Statistical modeling of acute and chronic pain patient-reported outcomes obtained from ecological momentary assessment.

ABSTRACT: Ecological momentary assessment (EMA) allows for the collection of participant-reported outcomes (PROs), including pain, in the normal environment at high resolution and with reduced recall bias. Ecological momentary assessment is an important component in studies of pain, providing detailed information about the frequency, intensity, and degree of interference of individuals' pain. However, there is no universally agreed on standard for summarizing pain measures from repeated PRO assessment using EMA into a single, clinically meaningful measure of pain. Here, we quantify the accuracy of summaries (eg, mean and median) of pain outcomes obtained from EMA and the effect of thresholding these summaries to obtain binary clinical end points of chronic pain status (yes/no). Data applications and simulations indicate that binarizing empirical estimators (eg, sample mean, random intercept linear mixed model) can perform well. However, linear mixed-effect modeling estimators that account for the nonlinear relationship between average and variability of pain scores perform better for quantifying the true average pain and reduce estimation error by up to 50%, with larger improvements for individuals with more variable pain scores. We also show that binarizing pain scores (eg, <3 and ≥3) can lead to a substantial loss of statistical power (40%-50%). Thus, when examining pain outcomes using EMA, the use of linear mixed models using the entire scale (0-10) is superior to splitting the outcomes into 2 groups (<3 and ≥3) providing greater statistical power and sensitivity.

Deciphering nociplastic pain: clinical features, risk factors and potential mechanisms.

Nociplastic pain is a mechanistic term used to describe pain that arises or is sustained by altered nociception, despite the absence of tissue damage. Although nociplastic pain has distinct pathophysiology from nociceptive and neuropathic pain, these pain mechanisms often coincide within individuals, which contributes to the intractability of chronic pain. Key symptoms of nociplastic pain include pain in multiple body regions, fatigue, sleep disturbances, cognitive dysfunction, depression and anxiety. Individuals with nociplastic pain are often diffusely tender - indicative of hyperalgesia and/or allodynia - and are often more sensitive than others to non-painful sensory stimuli such as lights, odours and noises. This Review summarizes the risk factors, clinical presentation and treatment of nociplastic pain, and describes how alterations in brain function and structure, immune processing and peripheral factors might contribute to the nociplastic pain phenotype. This article concludes with a discussion of two proposed subtypes of nociplastic pain that reflect distinct neurobiological features and treatment responsivity.

Problems with opioids beyond misuse.

The U.S. is grappling with an opioid epidemic, with millions of adults on long-term opioid therapy (LTOT). Although patients often report pain relief and improved daily function with opioids, research shows no significant differences in short-term outcomes between opioid and non-opioid users, as well as no long-term opioid benefits. This scoping review aims to identify lesser-known side effects of long-term opioid use and increase awareness of them, allowing healthcare providers and patients to better assess the risks and benefits of opioid use. Our data search from PubMed and Google Scholar used keywords related to opioids, chronic pain, hypogonadism, endocrinopathies, cancer progression, cardiovascular events, renovascular events, sleep disturbances, mood disorders and others, narrowing down to English-language full articles published from January 2018 to April 2023. This review emphasizes the probable serious adverse consequences of long-term opioid use on various body systems in patients with chronic pain. Given the lack of long-term benefits and significant adverse effects, our review underscores the critical need for healthcare providers to include these risks in discussions with patients when considering the long-term use of opioid therapy.

Nociplastic Pain and Pain-Motivated Drinking in Alcohol Use Disorder.

Heavy chronic alcohol use may produce pain amplification through neurochemical and neuroplastic changes at multiple levels of the nervous system. Similar changes are thought to underlie nociplastic pain. The American College of Rheumatology Fibromyalgia Survey has been used as a surrogate for nociplastic pain, including among individuals with alcohol use disorder (AUD). However, studies linking nociplastic pain to pain-motivated drinking are lacking. The present study aimed to determine if nociplastic pain is associated with pain-motivated drinking in AUD. To achieve this aim, a new scale-the Pain-Motivated Drinking Scale (PMDS)-was developed to measure how often participants were motivated by pain to drink alcohol. Measurement properties of this new scale were determined, including its factor structure, internal consistency reliability, and construct validity. In this cross-sectional observational study, participants with AUD (n = 138) were consecutively recruited from the patient pool at an academic addiction treatment facility. Seventy-two percent (95, 72.0%) reported they drank alcohol "to get relief from physical pain" at least some of the time, and over forty-two percent (56, 42.4%) reported pain relief motivated their drinking at least half of the time. PMDS had a single-factor structure, strong internal consistency reliability, and construct validity. A multiple hierarchical linear regression was run to determine if nociplastic pain was associated with pain-motivated drinking. Nociplastic pain was associated with PMDS even after controlling for potential confounders and pain severity. These findings suggest nociplastic pain is uniquely associated with pain-motivated drinking in AUD. PERSPECTIVE: Nociplastic pain is independently associated with pain-motivated drinking in alcohol use disorder (AUD). The Pain-Motivated Drinking Scale (PMDS) is a new scale to measure how often people drink to cope with pain. PMDS has promising psychometric properties. Nociplastic pain may be uniquely associated with pain-motivated drinking in AUD.

