Chronic pain and fatigue in musculoskeletal disease contribute significantly to disability, and recent studies suggest an association with reduced motivation and excessive fear avoidance. In this behavioural neuroimaging study, we aimed to identify the specific behavioural and neural changes associated with musculoskeletal pain and fatigue during reward and loss decision-making.Twenty-nine participants with chronic inflammatory arthritis and 28 healthy controls performed an instrumental learning task (four-armed bandit) during 3 T brain functional MRI. Computational analyses with reinforcement learning models were used to quantify the hidden variables involved in reward and loss decision-making, compare them across groups and, finally, relate them to brain activity.We found that participants with chronic pain had higher sensitivity to punishments and increased activity associated with the punishment prediction error in the right posterior insular cortex, putamen, pallidum and dorsolateral prefrontal cortex. Functional network connectivity analysis showed that insula centrality was correlated with subjective reports of fatigue and pain during the task.The findings of this exploratory study suggest that pain and fatigue in chronic pain relate to objective behavioural changes in loss decision-making, which can be mapped to a specific pattern of activity in brain circuits of motivation and decision-making. The proposed parametric signature, characterized most notably by increased punishment sensitivity, is distinct from patterns previously reported in psychiatric conditions and it aligns with predictions of the fear avoidance model of pain. In a behavioural neuroimaging study, Mancini et al. demonstrate that people with chronic inflammatory arthritis show increased sensitivity to punishments when making decisions about volatile wins and losses. This behavioural change can be mapped to a specific pattern of activity in neural networks involved in motivation.

Fibromyalgia is a chronic condition characterised by widespread pain, as well as sleep disturbances, fatigue, and memory and concentration difficulties. Research suggests that an alteration in how the brain represents multisensory inputs from the body may cause or maintain chronic pain conditions, including fibromyalgia. Extended reality (XR) and virtual reality setups generating multisensory conflicts have been shown to alleviate pain, however, the optimal duration for such interventions remains unexplored. Here, we aimed to determine an optimal duration for the cardio-visual full body illusion (FBI) in fibromyalgia, considering both tolerability and changes in pain. Participants wore headsets to view a video of their own body, filmed from behind, and their virtual body flashed in synchrony with their heartbeat. We used an established dose-finding protocol to determine the ideal duration (balancing benefit and tolerability). Seven cohorts of participants (N = 20) were exposed to different durations of the FBI, with adjustments to duration made according to predefined criteria. Measures included a numeric rating scale for pain intensity, pressure pain thresholds, and scales measuring fibromyalgia symptom severity and impact. We found a quadratic relationship between session duration and changes in self-reported pain-intensity, with 8–16-min durations yielding the most significant improvements. Notably, in the 12-min cohorts pain relief was sustained at 24-h follow-up, and this is the recommended duration for future research. These findings represent a key step towards developing an effective non-pharmacological intervention for fibromyalgia. Future dose-optimisation research should explore the optimum number of sessions and spacing between sessions.

BACKGROUND:Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition. METHODS:Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n=34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n=50). Gene expression of peripheral blood macrophages was assessed. RESULTS:In the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher's p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls. CONCLUSION:A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1.

Background: Previous research suggests that the processing of internal body sensations (interoception) affects how we experience pain. There is some evidence that people with fibromyalgia syndrome (FMS), which is a condition characterised by chronic pain and fatigue, may have altered interoceptive processing. However, extant findings are inconclusive, and some tasks previously used to measure interoception are of questionable validity. We used a task which overcomes problems with previous tasks – the Phase Adjustment Task (PAT) – to measure interoception in adults with FMS. Methods: We examined: (i) the tolerability of the PAT in an FMS sample (N = 154); (ii) if there are differences in facets of interoception (PAT performance, PAT-related confidence, and scores on the Private Body Consciousness Scale) between an FMS sample and an age- and gender-matched pain-free control sample (N = 94); and (iii) if subgroups of participants with FMS could be identified according to interoceptive accuracy levels. Results: After including additional task breaks and a recommended hand posture, we found that the PAT was tolerable in the FMS sample. Participants in the FMS sample were more likely to be classified as ‘interoceptive’ on the PAT, and had significantly higher self-reported interoception and interoceptive beliefs compared to participants in the pain-free sample. Within the FMS sample, participants who were classified as interoceptive on the PAT had significantly lower symptom impact than the unclassified participants. Conversely, self-reported interoception was positively correlated with FMS symptom severity and impact. Conclusions: The present findings suggest that interoception may be an important factor to consider in understanding and managing FMS symptoms, and that the PAT is a useful tool for assessing interoception in this population. We recommend future longitudinal work to better understand associations between fluctuating FMS symptoms and interoceptive processing.

