Contemporary management of pain in cirrhosis: Toward precision therapy for pain.

Chronic pain is highly prevalent in patients with cirrhosis and is associated with poor health-related quality of life and poor functional status. However, there is limited guidance on appropriate pain management in this population, and pharmacologic treatment can be harmful, leading to adverse outcomes, such as gastrointestinal bleeding, renal injury, falls, and hepatic encephalopathy. Chronic pain can be categorized mechanistically into three pain types: nociceptive, neuropathic, and nociplastic, each responsive to different therapies. By discussing the identification, etiology, and treatment of these three mechanistic pain descriptors with a focus on specific challenges in patients with cirrhosis, we provide a framework for better tailoring treatments, including nonpharmacologic therapies, to patients' needs.

Theoretical Schemas to Guide Back Pain Consortium (BACPAC) Chronic Low Back Pain Clinical Research.

BACKGROUND: Chronic low back pain (cLBP) is a complex with a heterogenous clinical presentation. A better understanding of the factors that contribute to cLBP is needed for accurate diagnosis, optimal treatment, and identification of mechanistic targets for new therapies. The Back Pain Consortium (BACPAC) Research Program provides a unique opportunity in this regard, as it will generate large clinical datasets, including a diverse set of harmonized measurements. The Theoretical Model Working Group was established to guide BACPAC research and to organize new knowledge within a mechanistic framework. This article summarizes the initial work of the Theoretical Model Working Group. It includes a three-stage integration of expert opinion and an umbrella literature review of factors that affect cLBP severity and chronicity. METHODS: During Stage 1, experts from across BACPAC established a taxonomy for risk and prognostic factors (RPFs) and preliminary graphical depictions. During Stage 2, a separate team conducted a literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to establish working definitions, associated data elements, and overall strength of evidence for identified RPFs. These were subsequently integrated with expert opinion during Stage 3. RESULTS: The majority (∼80%) of RPFs had little strength-of-evidence confidence, whereas seven factors had substantial confidence for either a positive association with cLBP (pain-related anxiety, serum C-reactive protein, diabetes, and anticipatory/compensatory postural adjustments) or no association with cLBP (serum interleukin 1-beta / interleukin 6, transversus muscle morphology/activity, and quantitative sensory testing). CONCLUSION: This theoretical perspective will evolve over time as BACPAC investigators link empirical results to theory, challenge current ideas of the biopsychosocial model, and use a systems approach to develop tools and algorithms that disentangle the dynamic interactions among cLBP factors.

Immune Checkpoint Inhibitors and Risk of Type 1 Diabetes.

OBJECTIVE: Type 1 diabetes mellitus (T1DM) is a rare, irreversible immune-related adverse event reported in patients receiving treatment with immune checkpoint inhibitors (ICI). However, clinical risk factors for ICI-induced T1DM (ICI-T1DM) and its impact on survival in patients remain unknown. RESEARCH DESIGN AND METHODS: We used Optum's Clinformatics Data Mart database for assessment of the incidence and characteristics of T1DM in a large de-identified cohort of patients treated with ICI between 2017 and 2020. We applied Fine-Gray and cause-specific hazard models to study associations between patient/treatment characteristics and ICI-T1DM and applied the Cox model with ICI-T1DM as a time-varying covariate to assess the impact of ICI-T1DM on survival. RESULTS: ICI-T1DM was observed in 261 of 30,337 (0.86%) patients. Dual use of antibodies to cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) was associated with increasing risk of ICI-T1DM (hazard ratio [HR] 1.62; 95% CI 1.15-2.26) vs. anti-PD-L1 or anti-PD-1 alone. Younger age (HR 1.19 for every 5-year decrease; 95% CI 1.13-1.25) and preexisting non-T1DM diabetes (HR 4.48; 95% CI 3.45-5.83) were also associated with higher risk of ICI-T1DM. Conversely, prior use of immunosuppressive medications (HR 0.57; 95% CI 0.34-0.95) was associated with lower incidence of ICI-T1DM, but part of its protective effect may be due to the increased mortality rate. Development of ICI-T1DM does not seem to significantly impact patient survival. CONCLUSIONS: The risk of ICI-T1DM is associated with the type of ICI therapy, patient age, and preexisting non-T1DM diabetes. These data may help guide risk assessment and screening practices for patients during ICI therapy.

Impact of Moving From a Widespread to Multisite Pain Definition on Other Fibromyalgia Symptoms.

OBJECTIVE: To investigate whether associations between pain and the additional symptoms associated with fibromyalgia are different in persons with chronic widespread pain (CWP) compared to multisite pain (MSP), with or without joint areas. METHODS: Six studies were used: 1958 British birth cohort, Epidemiology of Functional Disorders, Kid Low Back Pain, Managing Unexplained Symptoms (Chronic Widespread Pain) in Primary Care: Involving Traditional and Accessible New Approaches, Study of Health and its Management, and Women's Health Study (WHEST; females). MSP was defined as the presence of pain in ≥8 body sites in adults (≥10 sites in children) indicated on 4-view body manikins, conducted first to include joints (positive joints) and second without (negative joints). The relationship between pain and fatigue, sleep disturbance, somatic symptoms, and mood impairment was assessed using logistic regression. Results are presented as odds ratios (ORs) with 95% confidence intervals (95% CIs). RESULTS: There were 34,818 participants across the study populations (adults age range 42-56 years, male 43-51% [excluding WHEST], and CWP prevalence 12-17%). Among those reporting MSP, the proportion reporting CWP ranged between 62% and 76%. Among those reporting the symptoms associated with fibromyalgia, there was an increased likelihood of reporting pain, the magnitude of which was similar regardless of the definition used. For example, within WHEST, reporting moderate/severe fatigue (Chalder fatigue scale 4-11) was associated with a >5-fold increase in likelihood of reporting pain (CWP OR 5.2 [95% CI 3.9-6.9], MSP-positive joints OR 6.5 [95% CI 5.0-8.6], and MSP-negative joints OR 6.5 [95% CI 4.7-9.0]). CONCLUSION: This large-scale study demonstrates that regardless of the pain definition used, the magnitude of association between pain and other associated symptoms of fibromyalgia is similar. This finding supports the continued collection of both when classifying fibromyalgia, but highlights the fact that pain may not require to follow the definition outlined within the 1990 American College of Rheumatology criteria.

The "Honest Broker" method of integrating interdisciplinary research data.

Multiple clinical informatics systems have been developed within separate departments of the University of Michigan Medical School. We are in the process of creating an "Honest Broker" method of safely and securely linking together data from different clinical systems for a research project studying the co-morbidity of depression and cardiovascular disease. The Michigan Clinical Research Collaboratory (MCRC) is an NIH/NHLBI Roadmap initiative funded to re-engineer the clinical research enterprise.