Pain

Burn treatment has not appreciably changed in decades. Most treatments focus on infection prevention and control, as well as fluid management. This is because burns are universally infected with bacteria allowed to infiltrate deeper tissues by the absence of a skin barrier. If bacteria can now get into these tissues, the problem is only made worse by the large amount of hydration that now can get out into the environment from the open wound. Desiccation sets in with deeper tissues losing fluids. This renders tissue significantly more susceptible to further infection, as dry tissues are less perfused and less capable of fighting infectious insults. Desiccation also robs burned patients of fluids vital to sustain cardiopulmonary function. Without skin, patients essentially lose fluids and cannot perfuse even the most vital organs with time. Research in the field focuses on preventing complications and temporizing these two factors. No regenerative treatments are currently offered to accelerate wound healing, and few investigative treatments are ready for translation to human trials. Most of the pipelines for future treatment involve long development timelines and still focus chiefly on infection control instead of driving tissue to regenerate and heal faster. A significant gap is the need for a regenerative burn treatment that can be trialed while still allowing the use of current protocols. An adjuvant regenerative burn treatment is needed. The purpose of this study is to evaluate the role of local 4-aminopyridine (4-AP) on the treatment of burn wounds to accelerate healing.

The revolution in rheumatoid arthritis (RA) therapeutics has been transformative for many patient outcomes. Yet most patients continue to experience life disabling pain. Strikingly, even those who achieve full disease remission with state-of-the-art anti-tumour necrosis factor (TNF) treatments report substantially higher levels of pain when compared to the general population. Such disconnect presents one of the greatest contemporary challenges to the care of patients with RA. Considering the ongoing excess burden of pain in this patient population, trials of Janus kinase inhibitors (JAKinibs) present welcome data. JAKinibs deliver superior pain improvements in comparison to those receiving anti-TNF therapy. Of note, the majority of this effect has not been fully explained by markers of peripheral inflammation and remains to be understood. Moreover, JAKinibs appear to offer rapid analgesic benefit. Traditional DMARDS and modern biologics commonly take several weeks to bring relief whereas JAKinibs, such as filgotinib, begin to improve pain as early as 2 weeks, even before the observed attenuation of peripheral clinical inflammation. In light of these clinical observations, the investigators believe that RA is a mixed pain state i.e., pain pathways exist in addition to established peripheral inflammatory nociceptive mechanisms. In particular, the central nervous system (CNS) may have an important role in determining RA pain. Recently our group were the first to delineate distinct neurobiological pain signatures in the brains of RA patients by employing functional connectivity magnetic resonance imaging (fcMRI) - a recent adaptation of functional MRI data that examines the synchrony of neural activity which modulates the efficiency and extent of neuronal transmission between brain regions. Specifically, the investigators identified and replicated two distinct pain signatures: 1. enhanced functional connectivity between the Default Mode Network (DMN) and insula, which was unrelated to levels of peripheral inflammation but, intriguingly, is an established neurobiological marker of fibromyalgia (the prototypical CNS pain sensitization disorder, and 2. enhanced functional connectivity between the Dorsal Attention Network (DAN) and the left inferior parietal lobule (LIPL) which was related to levels of peripheral inflammation. Pre-clinical experiments have not only implicated the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway with peripheral immune system functioning but also the brain. In the CNS, this pathway promotes gene expression associated with inflammation which in turn generates pro-nociceptive cytokines. However, there is now also emerging evidence to support the pathway's direct role in synaptic transmission and neurotransmitter receptor modulation. Specifically, the JAK-STAT pathway appears important in N-methyl-d-aspartate (NMDA) related synaptic plasticity - a ubiquitous glutamate receptor of the human brain. Their induction is selectively blocked by JAK inhibitors. Increases in glutamate and subsequent binding to NMDA receptors cause chaotic and incoherent neuronal functional activity. Human studies of fibromyalgia have consistently evidenced both elevated glutamate levels within the insula and dysfunctional neural connectivity. Moreover, fibromyalgia pharmacotherapy (pregablin), considered to reduce neural glutamate, rectifies both insular glutamate and brain functional connectivity (DMN-insula). JAK inhibition (JAKi) may facilitate the reduction of glutamate-NMDA binding and ultimately pain alleviation by normalising the functional activity of these same neural connections.

