates><publisher>MyJove Corporation</publisher><isbn>1940-087X</isbn><accession-num>PMC2796663</accession-num><urls><related-urls><url>. Derivative from the well established and validated brush or cotton swab light pressure moving stimulus on the skin, mechanical dynamic allodynia was assessed for in all patients by clinician fingertip brush strokes in unaffected compared with maximally affected abdominal cutaneous pain areas 17- ADDIN EN.CITE <EndNote><Cite><Author>Jarrell</Author><Year>2009</Year><RecNum>268</RecNum><record><rec-number>268</rec-number><foreign-keys><key app="EN" db-id="wr2rawvpewdx2neerws5v0fox0p9raapz09f">268</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jarrell, John</author></authors></contributors><titles><title>Demonstration of Cutaneous Allodynia in Association with Chronic Pelvic Pain</title><secondary-title>Journal of Visualized Experiments : JoVE</secondary-title></titles><periodical><full-title>Journal of Visualized Experiments : JoVE</full-title></periodical><pages>1232</pages><number>28</number><dates><year>2009</year></dates><publisher>MyJove Corporation</publisher><isbn>1940-087X</isbn><accession-num>PMC2796663</accession-num><urls><related-urls><url>. This sign may be missed using the traditional “light pressure” palpation abdominal examination technique. The patient was first asked to indicate an area of abdominal skin that was not painful or felt normal. This was lightly brush-stroked with the clinician’s fingertips to help the patient calibrate their baseline normal sensation. The patient was then instructed to indicate if the sensation became painful or otherwise altered as the fingertip brushstrokes were moved systematically around the abdomen, in the same distribution as covered by traditional light palpation. Note was made of areas where the patient described increased pain to light finger brushstroke together with the patient reported pain level. Patients sometimes volunteered other sensory changes such as dysasthesia or numbness. When volunteered, these were recorded but were not otherwise systematically solicited. Patients may frequently exhibit non-verbal fingertip brushstroke evoked pain behaviours and autonomic signs in areas of cutaneous abdominal allodynia (including moaning, grimacing, breath-holding, sweating, pallor and nausea) but these were not systematically recorded.Since the term ‘cutaneous abdominal mechanical dynamic allodynia’ is overly cumbersome, it will be referred to elsewhere in the paper as the short form ‘abdominal allodynia’. We have also occasionally referred to visceral allodynia. This is defined as painful sensation due to nerve dysfunction arising from the lumenal viscera (as opposed to cutaneous) provoked by innocuous physiological events or stimuli. This was not directly tested for during this study as there is no standardised clinically available test for this and is confined to research settings using invasive methodologies.Statistical analysisA comparison of patient characteristics was made between patients with chronic continuous abdominal pain who fulfilled Rome IV CAPS criteria and those who did not (non-CAPS). Parameters compared were age, pain score, surgery post CCAP, previous surgery, number of tertiary appointments, gender, other functional diagnoses, other gastrointestinal diagnoses, cutaneous abdominal allodynia, nausea and vomiting, bloating, weight loss, and the concurrent use of opioid drugs. This was followed by a comparison of the tolerance and efficacy of different neuromodulating drugs between CAPS and non-CAPS patients, and of the respective symptom burden in CAPS versus non-CAPS patients on each drug.Within group analyses were then made for CAPS and non-CAPS patients independently, comparing characteristics of those patients who did and did not tolerate specific prescribed medication. These analyses were limited to cases where each medication or combination of medications was prescribed. In all analyses above, for continuous variables normality of distribution was determined by Shapiro-Wilk test. Normally distributed descriptive data are presented as mean ± standard deviation (SD), and non-normally distributed data as median (minimum, maximum). Statistical comparisons between normally distributed variables were made using unpaired t-tests. Statistical comparisons between non-normally distributed variables were made using Mann-Whitney U test. To compare the association of non-pharmacotherapeutic variables with CCAP symptom burden, univariate binary logistic regression was used. Dependent variables were the presence of abdominal allodynia and any surgery after CCAP diagnosis, independent variables are those listed above. Analyses were performed for CAPS and non-CAPS patients separately.A similar comparison was performed for CCAP patients who gave a history of concomitant (quiescent) structural gastrointestinal disease and those who did not and for CCAP patients who gave a history of surgery prior to CCAP onset and those who did not.For between group comparison of clinical characteristics between patients on opioid therapy, patients previously on opioid therapy, and opioid naive patients, univariate binary logistic regression was performed with opioid na?ve patients as the reference group. Odds ratios were generated for the presence of each symptom or clinical outcome in patients on or previously on opioids compared to opioid na?ve patients.For all analyses, statistically significant results are presented as p<0.05, and results that remained significant after Bonferroni correction are highlighted as such, the α values after correction being specific to each analysis. All analyses were performed using the statistical software package SPSS v22.0, IBM.ResultsClinical characteristics 103 patients with CCAP (mean age 40 ? 