James C. Eisenach

Objective Compare the effect of posterior surgical approach (PA) vs direct anterior approach (DAA) on speed of recovery from pain and dysfunction and on intrathecal oxytocin analgesia after total hip arthroplasty (THA). Study design Nested cohort within a randomized, controlled, double-blind trial Setting Hospital Subjects Individuals aged 31 to 80 years undergoing total hip arthroplasty (THA) Methods In this secondary analysis of a randomized controlled trial, the association between surgical approach and number of daily steps was assessed, and whether this was modified by receipt of intrathecal oxytocin. Data were collected from accelerometers and daily patient diaries in the first eight weeks postoperatively. Outcomes were analyzed using generalized linear regression models. Results Ninety patients underwent THA, of which 35 (38.9%) received a PA. Patients were predominantly female (57.8%) with a mean age of 60.6 (standard deviation [SD] 9.3) years. On postoperative day one patients who received a PA with placebo took more steps (mean difference [MD] 53.72, 95% CI: −1717.86, 1825.31) than patients who underwent a DAA. Trajectories were significantly modified by whether they received oxytocin, in which patients who underwent PA with oxytocin took more steps than patients who underwent DAA (pDiscussion Further studies are needed to understand mechanisms underlying oxytocin’s interaction with surgical approach and guide considerations for recovery after THA.

Ultraviolet B (UVB) radiation induces cutaneous inflammation, leading to thermal and mechanical hypersensitivity. Here, we examine the mechanical properties and profile of tactile and nociceptive peripheral afferents functionally disrupted by this injury and the role of oxytocin (OXT) as a modulator of this disruption. We recorded intracellularly from L4 afferents innervating the irradiated area (5.1 J/cm²) in 4-6 old week male mice (C57BL/6J) after administering OXT intraperitoneally, 6 mg/Kg. The distribution of recorded neurons was shifted by UVB radiation to a pattern observed after acute and chronic injuries and reduced mechanical thresholds of A and C- high threshold mechanoreceptors while reducing tactile sensitivity. UVB radiation did not change somatic membrane electrical properties or fiber conduction velocity. OXT systemic administration rapidly reversed these peripheral changes toward normal in both low and high-threshold mechanoreceptors and shifted recorded neuron distribution toward normal. OXT and V1aR receptors were present on the terminals of myelinated and unmyelinated afferents innervating the skin. We conclude that UVB radiation, similar to local tissue surgical injury, cancer metastasis, and peripheral nerve injury, alters the distribution of low and high threshold mechanoreceptors afferents and sensitizes nociceptors while desensitizing tactile units. Acute systemic OXT administration partially returns all of those effects to normal.

In the traditional clinical research model, patients are typically involved only as participants. However, there has been a shift in recent years highlighting the value and contributions that patients bring as members of the research team, across the clinical research lifecycle. It is becoming increasingly evident that to develop research that is both meaningful to people who have the targeted condition and is feasible, there are important benefits of involving patients in the planning, conduct, and dissemination of research from its earliest stages. In fact, research funders and regulatory agencies are now explicitly encouraging, and sometimes requiring, that patients are engaged as partners in research. Although this approach has become commonplace in some fields of clinical research, it remains the exception in clinical pain research. As such, the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials convened a meeting with patient partners and international representatives from academia, patient advocacy groups, government regulatory agencies, research funding organizations, academic journals, and the biopharmaceutical industry to develop consensus recommendations for advancing patient engagement in all stages of clinical pain research in an effective and purposeful manner. This article summarizes the results of this meeting and offers considerations for meaningful and authentic engagement of patient partners in clinical pain research, including recommendations for representation, timing, continuous engagement, measurement, reporting, and research dissemination.