Importance Myasthenia gravis (MG) is caused by autoantibodies that disrupt the neuromuscular junction. The neonatal fragment crystallizable receptor (FcRn) antagonists, efgartigimod and rozanolixizumab, reduce immunoglobulin G (IgG) level in the circulation and alleviate symptoms in patients with generalized MG. Objective To examine the efficacy and safety profile of batoclimab, a monoclonal IgG1 antibody, in patients with generalized MG. Design, Setting, and ParticipantsThis was a multicenter randomized clinical trial conducted from September 15, 2021, to June 29, 2022, at 27 centers in China. Adult patients 18 years or older with generalized MG were screened, and those who were antibody positive were enrolled. Intervention Eligible patients received batoclimab or matching placebo in addition to standard of care. Each treatment cycle consisted of 6 weekly subcutaneous injections of batoclimab, 680 mg, or matching placebo followed by 4 weeks of observation. A second treatment cycle was conducted in patients who required continuing treatment. Main Outcome and Measure The primary outcome was sustained improvement, as defined by a 3-point or greater reduction in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score from baseline for 4 or more consecutive weeks in the first cycle in individuals who were positive for acetylcholine receptor or muscle-specific kinase antibodies. Results A total of 178 adult patients with generalized MG were screened, 132 were randomly assigned, 131 tested positive for antibodies, and 1 tested negative for antibodies. A total of 132 patients (mean [SE] age, 43.8 [13.6] years; 88 women [67.2%]) were enrolled. The rate of sustained MG-ADL improvement in the first cycle in antibody-positive patients was 31.3% (20 of 64) in the placebo group vs 58.2% (39 of 67) in the batoclimab group (odds ratio, 3.45; 95% CI, 1.62-7.35; P = .001). The MG-ADL score diverged between the 2 groups as early as week 2. The mean (SE) maximum difference in MG-ADL score reduction occurred 1 week after the last dose (day 43, 1.7 [0.3] in the placebo group vs 3.6 [0.3] in the batoclimab group; group difference, -1.9; 95% CI, -2.8 to -1.0; nominal P < .001). The rates of treatment-related and severe treatment-emergent adverse events in patients were 36.9% (24 of 65) and 7.7% (5 of 65) in the placebo group vs 70.1% (47 of 67) and 3.0% (2 of 67) in the batoclimab group, respectively. Conclusions and Relevance Batoclimab increased the rate of sustained MG-ADL improvement and was well tolerated in adult patients with generalized MG. Clinical effects and the extent of IgG reduction were similar to those previously reported for efgartigimod and rozanolixizumab. Future studies of large sample size are needed to further understand the safety profile of batoclimab.

Small-fiber neuropathy (SFN), a pathology caused by severe loss of free-endings of unmyelinated sensory nerves, is difficult to diagnose and monitor. The use of cutaneous electrical stimulation as a diagnostic tool is hampered by the fact that the injected current penetrates deep into the skin and stimulates many other receptors. Interdigitated electrodes are recently proposed to control the depth of current penetration and selectively address small-fibers. Here, flexible and adhesive interdigitated electrodes made of Au coated with poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) are developed, that conform comfortably and reliably to human skin. It is shown that the PEDOT:PSS coating improves safety by significantly reducing the voltage required to inject current. The selectivity of the device is assessed by showing that it elicits a significantly slower reaction time than commercial cutaneous electrophysiology electrodes, as it exclusively activates unmyelinated fibers. The device is further evaluated on volunteers that undergo local capsaicin treatment to induce temporary loss of the nerve endings of small-fibers. Pre- and post-treatment electrical stimulation of the affected area with the device reveals impaired sensory detection that is not observed with commercial cutaneous electrophysiology electrodes. These results represent a significant step towards the use of electrical stimulation as a diagnostic and monitoring tool for SFN.

BACKGROUND:Persistent neuropathic pain (NP) is a prevalent and debilitating problem, often resistant to first-line treatment. Low-dose naltrexone (LDN) has shown promise in treating fibromyalgia and other forms of chronic pain. CASE REPORT:Retrospective analysis was performed on 14 of 18 patients with diverse forms of NP who met inclusion criteria by using LDN (1.5-4.5 mg) as a second-line medical pain therapy. Pain Numeric Rating Scale (NRS-11) in all patients decreased from 6.29 ± 2.20 to 3.71 ± 2.89 (P = 0.001) from initiation to final visit. Median treatment length was 252 days with longest being 1,054 days. All 6 patients who remained on LDN > 1 year reported reduced pain NRS-11 at last visit. Side effects were mild and did not result in cessation of therapy. CONCLUSIONS:LDN may show promise in treating persistent NP.