14; 88/103 (85%) female) were included. At first presentation to the clinic, only 18/103 (17%) had never used opioids (opioid na?ve), 13/103 (13%) had previously used opioids but were not currently on opioids, and 72/103 (70%) were currently using opioids. Just over half of patients (57/103, 55%) reported concomitant nausea and vomiting, whilst 45/103, 44% reported symptoms of bloating and abdominal distension and 24/103, 23% reported weight loss. Most patients (90/103. 87%) tolerated an oral diet, two patients received oral supplement drinks and three patients adhered to a liquid diet. Six patients required enteral tube feeding, whereas two received parenteral nutrition. Background pain scores were available for 59/103 patients based on a verbally solicited analogue score, given anchors by the clinician of 0 (no pain) to 10 (worst pain). The mean background pain score was 4.8 ? 1.7. Rome IV centrally mediated diagnostic criteria52/103 (50%) patients fully satisfied all of the Rome IV CAPS criteria (Table 1). Of the 51/103 (50%) who did not fulfil all Rome IV CAPS criteria (non-CAPS), 50/51 reported that their constant background pain was frequently exacerbated by 'physiological events' (post-prandial (n=36), on defecation (n=8), preceding defecation (n=5) during menstruation (n=2), with some patients reporting more than one type of physiological trigger for exacerbation and two also reporting no loss of function) and one reported no loss of function without physiological event exacerbation. A comparison was made between CCAP patients who fulfilled all Rome IV CAPS criteria and those (non-CAPS) who did not. There were no significant differences between these two groups in clinical characteristics (Table 2); drugs used (Table 3); drug effectiveness (Table 3) or tolerance (Table 3). Furthermore, there were no significant differences between the two groups with respect to effects of the presence of abdominal allodynia, pain scores or number of operations after diagnosis on the different pharmacotherapy regimes (supplementary tables 1-3). There were also no differences between the two groups with respect to non-pharmacotherapy parameters associated with abdominal allodynia (supplementary table 4).Neuropathic pain criteriaData were available for four of the neuropathic pain criteria (spontaneous, difficult to manage, abdominal allodynia, poor response to opioids) in all patients. Two neuropathic features were present in almost all patients (‘spontaneous’ pain 100/103 (97%), 'difficult to manage' 102/103 (99%), Table 1). Notably, 83/103 (81%) had evidence of abdominal allodynia on physical examination. Another important neuropathic feature 'poor response to opioids', was found in the majority of those who had taken opioids (61/81, 72%). Impact of opioids Intriguingly, the presence of abdominal allodynia on physical examination was highly significantly associated with current opioid use (p = 0.003, Table 4). There was a trend for previous opioid use to be associated with previous surgery, and both previous and current opioid use to be associated with bloating symptoms, but these did not retain significance after Bonferroni correction for multiple comparisons.Co-morbidities, aetiological triggers and other functional disordersWhilst the majority of patients could not identify a clear trigger for onset of their CCAP symptoms, 35/103 patients (34%) reported that their symptoms began as a direct result of an initiating trigger. Surgery triggered symptoms in n=19 (abdominal surgery (n=17); spinal surgery (n=1); knee surgery (n=1)). The onset of pain was also reported following an episode of gastroenteritis (n=7) and following both abdominal surgery and gastroenteritis (n=1).Additionally, other specific clear triggers of onset included (n=8); haemorrhagic ovarian cyst, viral illness, colonoscopy, grief reaction, diverticular disease associated colitis, road traffic accident, vasculitis, and pyelonephritis. There was no association of opioid with identification of a clear trigger.Overall, fifteen patients (15%) had concurrent functional or chronic pain diagnoses. Fibromyalgia was present in 7/103 (7%) patients. Other functional or chronic pain diagnoses included; chronic fatigue syndrome (n=4), chronic back pain (n=3), pseudoseizures (n=1), chronic knee pain (n=1) and chronic regional pain syndrome (n=1). Three patients had hypermobility type Ehlers Danlos Syndrome (hEDS), one had postural orthostatic tachycardia syndrome (POTS) and a further 3 patients had both hEDS and POTS concomitantly.Thirty-five patients (34%), had a history of organic diagnoses. Quiescent inflammatory bowel disease (Crohn’s disease n=8, Ulcerative Colitis n=1) and diverticular disease (n=8) were the most prevalent diagnoses. Other organic co-morbidities included endometriosis (n=5), gallstones (n=4), haemorrhoids (n=3), hernia (n=2), chronic pancreatitis (n=2) and peripheral neuropathy (n=2). In all patients, the referring clinician had indicated that the concomitant organic diagnosis was not active and did not explain the chronic severe pain.There were no significant differences between CCAP patients who gave a history of concomitant (quiescent) gastrointestinal diseases and those who did not (Table 5).Surgical interventions performed in patients with CCAPSeventy patients (68%), had a background of previous abdominal surgery and 27% of these patients identified surgical intervention as an initiating trigger to CCAP. Overall, the most common surgical interventions were; appendicectomy (n=26/70, 37%), cholecystectomy (n=15/70, 21%) and hysterectomy (n=19/70, 27%). Histology was not available from the referral centres in the majority of patients’ case records.Interestingly, the majority of patients who had surgical interventions 44/70 (63%) had at least one surgical procedure in order to identify the cause of, treat, or as a consequence of, their pain. Twenty five of these patients had multiple surgeries, with n=10 having 4 or more procedures. Surgery did not resolve the symptoms in any patient and 13/44 (35%) reported that surgery resulted in a direct worsening of their pain. Exploratory laparoscopy/laparotomy was the most common surgical intervention performed post-symptom onset. 