Rheumatology and Long COVID: lessons from the study of fibromyalgia.

Rheumatology, such as other subspecialties, has both a unique perspective to offer as well as an evolving role to play in the global COVID-19 pandemic. Our field has already contributed meaningfully to the development and repurposing of many of the immune-based therapeutics which are now standard treatments for severe forms of the disease as well as to the understanding of the epidemiology, risk factors and natural history of COVID-19 in immune-mediated inflammatory diseases. Still in evolution is our potential to contribute to burgeoning research efforts in the next phase of the pandemic: the syndrome of postacute sequelae of COVID-19 or Long COVID. While our field brings many assets to the study of Long COVID including our expertise in the investigation of chronic inflammation and autoimmunity, our Viewpoint focuses on the strong similarities between fibromyalgia (FM) and Long COVID. While one can speculate on how embracing and confident practising rheumatologists already are regarding these interrelationships, we assert that in the emerging field of Long COVID the potential lessons from the field of fibromyalgia care and research have been underappreciated and marginalised and most importantly now deserve a critical appraisal.

'I'm still here, I'm alive and breathing': The experience of Black Americans with long COVID.

AIMS AND OBJECTIVES: In this study, we aimed to characterize the impact of long COVID on quality of life and approaches to symptom management among Black American adults. BACKGROUND: As a novel condition, qualitative evidence concerning long COVID symptoms and their impact on quality of life can inform the refinement of diagnostic criteria and care plans. However, the underrepresentation of Black Americans in long COVID research is a barrier to achieving equitable care for all long COVID patients. DESIGN: We employed an interpretive description study design. METHODS: We recruited a convenience sample of 15 Black American adults with long COVID. We analysed the anonymized transcripts from race-concordant, semi-structured interviews using an inductive, thematic analysis approach. We followed the SRQR reporting guidelines. RESULTS: We identified four themes: (1) The impact of long COVID symptoms on personal identity and pre-existing conditions; (2) Self-management strategies for long COVID symptoms; (3) Social determinants of health and symptom management; and (4) Effects on interpersonal relationships. CONCLUSION: Findings demonstrate the comprehensive ramifications of long COVID on the lives of Black American adults. Results also articulate how pre-existing conditions, social risk factors, distrust due to systemic racism, and the nature of interpersonal relationships can complicate symptom management. RELEVANCE TO CLINICAL PRACTICE: Care approaches that support access to and implementation of integrative therapies may be best suited to meet the needs of long COVID patients. Clinicians should also prioritize eliminating patient exposure to discrimination, implicit bias, and microaggressions. This is of particular concern for long COVID patients who have symptoms that are difficult to objectively quantify, such as pain and fatigue. NO PATIENT OR PUBLIC CONTRIBUTION: While patient perspectives and experiences were the focus of this study, patients were not involved with the design or conduct of the study, data analysis or interpretation, or writing the manuscript.

Widespread Pain With Nociplastic Features is an Independent Predictor of Low Physical Activity in People with Multiple Sclerosis.

