Elevated 18:0 lysophosphatidylcholine contributes to the development of pain in tissue injury.

ABSTRACT: Tissue injuries, including burns, are major causes of death and morbidity worldwide. These injuries result in the release of intracellular molecules and subsequent inflammatory reactions, changing the tissues' chemical milieu and leading to the development of persistent pain through activating pain-sensing primary sensory neurons. However, the majority of pain-inducing agents in injured tissues are unknown. Here, we report that, amongst other important metabolite changes, lysophosphatidylcholines (LPCs) including 18:0 LPC exhibit significant and consistent local burn injury-induced changes in concentration. 18:0 LPC induces immediate pain and the development of hypersensitivities to mechanical and heat stimuli through molecules including the transient receptor potential ion channel, vanilloid subfamily, member 1, and member 2 at least partly via increasing lateral pressure in the membrane. As levels of LPCs including 18:0 LPC increase in other tissue injuries, our data reveal a novel role for these lipids in injury-associated pain. These findings have high potential to improve patient care.

Classification of painful or painless diabetic peripheral neuropathy and identification of the most powerful predictors using machine learning models in large cross-sectional cohorts.

BACKGROUND: To improve the treatment of painful Diabetic Peripheral Neuropathy (DPN) and associated co-morbidities, a better understanding of the pathophysiology and risk factors for painful DPN is required. Using harmonised cohorts (N = 1230) we have built models that classify painful versus painless DPN using quality of life (EQ5D), lifestyle (smoking, alcohol consumption), demographics (age, gender), personality and psychology traits (anxiety, depression, personality traits), biochemical (HbA1c) and clinical variables (BMI, hospital stay and trauma at young age) as predictors. METHODS: The Random Forest, Adaptive Regression Splines and Naive Bayes machine learning models were trained for classifying painful/painless DPN. Their performance was estimated using cross-validation in large cross-sectional cohorts (N = 935) and externally validated in a large population-based cohort (N = 295). Variables were ranked for importance using model specific metrics and marginal effects of predictors were aggregated and assessed at the global level. Model selection was carried out using the Mathews Correlation Coefficient (MCC) and model performance was quantified in the validation set using MCC, the area under the precision/recall curve (AUPRC) and accuracy. RESULTS: Random Forest (MCC = 0.28, AUPRC = 0.76) and Adaptive Regression Splines (MCC = 0.29, AUPRC = 0.77) were the best performing models and showed the smallest reduction in performance between the training and validation dataset. EQ5D index, the 10-item personality dimensions, HbA1c, Depression and Anxiety t-scores, age and Body Mass Index were consistently amongst the most powerful predictors in classifying painful vs painless DPN. CONCLUSIONS: Machine learning models trained on large cross-sectional cohorts were able to accurately classify painful or painless DPN on an independent population-based dataset. Painful DPN is associated with more depression, anxiety and certain personality traits. It is also associated with poorer self-reported quality of life, younger age, poor glucose control and high Body Mass Index (BMI). The models showed good performance in realistic conditions in the presence of missing values and noisy datasets. These models can be used either in the clinical context to assist patient stratification based on the risk of painful DPN or return broad risk categories based on user input. Model's performance and calibration suggest that in both cases they could potentially improve diagnosis and outcomes by changing modifiable factors like BMI and HbA1c control and institute earlier preventive or supportive measures like psychological interventions.

Conditioned pain modulation is more efficient in patients with painful diabetic polyneuropathy than those with nonpainful diabetic polyneuropathy.