10/44 patients (22%) had exploratory surgery with no abnormal findings and 25/44 patients (56%) had a subsequent interventional procedure. Adhesiolysis was the most frequently performed surgical intervention, in 14/44 patients (31%), but only one patient was found to have obstruction due to adhesions. Four patients had multiple adhesiolysis procedures, with no resolution of symptoms. Other surgical procedures post CCAP onset included; appendicectomy (n=3, normal histology in n=1 for whom histology was available), cholecystectomy (n=1 with normal histology), bowel resections (n=2; including repair of an inadvertent enterotomy during the division of adhesions) and hernia repairs (n=5). One patient had an ERCP with sphincterotomy as their pain was thought to be attributable to Sphincter of Oddi dysfunction; however, this resulted in post-sphincterotomy pancreatitis with no improvement of symptoms. There was a highly significant association between CCAP patients having had surgery prior to CCAP onset going on to have more operations post CCAP onset than CCAP patients who had never had a previous operation (p < 0.001). There were otherwise no significant differences between CCAP patients with or without previous surgery (Table 5).Clinical response to centrally acting neuromodulatorsAlmost all patients (95/103, 92%) received centrally acting neuromodulators, with clinical outcomes available for those that were followed-up in the tertiary neurogastroenterology clinic (51/95, 54%), as opposed to those that were solely discharged to their local chronic pain service. A positive response was seen in 34/51 (67%), non-response 10/51(19%) and intolerance 7/51 (14%). The tricyclic antidepressants (TCAs) had the lowest response rates, with 7/32 (22%) responding to amitriptyline and 5/21 (24%) responding to nortriptyline. 15/40 (38%) responded to gabapentin and 10/26 (38%) responded to pregabalin. Duloxetine was the only neuromodulator significantly better at achieving a response than amitriptyline (P = 0.003 Table 6), with 12/16 (75%) responding, and was the only drug to be tolerated by all patients in which it was tried. Linaclotide was used in 29/103 patients (28%) with outcomes available for 21/29. 12/21 (57%) reported a positive pain symptom response, 8/21 reported no response or worsening of symptoms and 1/21 did not tolerate linaclotide due to side effects. There was a trend towards linaclotide being more effective and better tolerated than amitriptyline but this did not retain significance after Bonferroni correction for multiple comparisons (Table 6).Patients with known outcomes were stratified into two groups according to the number of drugs they had taken concurrently. Eight patients were excluded as data regarding the relative time periods of the drug prescribing were not available. Combination therapy with >1 centrally acting neuromodulator (n=12/14, 86% response) was superior to centrally acting neuromodulator monotherapy (n=10/19, 53% response,), P = 0.007 (Table 7). DiscussionIn this largest cohort-specific analysis of the diagnosis and management of CCAP to date, our data are the first to elicit the clinical diagnostic and putative pathophysiological features vis-à-vis the Rome IV CAPS and the Delphi neuropathic pain criteria. In particular, we have found the presence of neuropathic pain features including abdominal allodynia to be a frequent finding. Moreover, we have found frequent physiological exacerbations of the chronic pain, which may reflect visceral allodynia. Other novel and important findings include the detrimental effects of prior surgical interventions increasing the risk for further futile surgical interventions and opioid analgesia in CCAP associated with increased abdominal allodynia, as a possible biomarker of opioids adversely altering pain neurobiology. To the authors’ knowledge, our outcome data on the use of centrally acting neuromodulators are also the first in a CCAP population which support recently published empirical guidance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb2JpbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 14-15.Our findings suggest the full current Rome IV CAPS criteria may exclude a significant number of patients with CCAP. In particular, almost half of the patients in our cohort reported constant background pain, but were also frequently exacerbated by physiological events. We appreciate that the reason underpinning the CAPS criteria exclusion of physiological event exacerbation is in order to try and discriminate more effectively from the more common episodic painful functional bowel disorders, and to highlight likely central as opposed to potentially more peripheral neural mechanisms. We submit however that the chronic and continuous nature of the pain itself is a sufficient discriminator from the episodic functional pain disorders, and moreover chronic and continuous pain per se is likely to have a central mechanism. Moreover, extensive comparisons between CCAP patients who met all the CAPS criteria and those who did not (primarily due to frequent physiological exacerbations) did not yield any significant differences between the two groups.Given the frequent finding of abdominal allodynia (a biomarker of central sensitisation), and our knowledge of viscerosomatic convergence at the level