BACKGROUND AND PURPOSE:Neuromyelitis optica spectrum disorder (NMOSD) is a severe neurological inflammatory disease mainly caused by pathogenic aquaporin-4 antibodies (AQP4-IgG). The safety and efficacy of the neonatal Fc receptor antagonist batoclimab addition to conventional intravenous methylprednisolone pulse (IVMP) therapy in patients with NMOSD acute attacks was assessed.METHODS:In an open-label, dose-escalation phase 1b study, NMOSD patients with acute myelitis and/or optic neuritis received four doses of weekly subcutaneous injections of either 340 mg or 680 mg batoclimab with concurrent IVMP and were followed up for 27 weeks. The primary end-points were safety and tolerability. Secondary end-points included pharmacodynamics and efficacy, with key efficacy assessment at week 4.RESULTS:In total nine NMOSD patients were enrolled, including two and seven in the 340 and 680 mg groups. Five patients had acute myelitis, while the remaining four had unilateral optic neuritis. Batoclimab add-on therapy had an overall good safety profile without serious adverse events. In the 680 mg group, mean immunoglobulin G (IgG) reached its maximum reduction at the last dose (day 22). In the meantime, AQP4-IgG was undetectable in six of seven subjects whose baseline AQP4-IgG titers ranged from 1:32 to 1:320. Expanded Disability Status Scale score was reduced by 1.3 ± 0.4 at week 4 (2.7 ± 1.3) compared with baseline (4.0 ± 1.0).CONCLUSIONS:Batoclimab add-on therapy to IVMP is safe and tolerated in patients with NMOSD. Preliminary evidence suggests a beneficial neurological effect. A randomized controlled trial would be needed to prove the efficacy.

Background Recommendations for the management of pain related to pelvic mesh implants are still under development. One limitation that has impeded progress in this area is that mesh-related pain has not been consistently defined or measured. Here, we reviewed the ways in which pain associated with pelvic mesh implants has been measured, and mapped the ways in which these existing measures capture the construct. Methods First, we reviewed existing accounts of the pain associated with pelvic mesh implants to develop a multifaceted construct definition, which includes aspects related to pain intensity, timing, body location, phenomenological qualities, impact/interference with daily living, and patient expectations and beliefs. Next, we reviewed the ways that the construct has been measured in the extant literature. Results Within 333 eligible studies, 28 different assessments of pain associated with pelvic mesh were identified, and 61% of studies reported using more than one measurement tool. Questionnaire measures included measures designed to assess urological and/or pelvic symptoms, generic measures and unvalidated measures. We did not identify any validated questionnaire measures designed to assess pain associated with pelvic mesh implants. The phenomenological, location, and expectation/belief components of the construct were not captured well by the identified questionnaire measures, and there is no evidence that any of the identified measures have appropriate psychometric properties for the assessment of pain related to pelvic mesh implants. Conclusions We recommend further qualitative research regarding women’s experiences of pelvic mesh-related pain assessment, and the development of a condition-specific patient reported outcome measure.

The reliability of expressed emotion (EE) ratings by the Camberwell Family Interview (CFI) and characteristics of EE were evaluated in families of patients with mood disorders in Japan. The subjects were 27 patients with mood disorders and 31 members of their families. The CFI was carried out with the family members. EE was rated by two raters independently, and the inter-rater reliability was evaluated according to Spearman’s correlation coefficient by ranks and the κ-value. The distribution of subscales of EE in these subjects was compared with that in families of patients with schizophrenia in Japan and families of patients with mood disorders abroad. Concerning critical comments (CC), hostility (H), and emotional over-involvement (EOI), which are important for EE rating, Spearman’s correlation coefficient and the κ-values were 0.4–0.8, and the reliability of EE ratings in mood disorders was not high. The proportion of positive agreement was particularly low in H and EOI. CCs were fewer in families of Japanese patients with mood disorders than in those with schizophrenia or families of American or European patients with mood disorders. Re-evaluation of the inter-rater reliability of EE ratings in mood disorders is needed. Expressed emotion was more suppressed in families of patients with mood disorders than in those of patients with schizophrenia. Expressed emotion was also more reserved in the Japanese subjects than in their Western counterparts.

Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial electromyography (n = 3 CIP participants and n = 8 healthy controls), we found that these patients also have abnormalities in the encoding of affective touch, which is mediated by the specialized afferents C-low threshold mechanoreceptors (C-LTMRs). In the mouse, we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch.