Exploring the relationship between underlying pain mechanisms and physical activity could inform interventions to optimize physical activity in persons with multiple sclerosis (PwMS). This cross-sectional nationwide survey examined whether pain phenotype is a significant predictor of self-reported physical activity in PwMS. The study included 938 persons with a self-reported diagnosis of MS (93% reported neurologist-diagnosed MS) who completed surveys of demographic, clinical information, pain intensity, indicators of underlying pain mechanisms (Fibromyalgia Survey Criteria and painDETECT), and physical activity (Godin Leisure-Time Exercise Questionnaire). Responses were used to categorize pain phenotypes as widespread pain with nociplastic features (WPNF), neuropathic, nociceptive, or mixed (neuropathic/WPNF). Following current physical activity guidelines, self-reported physical activity was categorized as active or insufficiently active/sedentary. Applying multivariable logistic regression, participants with no chronic pain had 2.30 higher odds of being physically active when compared to participants with chronic mixed pain. Similarly, participants with neuropathic and nociceptive pain had, respectively, 1.90 and 1.66 higher odds of being physically active compared to individuals with mixed pain. Higher scores on the fibromyalgia survey criteria (operationalized in this study as an indicator of WPNF) were a significant independent predictor of insufficient physical activity (OR = .93, P < .01). Findings indicate that experience and phenotype of chronic pain, in particular WPNF, are associated with physical inactivity in PwMS. This suggests that assessing pain phenotype may be important to identify individuals at risk of inadequate physical activity and may guide the tailoring of behavioral therapeutic approaches to help PwMS achieve the recommended level of physical activity. PERSPECTIVE: This study examines the association between pain mechanism and physical activity in multiple sclerosis. These findings highlight the possibility that a basic screening for pain mechanism could offer clinically useful information without requiring extensive neurobiological phenotyping and may inform the development of behavioral interventions to enhance physical activity in multiple sclerosis.

A qualitative study on opportunities to improve research engagement and inclusion of Black adults with systemic lupus erythematosus.

In response to racial inequities in systemic lupus erythematosus (SLE), we aimed to identify practical recommendations for increasing engagement and inclusion of Black adults in SLE research. We used a qualitative, interpretive description approach and recruited 30 Black adults diagnosed with SLE in Michigan to participate in semi-structured interviews. Theme development focused on what factors influenced research perceptions and how research did not meet participant needs and expectations. We developed five main themes: (1) Ethical and equitable research. Participants shared how the impacts of past and present-day racism impacted their willingness to participate in research. (2) Trusting researchers to conduct studies and translate findings to health care. Participants had concerns related to researcher intentions and expressed the importance of communicating research outcomes to participants and translating findings to health care. (3) Drug trial beneficence. When considering drug trials, several people did not consider the potential benefits worth the risk of side effects, and some said they would need to consult with their doctor before agreeing to participate. (4) Altruism. Participants explained how the desire to help others was a motivating factor for participating in research and donating biological samples. (5) Research priorities. Participants described a need for better treatments that value their overall health and well-being. Findings indicate that researchers can center the perspectives of Black people with SLE across the research life cycle-beyond a focus on adequate racial diversity among study participants.

Thoughtfully Integrating Cannabis Products Into Chronic Pain Treatment.

Cannabis products (CPs) and cannabis-based medicines (CBMs) are becoming increasingly available and are commonly used for pain management. The growing societal acceptance of cannabis and liberalization of cannabis laws allows patients to access CPs with minimal clinical oversight. While there is mechanistic plausibility that CPs and CBMs may be useful for pain management, the clinical trial literature is limited and does not refute or support the use of CBMs for pain management. Complicating matters, a large and growing body of observational literature shows that many people use CPs for pain management and in place of other medications. However, products and dosing regimens in existing trials are not generalizable to the current cannabis market, making it difficult to compare and reconcile these 2 bodies of literature. Given this complexity, clinicians need clear, pragmatic guidance on how to appropriately educate and work with patients who are using CBMs for pain management. In this review, we narratively synthesize the evidence to enable a clear view of current landscape and provide pragmatic advice for clinicians to use when working with patients. This advice revolves around 3 principles: (1) maintaining the therapeutic alliance; (2) harm reduction and benefit maximization; and (3) pragmatism, principles of patient-centered care, and use of best clinical judgment in the face of uncertainty. Despite the lack of certainty CPs and chronic pain management use, we believe that following these principles can make most of the clinical opportunity presented by discussions around CPs and also enhance the likelihood of clinical benefit from CPs.

Chronic overlapping pain conditions increase the risk of long COVID features, regardless of acute COVID status.

ABSTRACT: Chronic overlapping pain conditions (COPCs) refer to conditions that have similar central nervous system pathophysiologic mechanisms driving widespread pain as well as common comorbid symptoms such as fatigue and problems with sleep, memory, and mood. If COPCs predict the onset of long COVID, this could offer a valuable orientation for long COVID-related research and clinical care. This retrospective cohort study aimed to determine whether having a COPC predicts the onset of long COVID features using US electronic health records and 1:1 propensity score matching without replacement. The study cohorts included (1) people with acute COVID (n = 1,038,402), (2) people with acute influenza (n = 262,092), and (3) a noninfected cohort comprising people with a routine healthcare encounter (n = 1,081,593). Having a COPC increased the risk of long COVID features in all 3 study cohorts. Among those with COVID, having a pre-existing COPC increased the risk by 1.47 (95% CI = 1.46, 1.47). In the influenza cohort, COPCs increased the risk by 1.39 (95% CI = 1.38, 1.40). In the noninfected cohort, COPCs increased the risk by 1.57 (95% CI = 1.56, 1.59). These findings reinforce the likelihood that nociplastic mechanisms play a prominent role in long COVID. Recognizing that this ubiquitous nonspecific syndrome occurs frequently in the population can inform precision medicine therapies that avoid the pitfalls of viewing long COVID exclusively in the framework of postinfectious disease.