of the dorsal horn of the spinal cord, we think it is a reasonable interpretation that in the CCAP population, physiological event exacerbation may represent visceral allodynia whether due to peripheral and/or central sensitisation. In any case we would suggest that excluding nearly half of patients with CCAP due to physiological event exacerbations, from being considered as centrally mediated and thereby perhaps less consideration of the use of centrally acting gut-brain neuromodulators, may be clinically unhelpful as patients with CCAP do not readily fit into any other functional gastrointestinal disorder category due to the continuous nature of their pain.By contrast, evaluation of this patient group against neuropathic pain criteria identified that abdominal allodynia was present in most patients with CCAP (81%). Cutaneous mechanical dynamic allodynia to brush strokes is a well-established and validated clinical biomarker for neuropathic pain of central origin and is a direct consequence of central sensitization indicating the recruitment of A?? fibres as primary nociceptive afferent neurons and therefore the development of a neuropathic, amplified pain state PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJvbjwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 17-19. Fingertip brush strokes is a readily clinician-elicited physical sign on bedside examination and allows for a positive, objective diagnostic feature of neuropathic pain, to supplement solely symptom-based criteria. It was sufficiently common that we believe this might be added as a positive corroborating feature for centrally mediated abdominal pain disorders. It does however require a change in examination technique for patients with CCAP to include fingertip brushstroke examination to precede gentle palpation. Without recourse to concurrent central brain imaging technology, it will not be possible to discount possible contributions of hypervigilance to the patient sensation reports, and this may be a useful future avenue for research.In addition to clinical characteristics of CCAP patients, our study also explored iatrogenesis relating to opioids and surgery. Importantly, almost three quarters of patients who had used opioids in our study reported a poor response to these medications. Moreover, abdominal allodynia was significantly associated with opioid use, with patients on opioids more likely to exhibit the altered nociceptive behaviour underpinning allodynia. Allodynia in this context therefore may also be a bio-marker for opioid-induced hyperalgesia in the context of a pre-existing neuropathic pain state. This supports the notion that opioids are counterproductively altering pain neurobiology and should be avoided in the management of CCAP. Increased prevalence of abdominal surgeries in patients with functional gut disorders is well documented, as is the onset of post-surgical neuropathic pain and these findings are mirrored in our CCAP cohort PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb3Jzb29rPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 23-26. In particular we have identified that surgery prior to CCAP onset is associated with further surgery post-CCAP onset. We have also identified that surgical intervention is associated with poor clinical outcomes, and worsening symptoms in a third of patients. Moreover, our data have shown no clinical improvement with adhesiolysis and would support findings from published randomised controlled trials, which suggest avoidance of adhesiolysis unless bowel viability is under threat PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb2xlZ3JhYWY8L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFy
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ADDIN EN.CITE.DATA 27-28. It should be recognised that a limitation of this study was that we did not have access to the pathology reports of the surgical specimens from the referring centres.Finally after exploring clinical characteristics and iatrogenesis in CCAP patients, our study explored response to treatments. In particular, our data lend support to the use of centrally acting neuromodulators in patients with CCAP. Duloxetine appeared to be the most efficacious single agent neuromodulator, whilst neuromodulator combination therapy appeared to be more effective than monotherapy. Despite the lack of cohort-specific data on clinical efficacy and utility of these agents, current pharmacotherapeutic recommendations for centrally mediated gastrointestinal pain disorders are to use neuromodulatory medications derivatively from evidence in other painful functional gut disorders PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PbGVzZW48L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 16, 29-31. Our data thus provide additional clinical evidence to support the recent empirical guidelines on centrally acting neuromodulators and suggest benefit in 42% of patients with monotherapy, increasing to 52% response using augmentation therapy with more than one agent in combination. These 'real world' data are particularly important in light of the new recommendations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb2JpbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 14-15, given that most gastroenterologists have traditionally not been accustomed to nor trained to prescribe these types of medications PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Tb2JpbjwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 14. The efficacy of linaclotide for centrally mediated pain, both as monotherapy and in combination with other neuromodulators in our cohort is another interesting and novel finding. Linaclotide has emerging evidence as a neuromodulator, with analgesic effects demonstrated in clinical trials in IBS patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5RdWlnbGV5PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 21. Most recently in a study using cortical evoked potentials, linaclotide was found to improve abdominal pain in IBS by modulating afferent nerve signalling pathways to the brain ADDIN EN.CITE <EndNote><Cite><Author>Rao</Author><Year>2018</Year><RecNum>276</RecNum><record><rec-number>276</rec-number><foreign-keys><key app="EN" db-id="wr2rawvpewdx2neerws5v0fox0p9raapz09f">276</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rao, Satish S.