Exploring the value of a well-established conditioned pain modulation paradigm in women: A Translational Research in Pelvic Pain (TRiPP) study

Lysia Demetriou ^1,2* Danielle Perro ² Lydia Coxon ² Michal Krassowski ² Claire E Lunde ^2,3 Joana Ferreira-Gomes ⁴ Ana Charrua ⁴ Pedro Abreu-Mendes ⁴ Lars Arendt-Nielsen ^5,6 Qasim Aziz ⁷ Judy Birch ⁸ Kurtis Garbutt ² Andrew Horne ⁹ Anja Hoffman ¹⁰ Lone Hummelshoj ¹¹ Jane Meijlink ¹² Maik Obendorf ¹⁰ Esther Pogatzki-Zahn ¹³ Naoko Sasamoto ¹⁴ Kathryn Terry ^14,15 Rolf-Detlef Treede ¹⁶ Allison Vitonis ¹⁴ Jan Vollert ^16,17,18 Nilufer Rahmioglu ² Christian Becker ² Francisco Cruz ⁴ Stacey A Missmer ^14,19 Krina Zondervan ² Christine B Sieberg ²⁰ Jens Nagel ²¹ Katy Vincent ²

• ¹ University of Oxford, Oxford, United Kingdom
• ² Nuffield Department of Women's and Reproductive Health, Medical Sciences Division, University of Oxford, Oxford, England, United Kingdom
• ³ Department of Psychiatry and Behavioral Sciences, Boston Children's Hospital, Boston, Massachusetts, United States
• ⁴ Institute of Molecular and Cellular Biology, University of Porto, Porto, Porto, Portugal
• ⁵ Faculty of Medicine, Aalborg University, Aalborg, Denmark
• ⁶ Center for Neuroplasticity and Pain, Aalborg University, Aalborg East, Denmark
• ⁷ Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, England, United Kingdom
• ⁸ Pelvic Pain Support Network, Poole, England, United Kingdom
• ⁹ MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, Scotland, United Kingdom
• ¹⁰ Research & Development, Pharmaceuticals Experimental Medicine, Bayer AG, Berlin, Baden-Württemberg, Germany
• ¹¹ Endometriosis UK, London, United Kingdom
• ¹² International Painful Bladder Foundation, Amsterdam, Netherlands
• ¹³ Department of Anesthesiology, Operative Intensive Care Medicine and Pain Therapy, University Hospital Münster, Muenster, North Rhine-Westphalia, Germany
• ¹⁴ Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
• ¹⁵ Department of Epidemiology, School of Public Health, Harvard University, Boston, Massachusetts, United States
• ¹⁶ Mannheim Center for Translational Neurosciences, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Baden-Württemberg, Germany
• ¹⁷ Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, England, United Kingdom
• ¹⁸ Imperial College London, London, England, United Kingdom
• ¹⁹ Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, East Lansing, Michigan, United States
• ²⁰ Division of Adolescent/Young Adult Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
• ²¹ Merz Pharmaceuticals GmbH, Frankfurt, Hesse, Germany

Conditioned pain modulation (CPM) is considered a human proxy for descending inhibitory pain pathways. However, there is wide variation in the CPM response described in the literature and ongoing debate about its utility.Here we explored CPM in women with (n=59) and without (n=26) chronic pelvic pain (CPP), aiming to determine the magnitude of effect and factors influencing variability in the CPM response.Using a pressure pain threshold test stimulus and ischaemic pressure cuff conditioning stimulus (CS), we found no significant difference in the mean CPM effect between CPP and control participants. Using a robust statistical method (+/-2 standard error of measurement) to further investigate CPM, there was no significant difference in the proportion exhibiting inhibition between controls and CPP participants (X 2 =0.003, p=0.96). Notably, only 23.1% of our healthy controls demonstrated a 'true' CPM effect (n=4 inhibitory, n=2 facilitatory). Despite a rich data set, we were unable to identify any single questionnaire, clinical or psychophysical covariate correlating with the CPM effect.Despite using one of the recommended CPM paradigms we were only able to demonstrate 'true' CPM in 23.1% of control participants. Thus, the absence of differences between women with and without chronic pelvic pain must be interpreted with caution. Future studies using different CPM paradigms or larger sample sizes may find different results. Although CPM in chronic pain populations is of major theoretical mechanistic interest, the lack of an established assessment standard led us to question its added value in current clinical research.