Sam Chong

OBJECTIVE: This discussion document about the management of cancer pain is written from the pain specialists' perspective in order to provoke thought and interest in a multimodal approach to the management of cancer pain, not just towards the end of life, but pain at diagnosis, as a consequence of cancer therapies, and in cancer survivors. It relates the science of pain to the clinical setting and explains the role of psychological, physical, interventional and complementary therapies in cancer pain. METHODS: This document has been produced by a consensus group of relevant health care professionals in the United Kingdom and patients' representatives making reference to the current body of evidence relating to cancer pain. In the first of two parts, pathophysiology, oncological, pharmacological, and psychological treatment are considered. CONCLUSIONS: It is recognized that the World Health Organization (WHO) analgesic ladder, while providing relief of cancer pain towards the end of life for many sufferers worldwide, may have limitations in the context of longer survival and increasing disease complexity. To complement this, it is suggested that a more comprehensive model of managing cancer pain is needed that is mechanism-based and multimodal, using combination therapies including interventions where appropriate, tailored to the needs of an individual, with the aim to optimize pain relief with minimization of adverse effects.

BACKGROUND: It is important to evaluate sequalae for complex chronic health conditions such as endometriosis and mental health disorders. Endometriosis impacts 1 in 10 women. Mental health outcomes can be a primary determinant in many physical health conditions although this is an area not well researched particularly in women's health. This has been problematic for endometriosis patients in particular, who report mental health issues as well as other key comorbidities such as chronic pelvic pain and infertility. This could be partly due to the complexities associated with comprehensively exploring overlaps between physical and mental health disorders in the presence of multiple comorbidities and their potential mechanistic relationship. METHODS: In this evidence synthesis, a systematic methodology and mixed-methods approaches were used to synthesize both qualitative and quantitative data to examine the prevalence of the overlapping sequalae between endometriosis and psychiatric symptoms and disorders. As part of this, an evidence synthesis protocol was developed which included a systematic review protocol that was published on PROSPERO (CRD42020181495). The aim was to identify and evaluate mental health reported outcomes and prevalence of symptoms and psychiatric disorders associated with endometriosis. FINDINGS: A total of 34 papers were included in the systematic review and 15 were included in the meta-analysis. Anxiety and depression symptoms were the most commonly reported mental health outcomes while a pooled analysis also revealed high prevalence of chronic pelvic pain and dyspareunia. INTERPRETATION: It is evident that small-scale cross-sectional studies have been conducted in a variety of settings to determine mental health outcomes among endometriosis patients. Further research is required to comprehensively evaluate the mental health sequalae with endometriosis.

Importance Pain is a silent global epidemic impacting approximately a third of the population. Pharmacological and surgical interventions are primary modes of treatment. Cognitive/behavioural management approaches and interventional pain management strategies are approaches that have been used to assist with the management of chronic pain. Accurate data collection and reporting treatment outcomes are vital to addressing the challenges faced. In light of this, we conducted a systematic evaluation of the current digital application landscape within chronic pain medicine. Objective The primary objective was to consider the prevalence of digital application usage for chronic pain management. These digital applications included mobile apps, web apps, and chatbots. Data sources We conducted searches on PubMed and ScienceDirect for studies that were published between 1st January 1990 and 1st January 2021. Study selection Our review included studies that involved the use of digital applications for chronic pain conditions. There were no restrictions on the country in which the study was conducted. Only studies that were peer-reviewed and published in English were included. Four reviewers had assessed the eligibility of each study against the inclusion/exclusion criteria. Out of the 84 studies that were initially identified, 38 were included in the systematic review. Data extraction and synthesis The AMSTAR guidelines were used to assess data quality. This assessment was carried out by 3 reviewers. The data were pooled using a random-effects model. Main outcome(s) and measure(s) Before data collection began, the primary outcome was to report on the standard mean difference of digital application usage for chronic pain conditions. We also recorded the type of digital application studied (e.g., mobile application, web application) and, where the data was available, the standard mean difference of pain intensity, pain inferences, depression, anxiety, and fatigue. Results 38 studies were included in the systematic review and 22 studies were included in the meta-analysis. The digital interventions were categorised to web and mobile applications and chatbots, with pooled standard mean difference of 0.22 (95% CI: −0.16, 0.60), 0.30 (95% CI: 0.00, 0.60) and −0.02 (95% CI: −0.47, 0.42) respectively. Pooled standard mean differences for symptomatologies of pain intensity, depression, and anxiety symptoms were 0.25 (95% CI: 0.03, 0.46), 0.30 (95% CI: 0.17, 0.43) and 0.37 (95% CI: 0.05, 0.69), respectively. A sub-group analysis was conducted on pain intensity due to the heterogeneity of the results ( I 2 = 82.86%; p = 0.02). After stratifying by country, we found that digital applications were more likely to be effective in some countries (e.g., United States, China) than others (e.g., Ireland, Norway). Conclusions and relevance The use of digital applications in improving pain-related symptoms shows promise, but further clinical studies would be needed to develop more robust applications. Systematic Review Registration https://www.crd.york.ac.uk/prospero/ , identifier: CRD42021228343.

Abstract The aims of our study were to use whole genome sequencing in a cross-sectional cohort of patients to identify new variants in genes implicated in neuropathic pain, to determine the prevalence of known pathogenic variants and to understand the relationship between pathogenic variants and clinical presentation. Patients with extreme neuropathic pain phenotypes (both sensory loss and gain) were recruited from secondary care clinics in the UK and underwent whole genome sequencing as part of the National Institute for Health and Care Research Bioresource Rare Diseases project. A multidisciplinary team assessed the pathogenicity of rare variants in genes previously known to cause neuropathic pain disorders and exploratory analysis of research candidate genes was completed. Association testing for genes carrying rare variants was completed using the gene-wise approach of the combined burden and variance-component test SKAT-O. Patch clamp analysis was performed on transfected HEK293T cells for research candidate variants of genes encoding ion channels. The results include the following: (i) Medically actionable variants were found in 12% of study participants (205 recruited), including known pathogenic variants: SCN9A(ENST00000409672.1): c.2544T>C, p.Ile848Thr that causes inherited erythromelalgia, and SPTLC1(ENST00000262554.2):c.340T>G, p.Cys133Tr variant that causes hereditary sensory neuropathy type-1. (ii) Clinically relevant variants were most common in voltage-gated sodium channels (Nav). (iii) SCN9A(ENST00000409672.1):c.554G>A, pArg185His variant was more common in non-freezing cold injury participants than controls and causes a gain of function of NaV1.7 after cooling (the environmental trigger for non-freezing cold injury). (iv) Rare variant association testing showed a significant difference in distribution for genes NGF, KIF1A, SCN8A, TRPM8, KIF1A, TRPA1 and the regulatory regions of genes SCN11A, FLVCR1, KIF1A and SCN9A between European participants with neuropathic pain and controls. (v) The TRPA1(ENST00000262209.4):c.515C>T, p.Ala172Val variant identified in participants with episodic somatic pain disorder demonstrated gain-of-channel function to agonist stimulation. Whole genome sequencing identified clinically relevant variants in over 10% of participants with extreme neuropathic pain phenotypes. The majority of these variants were found in ion channels. Combining genetic analysis with functional validation can lead to a better understanding as to how rare variants in ion channels lead to sensory neuron hyper-excitability, and how cold, as an environmental trigger, interacts with the gain-of-function NaV1.7 p.Arg185His variant. Our findings highlight the role of ion channel variants in the pathogenesis of extreme neuropathic pain disorders, likely mediated through changes in sensory neuron excitability and interaction with environmental triggers.