Burn injuries can result in long term physical and mental sequelae, not only from the scarring but also the painful dressings. The standard of care today remains use of antibiotic topical dressings while awaiting demarcation of the burn depth, with surgical excision and grafting for deep partial thickness and full thickness areas. Demarcation can be appreciated on admission for full thickness burns but is often a prolonged process that can last weeks. The clinical evaluation of the depth of the burn is a complex decision that often is made more challenging by the presence of the proteinaceous pseudoeschar and the coagulated dermis itself. Surgical debridement is relatively 'coarse' and by its very nature requires removal of a thin layer of viable tissue to reach the level that is vascularized enough to support a skin graft. There has been growing interest in the use of adjuncts to reduce the amount tissue debrided and potentially reduce the need for surgery itself. Operatively, there have been some reports that use of hydro-dissection devices (Versajet™) may allow a more controlled debridement, resulting in less viable tissue being sacrificed. There is also a growing experience with enzymatic debridement, especially with Bromolein, derived from Pineapple (NexoBrid®). Neither of these have been shown to definitively improve care in randomized controlled trials, (RCTs) and there is suggestion that in some settings may actually cause harm. A relatively recent entry into the 'space' of non-surgical burn wound debridement is Plurogel®. Unlike Bromolein, Plurogel® is a concentrated surfactant in the form of a stable, viscous gel. Each micelle has a hydrophilic outer surface that softens and loosens wound debris, and a hydrophobic inner core that traps debris. The micelles link to form a matrix that continually expands and contracts. This creates a cleansing/rinsing action that disrupts the surface tension holding slough and necrotic tissue in place. PluroGel® helps in creating a moist wound healing environment, which softens, loosens and drives slough and necrotic debris away from the wound bed, promoting autolytic debridement. PluroGel® is approved for use in burn injuries in Canada, however there are no randomized control trials (RCTs) to support its use. As Plurogel® appears to fill a much-needed niche in burn wound care, and as our centre seeks to be innovative in patient care, we trialed Plurogel® on some of our appropriately consented burn patients. The anecdotal experience is that the eschar lifted within about a week and there was visible wound healing. Healing time appeared to be reduced as the product would gently debride while still providing a moist wound bed encouraging wound healing. Team members began to value the new product. This early positive experience is the impetus for us to embark on a pilot RCT to provide evidence for us to continue to use this product.

This trial seeks to establish whether or not touch sensation can be restored to the breast via neural stimulation. Data will also be obtained to inform future feasibility (including safety), efficacy, and acceptability trials.

To Evaluate the Efficacy and Safety of ONO-1110 in Patients with Fibromyalgia

Multi-center, prospective, single-blind, randomized and parallel controlled trials are used to evaluate the role and impact of "digital chronic pain treatment system equipment" based on MR mixed reality technology in the clinical basic treatment of patients clinically diagnosed with chronic pain.

The aim of the study is to check whether vagus nerve stimulation (VNS) combined with manual therapy (TM), given its neuroanatomical relationship with the structures involved in pain in the TMJ, is more effective in reducing pain, increasing joint range and increasing the quality ofthe patient lives than TM alone. The research team is made up of three physiotherapists. It has been decided to distribute the tasks as follows: * Physiotherapist 1 will be in charge of the treatment of all patients. * Physiotherapist 2 will be responsible for screening the sample and evaluating the study. * Physiotherapist 3 will be in charge of analyzing the results and statistics. This component of the team, being blinded and not knowing the group of origin of the patient, will be able to interpret the results without any type of convenience bias, showing absolutely transparency in the elaboration of the conclusions. Once the screening will be completed, the patients will be divided into two groups: an experimental group (TM + ENV) and a control group (TM + ENV placebo).The randomization will be carried out through the statistical program Epidat 4,237 9 obtaining two homogeneous groups. Each patient will be assigned a code with the aim that the physiotherapist who is in charge of the statistical analysis is not able to establish links between the data and the subjects to which it refers.

The goal of this clinical trial is to test a new community health worker-delivered program (Strengthening COnnections to Overcome Pain, or SCOOP) that teaches strategies for managing chronic pain and loneliness to older adults living in rural areas. The main questions it aims to answer are: 1. Does participating in SCOOP result in less pain interference with daily life? 2. Does participating in SCOOP result in decreased loneliness? 3. What is the level of participant engagement in SCOOP? Researchers will compare people who have participated in SCOOP with people who have not participated in SCOOP to see if SCOOP is helpful in decreasing pain interference and loneliness. Participants will: 1. Watch brief videos teaching strategies to manage pain and boost social connections. 2. Engage in up to 7 weekly coaching sessions with a community health worker. 3. Complete two telephone interviews about health, mental health, and functioning: one at baseline, and one 2 months later.

To compile real-world, direct from patient clinical outcomes and objective metrics in patients who have received or plan to receive a commercially approved interventional medical device therapy/procedure for chronic pain in routine clinical practice.

The study will be divided into three parts: Part A: Single Ascending Dose - healthy participants cohorts with up to 5 dose levels. Part B: Multiple Ascending Doses - healthy participants cohorts with up to 3 dose levels. Part C: Surgical patients cohorts with up to 3 dose levels. The primary Objective is to investigate the safety and tolerability of TT5 in single and multiple ascending intravenous doses in healthy participants and in surgical patients. The Secondary Objectives are To investigate the pharmacokinetics (PK) of TT5 after single and multiple ascending intravenous doses in healthy participants and after intravenous doses in surgical patients. * To investigate the acute and chronic psychological subjective response of the healthy participants and surgical patients to TT5 * To assess the pharmacodynamics (PD) of TT5 after intravenous doses in surgical patients. Exploratory Objectives areto explore potential fluid biomarkers for TT5