</author><author>Xiang, Xuelian</author><author>Patcharatrakul, Tanisa</author><author>Sharma, Amol</author><author>Parr, Rachael</author><author>Dalenberg, Elizabeth</author><author>Hall, Patricia</author></authors></contributors><titles><title>1021 - Investigation of the Mechanism of Action of Linaclotide on Abdominal Pain in Ibs-C: An Evaluation of the Afferent Gut-Brain Axis</title><secondary-title>Gastroenterology</secondary-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><pages>S-193-S-194</pages><volume>154</volume><number>6</number><dates><year>2018</year></dates><publisher>Elsevier</publisher><isbn>0016-5085</isbn><work-type>doi: 10.1016/S0016-5085(18)31053-9</work-type><urls><related-urls><url>(18)31053-9</url></related-urls></urls><electronic-resource-num>10.1016/s0016-5085(18)31053-9</electronic-resource-num><access-date>2018/06/24</access-date></record></Cite></EndNote>32. Our data suggest that it might be considered as an option for patients with CCAP, particularly when chronic constipation is a co-existing feature.We recognise that there are significant limitations to an uncontrolled retrospective single-centre case series review; however, given the rarity and difficulties in evidence collation for CCAP patients, we present a number of interesting and important new observations in addition to reinforcing already existing consensus. Interpretation of the centrally acting neuromodulator data needs to be with caution as prescriber bias cannot be excluded. Furthermore there may be some degree of patient selection bias in that some patients who did not respond to treatments may be likely to present for care optimisation than those who did. Additionally, outcome data were not available for all patients that received these medications. After initial diagnosis of a centrally mediated pain disorder, for many patients the distance of travel involved for this tertiary setting, meant local follow up with their local chronic pain team to review and modify the anti-neuropathic and opioid pain medication was more appropriate. Outcome data for neuromodulator treatment was therefore not available for these. Moreover we were unable to collect dose and duration of treatment data, although all patients received standard advice in these respects, as outlined in the methods section above. Given the rarity of these cases, it will be challenging to embark on any placebo controlled or head-to-head randomised and blinded studies in CCAP. Furthermore, our study did not evaluate the efficacy of psychological ADDIN EN.CITE <EndNote><Cite><Author>Keefer</Author><Year>2015</Year><RecNum>2</RecNum><record><rec-number>2</rec-number><foreign-keys><key app="EN" db-id="wr2rawvpewdx2neerws5v0fox0p9raapz09f">2</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Keefer, L.</author><author>Mandal, S.</author></authors></contributors><auth-address>Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.</auth-address><titles><title>The potential role of behavioral therapies in the management of centrally mediated abdominal pain</title><secondary-title>Neurogastroenterol Motil</secondary-title></titles><periodical><full-title>Neurogastroenterol Motil</full-title></periodical><pages>313-23</pages><volume>27</volume><number>3</number><edition>2014/11/28</edition><keywords><keyword>Abdominal Pain/psychology/*therapy</keyword><keyword>*Behavior Therapy</keyword><keyword>Central Nervous System Sensitization</keyword><keyword>Chronic Pain/psychology/*therapy</keyword><keyword>Humans</keyword><keyword>Mindfulness</keyword></keywords><dates><year>2015</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1365-2982 (Electronic)
1350-1925 (Linking)</isbn><accession-num>25428520</accession-num><urls><related-urls><url> or individualised pain management programmes, which would be important in the future given that pain does not respond to drug therapy in nearly half of patients. Future study of other non-drug interventions therefore, such as neurostimulation devices ADDIN EN.CITE <EndNote><Cite><Author>Kovacic</Author><Year>2017</Year><RecNum>290</RecNum><record><rec-number>290</rec-number><foreign-keys><key app="EN" db-id="wr2rawvpewdx2neerws5v0fox0p9raapz09f">290</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kovacic, K.</author><author>Hainsworth, K.</author><author>Sood, M.</author><author>Chelimsky, G.</author><author>Unteutsch, R.</author><author>Nugent, M.</author><author>Simpson, P.</author><author>Miranda, A.</author></authors></contributors><auth-address>Center for Pediatric Neurogastroenterology, Motility and Autonomic Disorders, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
Division of Clinical Pediatrics, Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.
Division of Quantitative Health Sciences, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
Center for Pediatric Neurogastroenterology, Motility and Autonomic Disorders, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: amiranda@mcw.edu.</auth-address><titles><title>Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial</title><secondary-title>Lancet Gastroenterol Hepatol</secondary-title></titles><periodical><full-title>Lancet Gastroenterol Hepatol</full-title></periodical><pages>727-737</pages><volume>2</volume><number>10</number><edition>2017/08/23</edition><dates><year>2017</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>2468-1253 (Electronic)</isbn><accession-num>28826627</accession-num><urls><related-urls><url>(17)30253-4 [pii]