The neural mechanisms underlying placebo analgesia have attracted considerable attention over the recent years. In contrast, little is known about the neural underpinnings of a nocebo-induced increase in pain. We previously showed that nocebo-induced hyperalgesia is accompanied by increased activity in the hippocampus that scaled with the perceived level of anxiety. As a key node of the neural circuitry of perceived threat and fear, the hippocampus has recently been proposed to coordinate defensive behaviour in a context-dependent manner. Such a role requires close interactions with other regions involved in the detection of and responses to threat. Here, we investigated the functional connectivity of the hippocampus during nocebo-induced hyperalgesia. Our results show an increase in functional connectivity between hippocampus and brain regions implicated in the processing of sensory-discriminative aspects of pain (posterior insula and primary somatosensory/motor cortex) as well as the periaqueductal grey. This nocebo-induced increase in connectivity scaled with an individual's increase in anxiety. Moreover, hippocampus connectivity with the amygdala was negatively correlated with the pain intensity reported during nocebo hyperalgesia relative to the placebo condition. Our findings suggest that the hippocampus links nocebo-induced anxiety to a heightened responsiveness to nociceptive input through changes in its crosstalk with pain-modulatory brain areas.

Background Pain is an unpleasant sensation that signals potential or actual bodily injury. The locations of bodily pain can be communicated and recorded by freehand drawing on 2D or 3D (manikin) surface maps. Freehand pain drawings are often part of validated pain questionnaires (eg, the Brief Pain Inventory) and use 2D templates with undemarcated body outlines. The simultaneous analysis of drawings allows the generation of pain frequency maps that are clinically useful for identifying areas of common pain in a disease. The grid-based approach (dividing a template into cells) allows easy generation of pain frequency maps, but the grid’s granularity influences data capture accuracy and end-user usability. The grid-free templates circumvent the problem related to grid creation and selection and provide an unbiased basis for drawings that most resemble paper drawings. However, the precise capture of drawn areas poses considerable challenges in producing pain frequency maps. While web-based applications and mobile-based apps for freehand digital drawings are widely available, tools for generating pain frequency maps from grid-free drawings are lacking. Objective We sought to provide an algorithm that can process any number of freehand drawings on any grid-free 2D body template to generate a pain frequency map. We envisage the use of the algorithm in clinical or research settings to facilitate fine-grain comparisons of human pain anatomy between disease diagnosis or disorders or as an outcome metric to guide monitoring or discovery of treatments. Methods We designed a web-based tool to capture freehand pain drawings using a grid-free 2D body template. Each drawing consisted of overlapping rectangles (Scalable Vector Graphics elements) created by scribbling in the same area of the body template. An algorithm was developed and implemented in Python to compute the overlap of rectangles and generate a pain frequency map. The utility of the algorithm was demonstrated on drawings obtained from 2 clinical data sets, one of which was a clinical drug trial (ISRCTN68734605). We also used simulated data sets of overlapping rectangles to evaluate the performance of the algorithm. Results The algorithm produced nonoverlapping rectangles representing unique locations on the body template. Each rectangle carries an overlap frequency that denotes the number of participants with pain at that location. When transformed into an HTML file, the output is feasibly rendered as a pain frequency map on web browsers. The layout (vertical-horizontal) of the output rectangles can be specified based on the dimensions of the body regions. The output can also be exported to a CSV file for further analysis. Conclusions Although further validation in much larger clinical data sets is required, the algorithm in its current form allows for the generation of pain frequency maps from any number of freehand drawings on any 2D body template.

We investigated the safety and explore potential efficacy of batoclimab administered subcutaneously in Chinese patients with generalized myasthenia gravis (gMG). A randomized, double-blinded, placebo-controlled, parallel phase II study was conducted. First, in the double-blinded treatment period, eligible patients received batoclimab (680 mg), batoclimab (340 mg), or placebo on days 1, 8, 15, 22, 29, and 36. In the open-label treatment period, patients received batoclimab (340 mg) on days 50, 64, and 78. In the follow-up period, patients were examined on days 92, 106, and 120. The primary endpoint was Myasthenia Gravis Activities of Daily Living (MG-ADL) score change on day 43 from baseline. In total, 30 eligible patients were enrolled, with 11, 10, and 9 patients in the batoclimab 680 mg, batoclimab 340 mg, and placebo groups, respectively. MG-ADL score changes from baseline to day 43 were −2.2 ± 0.9, −4.7 ± 0.6, and −4.4 ± 1.0 in the placebo, batoclimab 340 mg, and 680 mg groups, respectively. Similar changes were observed in Quantitative Myasthenia Gravis, Myasthenia Gravis Composite, and 15-item Myasthenia Gravis Quality of Life scores in the placebo, batoclimab 340 mg, and 680 mg groups, respectively. The proportion of patients with clinically significant improvement on day 43 was higher in the batoclimab groups. On day 120, all four scales in the placebo group had more significant improvement compared with the batoclimab groups, with total serum IgG levels reaching a plateau. No death or treatment-emergent adverse events (TEAEs) led to study discontinuation. Batoclimab is effective and safe in Chinese patients with gMG. This study was registered at ClinicalTrials.gov (NCT04346888) on 15 April 2020, with the first patient enrolled on 23 July 2020.