Relationship Between Nociplastic Pain Involvement and Medication Use, Symptom Relief, and Adverse Effects Among People Using Medical Cannabis for Chronic Pain.

OBJECTIVES: Cannabis is increasingly being used for chronic pain management, but cannabis' effects remain poorly characterized in chronic nociplastic pain (NPP), which is posited to be caused by disturbances in nervous system pain processing. In this cross-sectional study (n=1213), we used the 2011 Fibromyalgia (FM) Survey Criteria as a surrogate measure for degree of NPP among individuals using medical cannabis for chronic pain. METHODS: Using a quartile-split, we investigated associations between the degree of NPP and medication use, cannabis use characteristics, and symptom relief. Continuous variables were assessed using one-way analysis of variance and categorical variables with Pearson χ 2 test and binomial logistic regression for calculation of odds ratios. RESULTS: Participants were predominately female (59%), with a mean ± SD age of 49.4±13.6 years. Higher FM scores were associated with less self-reported improvement in pain and health since initiating medical cannabis use, as well as more cannabis-related side effects. Paradoxically, higher FM scores were also associated with higher usage of concomitant medication use (including opioids and benzodiazepines) but also with substituting cannabis for significantly more medication classes, including opioids and benzodiazepines. DISCUSSION: This article presents evidence that individuals in higher NPP quartiles have higher analgesic intake, higher odds of substituting cannabis for medications, higher side effect burden, and lower therapeutic effect from cannabis. These seemingly contradictory findings may reflect higher symptom burden, polypharmacy at baseline, or that NPP may be challenging to treat with cannabis. Further research is necessary to further explain cannabinoid effects in NPP.

Episodes of Atrial Fibrillation and Symptoms: A Temporal Analysis.

Background: Data on the relationship between symptoms and atrial fibrillation (AF) episodes are limited. Objective: The objective of this study was to determine the strength of temporal association between AF episodes and symptoms. Methods: This cross-sectional ambulatory assessment study was performed in a tertiary care center between June 2018 and December 2021. Patients with paroxysmal AF (1 episode of AF, burden not exceeding 95%) who used a mobile application and continuous wearable electrocardiogram monitor for 21 days were enrolled. The primary outcome was worse symptoms (symptoms above the mean score) over the study period. The association between worse symptoms and the presence of AF was evaluated for different time epochs. Multilevel mixed-effects models were used to quantify associations after accounting for confounders. Results: Worse symptoms were more likely to be associated with the presence of AF episodes 15 minutes prior to the reporting of palpitations (OR, 2.8 [95% CI, 1.6-5.0]; P < .001), shortness of breath (OR, 2.2 [95% CI, 1.3-3.7]; P = .003), dizziness/lightheadedness (OR, 2.0 [95% CI, 1.0-3.7]; P = .04), and fatigue (OR, 1.7 [95% CI, 1.0-2.9]; P = .03). The correlation between the severity of symptoms and AF lessened as the time interval from AF events to symptoms increased. Conclusion: There is a significant relationship between onset of AF episodes and reporting of symptoms. This association diminishes over time and varies across different symptoms. If confirmed in larger studies, these findings may inform AF interventions that target symptoms just in time prior to a clinical visit.

Recommendations for Improving Systemic Lupus Erythematosus Care From Black Adults: A Qualitative Study.