10.1016/S2468-1253(17)30253-4</electronic-resource-num><language>eng</language></record></Cite></EndNote>33, may also be valuable for these patients. Other areas of future research include determining whether there are additional genotypic or psychophysiological endophenotype markers for pain vulnerability; and more thorough prospective attempts to elicit other neurobiological signs such as cutaneous dysaesthesia/numbness and visceral allodynia/dysaesthesia.In conclusion, this large cohort series of CCAP patients has shed light on some of the clinical evidence gaps, and found risk factors for both poorer outcomes but also optimised therapy. We believe these findings can help inform future iterations of centrally mediated pain syndrome criteria as well as clinical decision making to help avoid harm and optimise positive outcomes for this group of patients.References: ADDIN EN.REFLIST 1.Drossman DA, Hasler WL. Rome IV -Functional GI Disorders: Disorders of Gut-Brain Interaction. Gastroenterology 2016;150(6):1257-1261.2.Keefer L, Drossman DA, Guthrie E, et al. Centrally Mediated Disorders of Gastrointestinal Pain. Gastroenterology 2016.3.Maxton DG, Whorwell PJ. Use of medical resource and attitudes to health care of patients with chronic abdominal pain. Br J Med Econ 1992;2:75-79.4.Drossman DA, Li Z, Andruzzi E, et al. U.S. householder survey of functional gastrointestinal disorders. Prevalence, sociodemography, and health impact. Dig Dis Sci 1993;38(9):1569-80.5.Koloski NA, Talley NJ, Boyce PM. Epidemiology and health care seeking in the functional GI disorders: a population-based study. Am J Gastroenterol 2002;97(9):2290-9.6.Keefer L, Mandal S. The potential role of behavioral therapies in the management of centrally mediated abdominal pain. Neurogastroenterol Motil 2015;27(3):313-23.7.Szigethy E, Knisely M, Drossman D. Opioid misuse in gastroenterology and non-opioid management of abdominal pain. Nat Rev Gastroenterol Hepatol 2018;15(3):168-180.8.Szigethy E, Schwartz M, Drossman DA. Opiate-Induced Bowel Dysfunction. Handbook of Gastrointestinal Motility and Functional Disorders 2015;Chapter 25:323-337.9.Grunkemeier DM, Cassara JE, Dalton CB, Drossman DA. The narcotic bowel syndrome: clinical features, pathophysiology, and management. Clin Gastroenterol Hepatol 2007;5(10):1126-39; quiz 1121-2.10.Clouse RE, Mayer EA, Aziz Q, et al. Functional Abdominal Pain Syndrome. Gastroenterology 2006;130(5):1492-1497.11.Mayer EA, Tillisch K. The brain-gut axis in abdominal pain syndromes. Annu Rev Med 2011;62:381-96.12.Nozu T, Kudaira M. Altered rectal sensory response induced by balloon distention in patients with functional abdominal pain syndrome. BioPsychoSocial Medicine 2009;3(1):13.13.Searle RD, Howell SJ, Bennett MI. Diagnosing postoperative neuropathic pain: a Delphi survey. Br J Anaesth 2012;109(2):240-4.14.Sobin WH, Heinrich TW, Drossman DA. Central Neuromodulators for Treating Functional GI Disorders: A Primer. Am J Gastroenterol 2017;112(5):693-702.15.Drossman DA, Tack J, Ford AC, Szigethy E, Tornblom H, Van Oudenhove L. Neuromodulators for Functional Gastrointestinal Disorders (Disorders of Gut-Brain Interaction): A Rome Foundation Working Team Report. Gastroenterology 2018;154(4):1140-1171 e1.16.Olesen SS, Graversen C, Bouwense SA, van Goor H, Wilder-Smith OH, Drewes AM. Quantitative sensory testing predicts pregabalin efficacy in painful chronic pancreatitis. PLoS One 2013;8(3):e57963.17.Baron R. Mechanisms of disease: neuropathic pain--a clinical perspective. Nat Clin Pract Neurol 2006;2(2):95-106.18.Jarrell J. Demonstration of Cutaneous Allodynia in Association with Chronic Pelvic Pain. Journal of Visualized Experiments : JoVE 2009(28):1232.19.Lolignier S, Eijkelkamp N, Wood JN. Mechanical allodynia. Pflügers Archiv - European Journal of Physiology 2015;467(1):133-139.20.Quigley EM, Tack J, Chey WD, et al. Randomised clinical trials: linaclotide phase 3 studies in IBS-C - a prespecified further analysis based on European Medicines Agency-specified endpoints. Aliment Pharmacol Ther 2013;37(1):49-61.21.Eutamene H, Bradesi S, Larauche M, et al. Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain. Neurogastroenterol Motil 2010;22(3):312-e84.22.Glissen Brown JR, Bernstein GR, Friedenberg FK, Ehrlich AC. Chronic Abdominal Wall Pain: An Under-Recognized Diagnosis Leading to Unnecessary Testing. J Clin Gastroenterol 2016;50(10):828-835.23.Borsook D, Kussman BD, George E, Becerra LR, Burke DW. Surgically induced neuropathic pain: understanding the perioperative process. Ann Surg 2013;257(3):403-12.24.de Leon-Casasola O. A review of the literature on multiple factors involved in postoperative pain course and duration. Postgrad Med 2014;126(4):42-52.25.Shipton E. Post-surgical neuropathic pain. ANZ J Surg 2008;78(7):548-55.26.Longstreth GF. Avoiding unnecessary surgery in irritable bowel syndrome. Gut 2007;56(5):608-10.27.Molegraaf MJ, Torensma B, Lange CP, Lange JF, Jeekel J, Swank DJ. Twelve-year outcomes of laparoscopic adhesiolysis in patients with chronic abdominal pain: A randomized clinical trial. Surgery 2017;161(2):415-421.28.Swank DJ, Swank-Bordewijk SCG, Hop WCJ, et al. Laparoscopic adhesiolysis in patients with chronic abdominal pain: a blinded randomised controlled multi-centre trial. The Lancet 2003;361(9365):1247-1251.29.Ford AC, Quigley EM, Lacy BE, et al. Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis. Am J Gastroenterol 2014;109(9):1350-65; quiz 1366.30.Calandre EP, Rico-Villademoros F, Slim M. Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use. Expert Rev Neurother 2016:1-15.31.Bouwense SA, Olesen SS, Drewes AM, van Goor H, Wilder-Smith OH. Pregabalin and placebo responders show different effects on central pain processing in chronic pancreatitis patients. J Pain Res 2015;8:375-86.32.Rao SS, Xiang X, Patcharatrakul T, et al. 1021 - Investigation of the Mechanism of Action of Linaclotide on Abdominal Pain in Ibs-C: An Evaluation of the Afferent Gut-Brain Axis. Gastroenterology 2018;154(6):S-193-S-194.33.Kovacic K, Hainsworth K, Sood M, et al. Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial. Lancet Gastroenterol Hepatol 2017;2(10):727-737.Tables:Table 1 – Proportions of patients with chronic continuous abdominal pain who met the diagnostic criteria for ‘centrally mediated abdominal pain syndrome (CAPS)’ and neuropathic AP, totalCriteriaN=103Rome IV CAPS criteria(Nearly) Continuous, n (%)103 (100)No relationship to gastrointestinal physiological events, n (%)53 (51)Function loss, n (%)100 (97)Not feigned, n (%)103 (100)Not explained by an alternative diagnosis, n (%)103 (100)3-6 months, n (%)103 (100)Neuropathic Pain criteriaSpontaneous, n (%)100 (97)Difficult to manage, n (%)102 (99)Allodynia, n (%)83 (81)Poor opioid response, n (%)61 (59)Shooting, n (%)13 (13)Burning, n (%)12 (12)Dysaesthesia, n (%)9 (9)Hyperalgesia, n (%)7 (7)Good response to neuropathic agents, n (%)35 (34)Table 2. Comparison of characteristics between chronic continuous abdominal pain patients who fulfilled all Rome IV CAPS criteria and those who did not (non-CAPS). * = statistically significant at p<0.05 (value did not retain significance after Bonferroni correction). Key: CAPS = centrally mediated abdominal pain syndrome; N & V = nausea and vomiting. CAPSnon-CAPSpAge (years)40 (18 - 80)33 (18 - 82)0.294Male Gender (%)1780.17Abdominal Allodynia (%)26120.065N&V (%)50380.295Bloating (%)58540.579Weight loss (%)85680.046*Pain score4.9 ± 2.04.7 ± 1.40.59Trigger (%)74580.095Other gastrointestinal disease (%)65640.828Other functional diagnosis (%)85860.875Psychology referral (%)55400.135Any previous surgery (%)26360.293Any surgery after diagnosis (%)47590.711Surgery after diagnosis (n)2.2 ± 1.52.3 ± 1.40.762Total surgery (n)1 (0 - 9)1 (0 - 19)0.927Tertiary appointments (n)1 (1 - 12)1 (1 - 11)0.616Table 3 A comparison of the frequency of prescription of neuromodulatory drugs and drug combinations, the effectiveness of neuromodulatory drugs and drug combinations and the tolerance of pharmacotherapy prescribed between chronic continuous abdominal pain patients who fulfil Rome IV CAPS criteria and those who did not (non-CAPS). Analyses were performed using chi square test on an intention to treat basis. Patients whose symptoms improved after using each drug were compared to those who either did not tolerate the drug or did not improve after its use. Patients who had never been prescribed the drug were excluded. * = statistically significant at p<0.05 (values did not retain significance after Bonferroni correction). Key: CAPS = centrally mediated abdominal pain syndrome; N & V = nausea and vomiting, NM = neuromodulatory drug, L = linaclotide.CAPSnon-CAPSpThe frequency of prescription of drugs and drug combinations amitriptyline (%)64360.097nortriptyline (%)53471.000gabapentin (%)47540.429pregabalin (%)62380.250duloxetine (%)44560.591linaclotide (%)52481.000Combination NM (%)69310.238Combination NM+L (%)56440.788Short acting opioids (%)54460.695Long acting opioids (%)54460.823Transdermal opioids (%)56430.641tramadol (%)54460.823codeine (%)44560.607Combination morphine (%)56440.680Combination opioids (%)52491.000The effectiveness of neuromodulatory drugs and drug combinationsamitriptyline (%)33170.144nortriptyline (%)5000.047*gabapentin (%)50390.540pregabalin (%)60110.035*duloxetine (%)71780.766linaclotide (%)54700.764Combination NM (%)891000.318Combination NM+L (%)100860.466The tolerance of pharmacotherapyN% toleratedN% toleratedamitriptyline217112670.775nortriptyline10809560.252gabapentin207523780.801pregabalin15809890.572duloxetine71009100n/alinaclotide1191101000.329NM Monotherapy128310400.035*NM combination91004100n/aNM combination + linaclotide91007100n/aTable 4 A between group comparison of clinical characteristics between patients on opioid therapy, patients previously on opioid therapy, and opioid naive patients. Analyses were performed using binary logistic regression with opiate na?ve patients as the reference group. * = statistically significant at p<0.05, # = retained significance after Bonferroni correction. Key: N & V = nausea and vomiting. OR = odds ratio compared to reference group; CI = confidence intervals.OR95% CIpAbdominal Allodynia Current7.631.98 – 29.420.003*#Previous1.050.22 – 5.000.951N&V Current1.150.34 – 3.710.810Previous0.540.11 – 2.550.433Bloating Current5.311.10 0 25.310.037*Previous8.401.27 – 55.390.027*Weight loss Current1.380.34 – 5.500.653Previous0.330.03 – 3.720.372Above median pain score (4.5)Current0.860.13 – 5.680.873Previous0.480.11 - 1.950.290Trigger Current2.380.61 – 9.370.214Previous1.830.31 – 9.370.498Other gastrointestinal disease Current0.960.29 – 3.210.951Previous0.900.18 – 4.560.899Other functional diagnosis Current0.950.18 – 4.950.959Previous1.200.14 – 10.110.867Psychology referral Current1.200.38 – 3.800.757Previous1.400.29 – 6.620.671Any previous surgery Current0.750.21 – 2.730.663Previous0.270.09 – 0.780.016*Any surgery after diagnosis Current2.760.78 – 9.820.117Previous0.350.11 – 1.170.0892 or more tertiary appointments Current1.430.43 – 4.790.561Previous0.720.25 – 2.020.528Table 5 Comparison of characteristics between chronic continuous abdominal pain patients who have concomitant (quiescent) gastrointestinal disease and those who do not, and who have undergone previous surgery and those who have