ABSTRACT: Endogenous pain modulation, as tested by the conditioned pain modulation (CPM) protocol, is typically less efficient in patients with chronic pain compared with healthy controls. We aimed to assess whether CPM is less efficient in patients with painful diabetic polyneuropathy (DPN) compared with those with nonpainful DPN. Characterization of the differences in central pain processing between these 2 groups might provide a central nervous system explanation to the presence or absence of pain in diabetic neuropathy in addition to the peripheral one. Two hundred seventy-one patients with DPN underwent CPM testing and clinical assessment, including quantitative sensory testing. Two modalities of the test stimuli (heat and pressure) conditioned to cold noxious water were assessed and compared between patients with painful and nonpainful DPN. No significant difference was found between the groups for pressure pain CPM; however, patients with painful DPN demonstrated unexpectedly more efficient CPMHEAT (-7.4 ± 1.0 vs -2.3 ± 1.6; P = 0.008). Efficient CPMHEAT was associated with higher clinical pain experienced in the 24 hours before testing (r = -0.15; P = 0.029) and greater loss of mechanical sensation (r = -0.135; P = 0.042). Moreover, patients who had mechanical hypoesthesia demonstrated more efficient CPMHEAT (P = 0.005). More efficient CPM among patients with painful DPN might result from not only central changes in pain modulation but also from altered sensory messages coming from tested affected body sites. This calls for the use of intact sites for proper assessment of pain modulation in patients with neuropathy.

The use of high dose topical capsaicin in the management of peripheral neuropathy: narrative review and local experience.

Capsaicin, derived from the chilli pepper plant, is available in high concentration (8%) patches to provide topical therapy for neuropathic pain. Its analgesic effects relate to defunctionalisation and nerve terminal retraction of predominantly C fibres in the dermis and epidermis. Systematic reviews and meta-analysis support its use for the management of post-herpetic neuralgia and HIV neuropathy with some evidence for use in painful peripheral diabetic neuropathy. The article concludes with advice on the practicalities of running a topical 8% capsaicin clinic for peripheral neuropathic pain.

Leptin and fractalkine: novel subcutaneous cytokines in burn injury.

Burn injury is a pathology underpinned by progressive and aberrant inflammation. It is a major clinical challenge to survival and quality of life. Although the complex local and disseminating pathological processes of a burn injury ultimately stem from local tissue damage, to date relatively few studies have attempted to characterise the local inflammatory mediator profile. Here, cytokine content and associated transcriptional changes were measured in rat skin for three hours immediately following induction of a scald-type (60°C, 2 min) burn injury model. Leptin (P=0.0002) and fractalkine (P=0.0478) concentrations were significantly elevated post-burn above pre-burn and control site values, coinciding with the development of burn site oedema and differential expression of leptin mRNA (P=0.0004). Further, gene sequencing enrichment analysis indicated cytokine-cytokine receptor interaction (P=1.45×10-6). Subsequent behavioural studies demonstrated that, following subcutaneous injection into the dorsum of the paw, both leptin and fractalkine induced mechanical allodynia, heat hyperalgesia and the recruitment of macrophages. This is the first report of leptin elevation specifically at the burn site, and the first report of fractalkine elevation in any tissue post-burn which, together with the functional findings, calls for exploration of the influence of these cytokines on pain, inflammation and burn wound progression. In addition, targeting these signalling molecules represents a therapeutic potential as early formative mediators of these pathological processes.

Chronic pain in critical care survivors: a narrative review.

Chronic pain is an important problem after critical care admission. Estimates of the prevalence of chronic pain in the year after discharge range from 14% to 77% depending on the type of cohort, the tool used to measure pain, and the time point when pain was assessed. The majority of data available come from studies using health-related quality of life tools, although some have included pain-specific tools. Nociceptive, neuropathic, and nociplastic pain can occur in critical care survivors, but limited information about the aetiology, body site, and temporal trajectory of pain is currently available. Older age, pre-existing pain, and medical co-morbidity have been associated with pain after critical care admission. No trials were identified of interventions to target chronic pain in survivors specifically. Larger studies, using pain-specific tools, over an extended follow-up period are required to confirm the prevalence, identify risk factors, explore any association between acute and chronic pain in this setting, determine the underlying pathological mechanisms, and inform the development of future analgesic interventions.

Microdialysis Workflow for Metabotyping Superficial Pathologies: Application to Burn Injury.