Patients with advanced stage cancers frequently suffer from severe pain as a result of bone metastasis and bone destruction, for which there is no efficacious treatment. Here, using multiple mouse models of bone cancer, we report that agonists of the immune regulator STING (stimulator of interferon genes) confer remarkable protection against cancer pain, bone destruction, and local tumor burden. Repeated systemic administration of STING agonists robustly attenuates bone cancer-induced pain and improves locomotor function. Interestingly, STING agonists produce acute pain relief through direct neuronal modulation. Additionally, STING agonists protect against local bone destruction and reduce local tumor burden through modulation of osteoclast and immune cell function in the tumor microenvironment, providing long-term cancer pain relief. Finally, these in vivo effects are dependent on host-intrinsic STING and IFN-I signaling. Overall, STING activation provides unique advantages in controlling bone cancer pain through distinct and synergistic actions on nociceptors, immune cells, and osteoclasts.

"My pain is exhausting, and it's rarely just pain. If not accompanied by diarrhoea, fatigue, or other debilitating symptoms, it's joined by a spiral of anxious thoughts about what the pain means……. I was constantly at doctors' and hospital appointments, but I was rarely asked about my pain. Even now, unless I'm in flare up, no one asks me about my pain or fatigue…. truthfully, those doctors and nurses don't have time to ask me about symptoms if I'm not flaring up…….IBD clinics even when interested aren't funded to manage those symptoms…and healthcare professionals dismissed my symptoms as they don't know what to say, as they don't understand pain in IBD, and they feel as powerless as I do……given that pain is one of the top presenting complaints in IBD, I find it astonishing how little I get asked about it". (Lucy Y, first diagnosed with Crohn's disease 23 years ago. Reproduced with permission). 1. Introduction Crohn's disease and ulcerative colitis ("inflammatory bowel disease" [IBD]) are chronic relapsing intermittently acute conditions, characterised by pathological changes in gut tissue, symptoms of diarrhoea, blood loss, and abdominal pain, long-term complications (fistulae, abscesses, and strictures), extra-abdominal manifestations such as arthritis, and systemic illness. Symptoms dominate IBD disease activity indices,39,42 but the primary target for treatment is inflammation of the gut mucosa. This treatment has significantly improved over the past decade, notably through the use of immunomodulator and biologic drugs. However, the pattern, severity, impact, and prognosis of symptoms still vary substantially from patient-to-patient. Clinicians caring for people with IBD focus on controlling the active bowel disease. Objective measures of disease activity, using endoscopy and imaging or surrogates such as faecal calprotectin, provide targets for disease-modifying drugs in trials and the clinic. However, there is a discrepancy between measures of gut inflammation and the extent and severity of patients' symptoms,30 and neither are straightforwardly related to measures of the overall impact on patients' lives.30 Early mucosal healing defined by endoscopy is associated with long-term improvements in symptom severity, but one-third of patients with healed mucosa do not achieve clinical remission.76,77 In particular, abdominal pain that persists beyond flares, despite optimal treatment of the gut disease, presents a common, disabling, and unresolved problem,64,101 affecting patients' quality of life (QoL) and psychological well-being58,75 and posing challenges for management.66,87 For clinicians, this means disease-targeted treatment alone may not resolve the patient's pain and pain-related distress. The result is that chronic abdominal pain may dominate patients' lives—underrecognised in both specialist and primary care settings, poorly assessed, and inadequately treated. In this Topical Review, we consider evidence about chronic abdominal pain in people with IBD. Our aim was to identify the extent to which general principles of modern chronic pain management92 should have equal place in the IBD clinic and consultation alongside the clinician's concern for diagnosing and treating underlying gut pathology, to ensure that pain in all patients with IBD is properly recognised, formally assessed, and treated safely and effectively. 2. Occurrence, impact, and assessment of abdominal pain in inflammatory bowel disease Pain is a prominent IBD symptom.27,61,79 In large cohorts of patients with IBD, 60% report abdominal pain,60 substantially more than the 25% prevalence observed in general population samples1,51; half have experienced it for more than 5 years.100 Pain contributes to the impact of IBD on QoL.47,58,60,75,99,101 Qualitative studies illustrate how pain and other symptoms affect all aspects of the lives of people with IBD, including those (such as proximity to a toilet) specific to gut problems.21 People with IBD describe "vicious circles" between pain and their other symptoms that create barriers to understanding and treatment of pain.86 Reactions to pain vary from defeat to tolerance to acceptance, but all have emotional impact.86 Pain is often not included as a predictor of QoL outcomes in prospective epidemiological research,94 but emerges as an independent prognostic factor when it is.95 The dissociation between abdominal pain and indices of gut inflammation highlights that pain should be a target for management in