Importance: Racial inequities in incidence, morbidity, and mortality are a defining feature of systemic lupus erythematosus (SLE). Health care systems are integral to addressing these inequities. However, qualitative evidence that highlights Black SLE care experiences is limited. Objective: To identify opportunities for improving SLE care based on the experiences and perspectives of Black adults with SLE. Design, Setting, and Participants: In this qualitative study, an interpretive description approach was used and data were analyzed using inductive thematic analysis. Semistructured interviews with Black adults in Michigan who were diagnosed with SLE were conducted. Interviews occurred from November 2, 2021, to July 19, 2022, and data analysis occurred from May 6, 2022, to April 12, 2023. Main Outcomes and Measures: Deidentified transcripts from the interviews were analyzed to develop themes that focused on opportunities to improve quality of care and symptom management. Results: The participants included 30 Black adults with SLE (97% women; mean age, 41 years; range, 18-65 years). Four main themes were identified: (1) awareness of SLE signs and symptoms before diagnosis (participants emphasized delays in diagnosis and how knowledge concerning SLE could be limited in their families and communities); (2) patient-clinician interactions (participants faced discrimination in health care settings and talked about the value of coordinated and supportive health care teams); (3) medication adherence and health effects (participants experienced a range of adverse effects from medications that treat SLE and described how monitoring medication use and efficacy could inform tailored care approaches); and (4) comprehensive care plans after diagnosis (participants reported persistent pain and other symptoms despite treatment). In the context of disease management, participants emphasized the importance of behavioral change and the negative impact of social risk factors. Conclusions and Relevance: The findings of this qualitative study suggest how limited information about SLE, experiences of racism, treatment regimens, and social risk factors may affect Black people with SLE. Future research should further engage and include Black communities within the context of treatment and intervention development to reduce racial inequities.

Large-scale momentary brain co-activation patterns are associated with hyperalgesia and mediate focal neurochemistry and cross-network functional connectivity in fibromyalgia.

ABSTRACT: Fibromyalgia has been characterized by augmented cross-network functional communication between the brain's sensorimotor, default mode, and attentional (salience/ventral and dorsal) networks. However, the underlying mechanisms of these aberrant communication patterns are unknown. In this study, we sought to understand large-scale topographic patterns at instantaneous timepoints, known as co-activation patterns (CAPs). We found that a sustained pressure pain challenge temporally modulated the occurrence of CAPs. Using proton magnetic resonance spectroscopy, we found that greater basal excitatory over inhibitory neurotransmitter levels within the anterior insula orchestrated higher cross-network connectivity between the anterior insula and the default mode network through lower occurrence of a CAP encompassing the attentional networks during sustained pain. Moreover, we found that hyperalgesia in fibromyalgia was mediated through increased occurrence of a CAP encompassing the sensorimotor network during sustained pain. In conclusion, this study elucidates the role of momentary large-scale topographic brain patterns in shaping noxious information in patients with fibromyalgia, while laying the groundwork for using precise spatiotemporal dynamics of the brain for the potential development of therapeutics.

Chronic pain management in sickle cell disease: A systematic scoping review of controlled trials.

Existing treatment for chronic pain in sickle cell disease (SCD) is opioid-dependent, which is ineffective and carries risks. We conducted a scoping literature review to assess the size and scope of available literature about controlled trials of therapies for SCD chronic pain and identify research gaps. The search strategy in PubMed and EMBASE utilized keywords for chronic pain and sickle cell and identified seven original articles that met inclusion criteria. Six of the studies recruited from clinics while one recruited from community sources. Cannabis and behavioral modification were associated with improvements in pain scores. However, existing evidence does not represent best practices for assessing chronic pain, and this along with small sample sizes prevents translation to clinical care. The limited evidence concerning treatment for SCD chronic pain highlights the need for larger trials of opioid alternatives and the utilization of chronic pain measures that capture nociplastic pain in SCD.

Central sensitization in alcohol use disorder: correlates of pain, addiction and health-related quality of life.

BACKGROUND: Central sensitization is an important mechanism underlying many chronic pain conditions. Chronic pain and alcohol use disorder (AUD) are highly comorbid. Despite great scientific interest in brain mechanisms linking chronic pain and AUD, progress has been impeded by difficulty assessing central sensitization in AUD. OBJECTIVE: The present study is the first to employ a validated surrogate measure to describe central sensitization in a clinical sample with AUD. METHODS: Participants with AUD (n = 99) were recruited from an academic addiction treatment center. A well-established surrogate measure of central sensitization, The American College of Rheumatology Fibromyalgia Survey Criteria (ACRFMS) was administered. Participants also responded to questions about quality of life (RAND-36), and AUD. Descriptive analyses and Spearman's rho correlations were performed. RESULTS: Chronic pain and evidence of central sensitization were prevalent. Greater central sensitization was associated with worse health-related quality of life. Participants higher in central sensitization expressed greater endorsement of pain as a reason for AUD onset, maintenance, escalation, treatment delay, and relapse. CONCLUSION: The present study bolsters prior assertions that AUD and chronic pain might compound one another via progressive sensitization of shared brain circuitry. These results may inform future mechanistic research and precision AUD treatment.