Burn injury can be a devastating traumatic injury, with long-term personal and social implications for the patient. The many complex local and disseminating pathological processes underlying burn injury's clinical challenges are orchestrated from the site of injury and develop over time, yet few studies of the molecular basis of these mechanisms specifically explore the local signaling environment. Those that do are typically destructive in nature and preclude the collection of longitudinal temporal data. Burn injury therefore exemplifies a superficial temporally dynamic pathology for which experimental sampling typically prioritizes either specificity to the local burn site or continuous collection from circulation. Here, we present an exploratory approach to the targeted elucidation of complex, local, acutely temporally dynamic interstitia through its application to burn injury. Subcutaneous microdialysis is coupled with ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) analysis, permitting the application of high-throughput metabolomic profiling to samples collected both continuously and specifically from the burn site. We demonstrate this workflow's high yield of burn-altered metabolites including the complete structural elucidation of niacinamide and uric acid, two compounds potentially involved in the pathology of burn injury. Further understanding the metabolic changes induced by burn injury will help to guide therapeutic intervention in the future. This approach is equally applicable to the analysis of other tissues and pathological conditions, so it may further improve our understanding of the metabolic changes underlying a wide variety of pathological processes.

Chronic Pain and Chronic Opioid Use After Intensive Care Discharge - Is It Time to Change Practice?

Almost half of patients treated on intensive care unit (ICU) experience moderate to severe pain. Managing pain in the critically ill patient is challenging, as their pain is complex with multiple causes. Pharmacological treatment often focuses on opioids, and over a prolonged admission this can represent high cumulative doses which risk opioid dependence at discharge. Despite analgesia the incidence of chronic pain after treatment on ICU is high ranging from 33-73%. Measures need to be taken to prevent the transition from acute to chronic pain, whilst avoiding opioid overuse. This narrative review discusses preventive measures for the development of chronic pain in ICU patients. It considers a number of strategies that can be employed including non-opioid analgesics, regional analgesia, and non-pharmacological methods. We reason that individualized pain management plans should become the cornerstone for critically ill patients to facilitate physical and psychological well being after discharge from critical care and hospital.

Lessons learnt from establishing a high dose opioid review clinic for people living with HIV.

People living with HIV represent a unique aging population, living with a chronic condition associated with significant pain. A number take high dose, long-term opioids to manage moderate to severe chronic pain, presenting specific risks. This article highlights the size and impact of this problem and outlines the service objectives and set up of a specialist clinic to manage people living with HIV on high dose opioids, alongside its successes and learning points.

The value of pupillary dilation in pre-emptive analgesia: is there more to this than meets the eye?

The pupillary dilatation reflex may present an objective method of predicting whether sedated patients require additional analgesia for painful procedures. Behavioural pain assessment tools identify pain only once it has occurred and are unable to guide pre-emptive management. The pupillary dilatation reflex response to a tetanic stimulus has been utilised to assess analgesic requirements in patients under anaesthesia and for those with postoperative pain. This tool appears promising to assess pain in the critically ill; however, a number of questions remain unanswered regarding the influence of sedation on this response. These questions require further exploration before the pupillary dilatation reflex can be widely adopted into clinical practice.

Peripheral mechanisms of burn injury-associated pain.

It is estimated that burn injury affects about 1 in 3000 people annually world-wide. Burn injury induces severe pain, which is difficult to control in the great majority of cases making burn injury-associated pain a serious clinical challenge. In order to meet this clinical need, novel targets should be identified. Like pain developing in other peripheral pathologies, burn injury-associated pain is also initiated and maintained by signalling between the injured tissues and primary sensory fibres that supply those tissues. This signalling is underlain by the formation and accumulation of a mixture of agents at the site of the injury, some of which could be targets for intervention. However, at present the composition of this "burn injury tissue fluid" is incompletely established. Here, we summarise our current understanding of the composition of this burn injury tissue fluid and explore how already known agents in that tissue fluid may activate nociceptors to initiate and maintain pain associated with burn injury.