its own right.13,14 Yet, routine clinical assessment of patients with IBD does not necessarily include pain. It is one of 5 items in a commonly used clinical severity scale for Crohn's disease,39 but not part of the widely used Mayo Clinic four-item scale for ulcerative colitis,42 and only one small part of a common measure of IBD QoL.54 Each of these scales has its uses for disease assessment, but pain assessments and measures of gut inflammation should form distinct and separate components of consultations with patients who have IBD, so that the need for additional pain management, beyond the relief achieved by control of mucosal inflammation, can be established, monitored, and acted upon. One problem in achieving this is that there is no widely accepted fully tested pain assessment for patients with IBD, and there are challenges to developing one. In particular, it is not easy to separate pain from other IBD experiences (eg, bowel disturbance and psychological distress31) that together impair QoL in areas as diverse as sleep, eating and food enjoyment, fatigue, work capacity, and social relationships.47 Meanwhile, application of current recommendations for chronic pain classification in ICD-11, notably the regular use of numerical rating scales for pain intensity, pain-related distress, and interference with activity,92 would help reverse the neglect of this symptom in the clinic. 3. Mechanisms of abdominal pain in inflammatory bowel disease Reversible causes of abdominal pain in IBD include strictures, abscesses, fistulae, and small intestinal bacterial overgrowth. Renal or gall bladder calculi, common in patients with IBD, form part of the differential diagnosis. Patients with IBD have a higher risk of colorectal cancer, primary sclerosing cholangitis, and cholangiocarcinoma. Surgery as part of IBD management, in particular multiple operations, confers the additional risk of postsurgical pain. Most abdominal pain in people with IBD, however, is assumed to be triggered through activation of nociceptors in the gut by chemical, thermal, or mechanical stimuli.74 Disease remission, assessed by resolution of gut inflammation or restoration of normal bowel habit, might therefore be expected to improve or resolve abdominal pain. However, 30% to 50% of patients with IBD report significant pain despite disease remission,27,61,79 and patients themselves distinguish pain concurrent with active bowel disease from pain that persists beyond it.60 Visceral nociceptors innervate the gut sparsely; hence, deep abdominal pain or discomfort is often diffuse and poorly localised.15 These nociceptors, like other sensory afferents, have cell bodies in the dorsal root ganglia and possess molecular specificity.44 Most visceral afferents are autonomic and their roles in nociception and pain are unknown.35 Abnormally prolonged sensitisation of visceral afferents in the gastrointestinal tract after acute inflammation can contribute to chronic pain.12 CNS sensitisation is also apparent at the cellular level during acute inflammation29 and further amplifies signalling from ascending spinal pathways. This process is maintained by dysregulation of descending control that emanates from the brain,26 where structural and functional abnormalities in prefrontal and limbic regions have been observed.6,45,89 Those brain regions are also involved in emotional regulation and learning98 and may determine the capacity for behavioural adjustments needed to manage pain adaptively (for a given physical or social environment). The prefrontal–limbic abnormalities may explain the increased risks of mood and anxiety disorders in patients with IBD,33 disorders linked to persistence and severity of their pain.85 Such comprehensive models counter the long history of "psychogenic" theories of abdominal pain.84,93 Although healthcare professionals understand clearly that psychosocial factors contribute to the overall burden of living with IBD, less attention has been paid to how affective and cognitive factors modulate pain. New models highlight not only the role of cognitive, behavioral, and environmental factors underlying pain perception but also their interaction with visceral inflammation.50 However, the extent to which neuroanatomical changes determine the chronicity of pain in IBD is unclear nor is it known why or how they outlive episodes of gut inflammation to explain pain despite disease remission in susceptible patients with IBD. One clinical field producing insights to this problem is irritable bowel syndrome (IBS). Irritable bowel syndrome is a functional pain disorder that has abdominal pain as its cardinal symptom and can coaggregate with IBD.70 Research clarifying the complexity of visceral sensations of patients with IBS has benefited from biopsychosocial research that draws on rapidly advancing methods and tools for genetic, cellular (eg, visceral nociceptors), systems-based (eg, gut and nervous system), and behavioural (eg, avoidance, maladaptive coping, cognitive biases, and reactivity) studies.24,71 The extent of overlap between IBD and IBS clinical phenotypes and their gut pathophysiological profiles remains controversial,7 but integrated explanations and mechanisms for why abdominal pain persists in the absence of continuing gut mucosal inflammation are likely relevant for both conditions.66,70 Harnessing these insights to develop new or better approaches to pain management for persons with IBD will need not only a clearer understanding of what aspects of IBD pain are particularly challenging to patients, but also where and why existing treatments have failed or are limited. 