TLR 2 and 4 responsiveness from isolated peripheral blood mononuclear cells from rats and humans as potential chronic pain biomarkers

Background: Chronic pain patients have increased peripheral blood mononuclear cell Interkeukin-1β production following TLR2 and TLR4 simulation. Here we have used a human-to-rat and rat-to-human approach to further investigate whether peripheral blood immune responses to TLR agonists might be suitable for development as possible systems biomarkers of chronic pain in humans. Methods and Results: Study 1: using a graded model of chronic constriction injury in rats, behavioral allodynia was assessed followed by in vitro quantification of TLR2 and TLR4 agonist-induced stimulation of IL-1β release by PBMCs and spinal cord tissues (n = 42; 6 rats per group). Statistical models were subsequently developed using the IL-1β responses, which distinguished the pain/no pain states and predicted the degree of allodynia. Study 2: the rat-derived statistical models were tested to assess their predictive utility in determining the pain status of a published human cohort that consists of a heterogeneous clinical pain population (n = 19) and a pain-free population (n = 11). The predictive ability of one of the rat models was able to distinguish pain patients from controls with a ROC AUC of 0.94. The rat model was used to predict the presence of pain in a new chronic pain cohort and was able to accurately predict the presence of pain in 28 out of the 34 chronic pain participants. Conclusions: These clinical findings confirm our previous discoveries of the involvement of the peripheral immune system in chronic pain. Given that these findings are reflected in the prospective graded rat data, it suggests that the TLR response from peripheral blood and spinal cord were related to pain and these clinical findings do indeed act as system biomarkers for the chronic pain state. Hence, they provide additional impetus to the neuroimmune interaction to be a drug target for chronic pain.Yuen H. Kwok, Jonathan Tuke, Lauren L. Nicotra, Peter M. Grace, Paul E. Rolan, Mark R. Hutchinso

Complex management of a patient with refractory primary erythromelalgia lacking a SCN9A mutation

Sarah A Low,1 Wendye Robbins,2,3 Vivianne L Tawfik2 1Department of Internal Medicine, Banner University Medical Center, University of Arizona College of Medicine, Tucson, AZ, 2Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Palo Alto, 3Blade Therapeutics, South San Francisco, CA, USA Abstract: A 41-year-old woman presented with burning and erythema in her extremities triggered by warmth and activity, which was relieved by applying ice. Extensive workup was consistent with adult-onset primary erythromelalgia (EM). Several pharmacological treatments were tried including local anesthetics, capsaicin, ziconotide, and dantrolene, all providing 24–48 hours of relief followed by symptom flare. Interventional therapies, including peripheral and sympathetic ganglion blocks, also failed. Thus far, clonidine and ketamine have been the only effective agents for our patient. Genetic testing was negative for an EM-associated mutation in the SCN9A gene, encoding the NaV1.7 sodium channel, suggesting a mutation in an alternate gene. Keywords: erythromelalgia, chronic pain, genetic testing, sodium channels, ketamin

Successful treatment of chronic knee pain following localization by a sigma-1 receptor radioligand and PET/MRI: a case report

Peter William Cipriano,1 Sheen-Woo Lee,1,2 Daehyun Yoon,1 Bin Shen,1 Vivianne Lily Tawfik,3 Catherine Mills Curtin,4 Jason L Dragoo,5 Michelle Louise James,1 Christopher Robert McCurdy,6 Frederick Te-Ning Chin,1 Sandip Biswal1 1Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA; 2Department of Radiology, Gachon University Gil Hospital, Incheon, South Korea; 3Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA; 4Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA, USA; 5Department of Orthopedic Surgery, Stanford University School of Medicine, Stanford, CA, USA; 6Clinical and Translational Science Institute, Translational Drug Development Core, University of Florida, Gainesville, FL, USA Background: The ability to accurately diagnose and objectively localize pain generators in chronic pain sufferers remains a major clinical challenge since assessment relies on subjective patient complaints and relatively non-specific diagnostic tools. Developments in clinical molecular imaging, including advances in imaging technology and radiotracer design, have afforded the opportunity to identify tissues involved in pain generation based on their pro-nociceptive condition. The sigma-1 receptor (S1R) is a pro-nociceptive receptor upregulated in painful, inflamed tissues, and it can be imaged using the highly specific radioligand 18F-FTC-146 with PET. Case presentation: A 50-year-old woman with a 7-year history of refractory, left-knee pain of unknown origin was referred to our pain management team. Over the past several years, she had undergone multiple treatments, including a lateral retinacular release, radiofrequency ablation of a peripheral nerve, and physical therapy. While certain treatments provided partial relief, her pain would inevitably return to its original state. Using simultaneous positron emission tomography/magnetic resonance imaging (PET/MRI) with the novel radiotracer 18F-FTC-146, imaging showed increased focal uptake of 18F-FTC-146 in the intercondylar notch, corresponding to an irregular but equivocal lesion identified in the simultaneously acquired MRI. These imaging results prompted surgical removal of the lesion, which upon resection was identified as an inflamed, intraarticular synovial lipoma. Removal of the lesion relieved the patient’s pain, and to date the pain has not recurred.Conclusion: We present a case of chronic, debilitating knee pain that resolved with surgery following identification of the pathology with a novel clinical molecular imaging approach that detects chronic pain generators at the molecular and cellular level. This approach has the potential to identify and localize pain-associated pathology in a variety of chronic pain syndromes. Keywords: PET/MRI, sigma-1 receptor, chronic pain, knee pain, molecular imaging, intraarticular synovial lipoma, 18F-FTC-14