not. * = statistically significant at p<0.05 (value did not retain significance after Bonferroni correction), # = retained significance after Bonferroni correction. Key: N & V = nausea and vomiting. yesnoConcomitant quiescent gastrointestinal diseaseAge (years)44 ± 1738 ± 120.041*Male Gender (%)2280.102Abdominal Allodynia (%)81821.000N&V (%)38470.658Bloating (%)58540.509Weight loss (%)16280.207Pain score4.3 ± 1.65.1 ± 1.80.114Trigger (%)40330.503Other functional diagnosis (%)12151.000Psychology referral (%)59520.517Any previous surgery (%)72721.000Any surgery after diagnosis (%)50350.338Surgery after diagnosis (n)1 (0 – 5)1 (0 – 5)0.902Total surgery (n)1 (0 – 19)1 (1 – 9)0.954Tertiary appointments (n)2 (1 – 11)1 (1 – 12)0.337Current opioids (%)72720.993Previous opioids (%)1313Previous surgeryAge (years)41 ± 1338 ± 180.378Male Gender (%)1580.498Abdominal Allodynia (%)80850.770N&V (%)533690.170Bloating (%)41500.488Weight loss (%)24231.000Pain score4.9 ± 1.74.9 ± 2.10.967Trigger (%)74580.095Other gastrointestinal disease (%)42190.053Other functional diagnosis (%)9270.043*Psychology referral (%)50650.246Any surgery after diagnosis (%)620<0.001*#Surgery after diagnosis (n)1 (1 – 5)0 (0 – 0)-Tertiary appointments (n)1 (1 – 12)1 (1 – 7)0.616Current opioids (%)76620.146Previous opioids (%)1412Table 6 A comparison of the tolerance and effectiveness of different neuromodulatory drugs and linaclotide. Analyses were performed using binary logistic regression with amitriptyline as the reference drug. * = statistically significant at p<0.05, # retained significance after Bonferroni correction, $ = OR value >1,000 likely spurious due to small numbers. Key: OR = odd’s ratio for effectiveness or tolerance compared to reference drug; CI = confidence intervals. OR95% CIpEffectivenessamitriptyline (%)refrefrefduloxetine (%)8.002.0431.370.003*#gabapentin (%)2.110.805.590.133linaclotide (%)4.331.3513.920.014*nortriptyline (%)0.950.273.410.940pregabalin (%)1.900.625.810.258Toleranceamitriptyline (%)refrefrefduloxetine (%)$--0.998gabapentin (%)1.430.514.000.490linaclotide (%)8.701.0274.000.048*nortriptyline (%)0.940.283.190.924pregabalin (%)2.170.598.020.244Table 7 A comparison of the effectiveness of and clinical burden associated with combination neuromodulatory (comb), combination therapy with linaclotide (comb + L), and monotherapy. Analyses were performed using binary logistic regression with monotherapy as the reference group. * = statistically significant at p<0.05, # = retained significance after Bonferroni correction, $ = OR value >1,000 likely spurious due to small numbers. Key: N & V = nausea and vomiting. : OR = odd’s ratio for effectiveness and clinical burden compared to reference; CI = confidence intervals.OR95% CIpEffectivenessComb21.02.28 - 1920.007*#Comb + L$-0.998Abdominal Allodynia Comb1.220.19 – 7.810.832Comb + L0.490.10 – 2.220.354N&V Comb2.250.53 – 9.540.271Comb + L1.670.45 – 6.190.446Bloating Comb1.400.35 – 5.540.632Comb + L2.640.69 – 10.810.159Weight loss Comb1.0200.20 – 5.210.981Comb + L1.130.25 – 5.120.871Above median pain score (4.5)Comb1.270.24 – 6.820.778Comb + L$-0.999Trigger Comb0.640.15 – 2.740.550Comb + L0.870.23 – 3.250.832Other gastrointestinal disease Comb0.430.09 – 2.030.289Comb + L0.870.23 – 3.250.832Other functional diagnosis Comb0.530.05 – 5.680.598Comb + L1.460.25 – 8.400.671Psychology referral Comb0.490.12 – 1.970.316Comb + L0.740.20 – 2.740.646Any previous surgery Comb1.270.29 – 5.560.736Comb + L1.710.41 – 7.140.459Any surgery after diagnosis Comb1.920.48 – 7.770.360Comb + L1.200.33 – 4.360.7822 or more tertiary appointments Comb2.310.49 – 10.820.298Comb + L1.520.39 – 5.910.543Supplementary Table 1. The presence of abdominal allodynia in patients with chronic continuous abdominal pain on different pharmacotherapy regimens, comparing those who fulfil Rome IV CAPS criteria and those who did not (non-CAPS). * = statistically significant at p<0.05 (value did not retain significance after Bonferroni correction). Key: CAPS = centrally mediated abdominal pain syndrome; NM = neuromodulator, L = linaclotide.CAPSNon-CAPSpCases% allodyniaCases% allodyniaamitriptyline15678880.278nortriptyline8637860.310gabapentin156718890.120pregabalin12838750.648duloxetine78691000.242linaclotide537450880.065NM monotherapy108041000.334NM combination97841000.305NM combination + L94471000.016*Supplementary Table 2. Pain scores in patients with chronic continuous abdominal pain on different pharmacotherapy regimens, comparing those who fulfil Rome IV CAPS criteria and those who did not (non-CAPS). Key: CAPS = centrally mediated abdominal pain syndrome; NM = neuromodulator, L = linaclotide.CAPSNon-CAPSpMeanSDMeanSDamitriptyline5.672.334.500.710.517nortriptyline3.251.774.501.730.454gabapentin5.051.924.861.030.784pregabalin5.002.584.880.850.929duloxetine6.102.974.790.760.28linaclotide4.941.994.671.380.558NM monotherapy5.002.394.380.950.632NM combination4.201.305.000.710.31NM combination + L7.001.005.830.760.184Supplementary Table 3. Number of operations after chronic continuous abdominal pain diagnosis in patients on different pharmacotherapy regimens, comparing those who fulfil Rome IV CAPS criteria with those who did not (non-CAPS). * = statistically significant at p<0.05 (value did not retain significance after Bonferroni correction). Key: CAPS = centrally mediated abdominal pain syndrome; NM = neuromodulator, L = linaclotide.CAPSNon-CAPSpMeanSDMeanSDamitriptyline2.701.831.000.000.399nortriptyline1.200.451.000.000.482gabapentin2.201.752.631.190.566pregabalin2.251.892.331.150.949duloxetine1.670.582.501.970.51linaclotide2.171.492.301.380.763NM monotherapy1.751.501.500.710.841NM combination1.831.604.001.410.142NM combination + L3.751.261.750.960.045* ................
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