4. Comorbid pain Extra-abdominal disease is an additional source of chronic pain in people with IBD; these pain comorbidities include back and joint pain linked to axial and peripheral spondyloarthritis,38,95 and conditions with higher prevalence in people with IBD such as migraine62 and fibromyalgia.55 Such extra-abdominal pain is a prominent predictor of reduced QoL and work productivity after adjustment for IBD activity.38,95 Shared underlying causes of visceral pain may complicate the picture,3 further illustrating the multiple mechanisms involved in the pain of patients with IBD.25 The co-occurrence of pain syndromes adds to the complexities and challenges of treating the individual patient, including different targets for treatment of specific conditions such as fibromyalgia and spondyloarthritis. 5. Pharmacological approaches to chronic pain in patients with inflammatory bowel disease Evidence continues to emerge that long-term pain outcomes are improved by active therapeutic targeting of mucosal inflammation.91 Tofacitinib therapy, for example, significantly improved QoL vs placebo in patients with moderate-to-severe active ulcerative colitis, including significant relief of abdominal pain.68 However, many patients will require additional pain management. The well-known problems of using analgesic medication for long-term pain are exacerbated for patients with IBD.98 Many analgesics have low efficacy and cause gut-related adverse effects in patients with IBD, including, paradoxically, pain.100 The challenge is how to adequately treat chronic abdominal pain while avoiding the harms associated with medication use. 5.1 Opioids Opioids are problematic. Immediate pain relief with short-term opioid use does not translate into improved functioning with long-term use.23,36. Opioids can cause gastrointestinal-related adverse effects, collectively called opioid-induced bowel dysfunction and including constipation, incomplete evacuation, bloating, and gastric reflux. Patients with IBD are at high risk for this condition because they suffer from chronic relapsing-remitting pain. Chronic high-dose opioid use can also induce visceral hyperalgesia (narcotic bowel syndrome) in a small subset of patients with IBD. This is highly intractable to treatment and a cause of prolonged hospital admission.22,36,52 Despite these problems, prescription opioid use is higher among patients with IBD compared with non-IBD patients57 and, in England, for example, increased significantly from 1990 through 2013.16 An estimated 5% of patients with IBD become heavy users of opioids within 10 years of diagnosis. IBD is an independent risk factor for becoming a heavy opioid user,88 and risk increases with psychiatric comorbidity such as depression or anxiety.37 Research continues into whether currently available opioids can be delivered, or new opioids developed, with radically less potential for addiction and serious side effects,18 and into strategies for limiting, reducing, and tightly monitoring opioid use in patients with IBD.19,20 The specificity of visceral pain-signalling neurons provides potential for developing peripherally restricted analgesics specific for visceral pain, devoid of CNS effects.15,18,44 Meanwhile, chronic use of currently licensed prescription opioids is associated with poorer control of pain,11 increased healthcare use,65 and higher mortality in patients with IBD.16 Long-term use of opioids therefore should, as far as possible, be avoided for pain management in these patients, and alternatives offered. National guidelines on opioid use for long-term pain concur in recommending education for informed consent and monitoring, commensurate with risk assessments.40 If continual or repeated opioid-based analgesics are necessary, for example in patients with major abdominal fistulae, they should preferably be prescribed in settings with access to nonpharmacological interventions and resources for managing acute and long-term consequences of dose reduction or discontinuation.4,20 5.2 Alternatives to opioids Alternative drugs to opioids also carry problems for this patient group. Nonsteroidal anti-inflammatory drugs are limited by risk of disease exacerbation.12,59,81 Results of phase 2 trials suggest a potential role for anticonvulsants used for neuropathic pain, such as gabapentin and pregabalin,81 known to improve rectal hypersensitivity in patients with IBS.46,56 But while this might justify clinical trials in patients with IBD, none have been reported, and furthermore the addictive potential of these drugs and the additional burden on patients posed by their side-effect profile raise questions about their application to long-term nonmalignant abdominal pain. Tricyclic antidepressants and selective norepinephrine reuptake inhibitors improve abdominal pain without some of the GI risks associated with conventional analgesics.28,32,52 A meta-analysis of randomised controlled trials in IBS found that low-dose tricyclic antidepressants alleviate abdominal pain,72 possibly by reducing afferent signals from the gastrointestinal tract.34,63 Again there are no trials in patients with IBD, and treating chronic pain with these drugs carries familiar concerns about long-term dependency, side effects, and withdrawal. Both endocannabinoid receptors (CB1 and CB2) are found in the gut and are potential targets for pain relief in IBD.2,78 A phase 2a clinical trial of a CB2 agonist (olorinab) is underway, including pain as an outcome, in people with Crohn's disease and functional symptoms.17 However, psychotropic