Objective: Compare intrathecal oxytocin, 100 µg to placebo on ongoing neuropathic pain and mechanical hyperalgesia and allodynia. Study design: Randomized, controlled, double-blind cross-over Setting: Clinical research unit Subjects: Individuals aged 18 to 70 years with neuropathic pain for at least 6 months. Methods: Individuals received intrathecal injections of oxytocin and saline, separated by at least 7 days, and ongoing pain in neuropathic area (VAS [visual analog scale]) and areas of hypersensitivity to von Frey filament and cotton wisp brushing were measured for 4 hours. Primary outcome was VAS pain in the first 4 hours after injection, analyzed by linear mixed effects model. Secondary outcomes were verbal pain intensity scores at daily intervals for 7 days and areas of hypersensitivity and elicited pain for 4 hours after injections. Results: The study was stopped early after completion of 5 of 40 subjects planned due to slow recruitment and funding limitations. Pain intensity prior to injection was 4.75 ± 0.99 and modeled pain intensity decreased more after oxytocin than placebo to 1.61 ± 0.87 and 2.49 ± 0.87, respectively (P = .003). Daily pain scores were lower in the week following injection of oxytocin than saline (2.53 ± 0.89 vs 3.66 ± 0.89; P = .001). Allodynic area decreased by 11%, but hyperalgesic area increased by 18% after oxytocin compared to placebo. There were no study drug related adverse effects. Conclusion: Although limited by the small number of subjects studied, oxytocin reduced pain more than placebo in all subjects. Further study of spinal oxytocin in this population is warranted. Trial registration: This study was registered at ClinicalTrials.gov on 03/27/2014 (NCT02100956). The first subject was studied on 06/25/2014.

Objective: To investigate the effect of intrathecal oxytocin compared to placebo on pain and hypersensitivity in individuals with chronic neuropathic pain. Study design: Randomized, controlled, double-blind cross-over study Setting: Outpatient clinical research unit. Subjects: Individuals between ages of 18 and 70 years with neuropathic pain caudal to the umbilicus for at least 6 months. Methods: Individuals received two blinded intrathecal injections of either oxytocin or saline, separated by at least 7 days, and ongoing neuropathic pain (VAS: visual analog scale) and areas of hypersensitivity were measured at intervals for 4 hours. The primary outcome was VAS pain, analyzed by linear mixed effects model. Secondary outcomes were verbal pain intensity scores at intervals for 7 days and areas of hypersensitivity and elicited pain for 4 hr after injections. Results: The study was stopped early after completion of 5 of 40 subjects planned due to slow recruitment and funding limitations. Pain intensity prior to injection was 4.75 ± 0.99 and modeled pain intensity decreased more after oxytocin than placebo to 1.61 ± 0.87.and 2.49 ± 0.87, respectively (p=0.003). Daily pain scores were lower in the week following injection of oxytocin than saline (2.53 ± 0.89 vs 3.66 ±0.89; p=0.001). Hypersensitivity differed between oxytocin and placebo by small amounts in opposite directions depending on modality tested. There were no study drug related adverse effects. Discussion: Although limited by the small number of subjects studied, oxytocin reduced pain more than placebo in all subjects. Further study of spinal oxytocin in this population is warranted.

Preclinical pain research has applied state-of-the-art methods over the past 40 years to describe, characterize, and image molecules, cells, and circuits in rodents to understand the pathophysiology of chronic pain. Despite generating a plethora of novel analgesic targets, pharmaceuticals for chronic pain treatment remain largely limited to the same 6 drug classes as present 40 years ago. It is possible that 40 years of effort has brought us to the verge of a paradigm shift and an explosion of novel analgesic drug classes with remarkable safety, efficacy, and tolerability. We think it more likely that advances will not occur until we follow the description of exciting discoveries with hypothesis testing using clinically relevant preclinical animal models and ethologically relevant outcome measures, which better reflect the clinical characteristics of chronic pain syndromes. Furthermore, to be valuable, experiments using such models must be conducted to the highest levels of internal validity, rigor, and reproducibility. Efforts by funders, most recently the Helping End Addiction Long-Term by the National Institutes of Health, aim to address some of these challenges and enhance communication and collaboration between preclinical and clinical investigators. However, the greater problem is a culture that emphasizes novelty and number of publications over scientific rigor and robust replication leading to a high likelihood of false-positive results. A path forward is provided by the evolution of clinical research beginning 50 years ago that resulted in methods to reduce bias and enhance transparency and ethics of reporting, moving from case reports to randomized controlled trials to innovative study designs with a focus on rigor, generalizability, and reproducibility. We argue that culture changed in clinical science in part because powerful forces outside the peer review system, especially from federal regulators that approve new drugs and human studies committees that addressed ethical failures of earlier research, mandated change in studies within their purview. Whether an external force will affect change in peclinical pain research is unclear.