effects from agonist activity at CB1 receptors remain a concern for most prescribable preparations, and evidence of efficacy from clinical trials of cannabis-based medicine for management of chronic pain in noncancer conditions generally is lacking.82 There is a need to understand the mechanism of abdominal pain relief afforded by cannabis-based medicines in patients who report benefit,43,73,83,96,97 and for robust investigations of efficacy and effectiveness in persons with IBD both short- and long-term. 6. Psychological approaches The focus of psychological interventions in IBD has mainly been concerned with adherence to treatment and modification of lifestyle factors, including stress-induced flares, but is now addressing pain and symptoms, and applying skills for working around IBD pain.5,8 Direct pain reduction by psychological methods has been demonstrated,10,66,67 but requires replication in larger studies.66 Self-management skills have in principle been endorsed by international guidelines.49 Of specific psychological modalities, hypnotherapy has shown promise in abdominal pain,69 although only one trial involved patients with IBD, targeting gut activity, pain, or coping with pain: gut‐directed hypnotherapy extended time between flares in ulcerative colitis compared to attention controls.48 The therapeutic value of psychological approaches has been attributed to anti-inflammatory effects,48,80,87 but empirical mechanistic studies are lacking. One source of evidence comes from studies of psychological interventions that are concerned more generally with relieving stress and improving quality of life in persons with IBD, factors linked to their pain experience.85 Meta‐analysis of 21 randomised controlled trials, however, yielded no evidence that psychological interventions improved emotional states and QoL, or reduced disease activity in the short‐ or long-term, in adults with IBD.90 A narrative review echoes this conclusion.5 Nevertheless, where unhelpful beliefs about IBD and negative biases in processing information underlie maladaptive behaviours, there is no a priori reason why cognitive methods (including cognitive and behavioural methods, problem solving, and emotional regulation53) should not be effective in relieving pain-related distress and disability. A recent wait-list controlled study paints a more positive efficacy profile for multicomponent cognitive behavioural therapy, at least in decreasing effects of IBD on QoL as well as reducing anxiety and depression in those with lower baseline levels.9 Given the complexity of visceral pain, its strong psychological underpinnings, and the increased impact it exerts across multiple life domains as pain persists, additional research targeting visceral pain in patients with IBD is called for. This will likely require a theoretically informed, empirically derived conceptual model that reflects the clinical realities of patients with IBD, the trajectory of their symptoms and triggers, and is not "borrowed" from other symptomatically similar but not necessarily mechanistically similar GI diseases. A well-defined, empirically rooted conceptual model built specifically for IBD should go a long way to reconcile discrepant findings regarding the role of stress and the efficacy of interventions that target stress-sensitive symptoms, such as pain, through psychological treatments. 7. Conclusion and future directions Pain is a common symptom in IBD, and represents a major health burden, significantly impacting QoL and psychological well-being. While optimal pharmacological treatment of gut inflammation is important for long-term control of symptoms, including pain, many persons with IBD continue to experience long-term abdominal pain. Chronic abdominal pain in these persons has multiple aetiologies and is complex. Available treatment options are limited. Current pain management strategies are not specific for IBD and many, notably opioid use, are ineffective and associated with several detrimental off-target effects. There is a clear need to develop practical patient-focused policies for safe, rational, appropriate, and effective use of current analgesic medications, and better alternatives for long-term pain management. Several priorities for future research and practice stand out. First, develop and apply pain assessment for patients with IBD and ensure that pain is routinely assessed as a potential influence on outcomes in longitudinal studies. Second, integrate investigation of central and visceral hypersensitivity and pain processing with clinical and psychological studies as the basis for identifying and testing novel interventions, from molecular-specific drugs to tailored behavioural change. Third, improve the content and delivery of existing treatments, notably psychological approaches to chronic pain, for individuals, and the access of persons with IBD to all the options for chronic pain management established for other long-term painful conditions. Many of the clinical and research issues are shared by all chronic pain conditions. Whilst the unique challenges facing patients with IBD and their clinicians must be recognised, it is also vital that silos between different clinical disciplines allied to different body viscera,41 and to relevant pain management expertise,9,38,49 are broken down, so the many shared problems of managing and understanding visceral and associated extra-abdominal pain in the context of IBD can be tackled more efficiently and effectively. Conflict of interest statement The authors have no conflicts of interest to declare.