Protocol for a pragmatic trial of Cannabidiol (CBD) to improve chronic pain symptoms among United States Veterans.

BACKGROUND: Chronic pain affects over 100 million Americans, with a disproportionately high number being Veterans. Chronic pain is often difficult to treat and responds variably to medications, with many providing minimal relief or having adverse side effects that preclude use. Cannabidiol (CBD) has emerged as a potential treatment for chronic pain, yet research in this area remains limited, with few studies examining CBD's analgesic potential. Because Veterans have a high need for improved pain care, we designed a clinical trial to investigate CBD's effectiveness in managing chronic pain symptoms among Veterans. We aim to determine whether CBD oral solution compared to placebo study medication is associated with greater improvement in the Patient Global Impression of Change (PGIC). METHODS: We designed a randomized, double-blind, placebo-controlled, pragmatic clinical trial with 468 participants. Participants will be randomly assigned in a 1:1 ratio to receive either placebo or a CBD oral solution over a 4-week period. The trial is remote via a smartphone app and by shipping study materials, including study medication, to participants. We will compare the difference in PGIC between the CBD and placebo group after four weeks and impacts on secondary outcomes (e.g., pain severity, pain interference, anxiety, suicide ideation, and sleep disturbance). DISCUSSION: Once complete, this trial will be among the largest to date investigating the efficacy of CBD for chronic pain. Findings from this clinical trial will contribute to a greater knowledge of CBD's analgesic potential and guide further research. Given the relative availability of CBD, our findings will help elucidate the potential of an accessible option for helping to manage chronic pain among Veterans. TRIAL REGISTRATION: This protocol is registered at clinicaltrials.gov under study number NCT06213233.

Self-guided digital behavioural therapy versus active control for fibromyalgia (PROSPER-FM): a phase 3, multicentre, randomised controlled trial.

BACKGROUND: International guidelines have recommended cognitive behavioural therapy, including acceptance and commitment therapy (ACT), as it offers validated benefits for managing fibromyalgia; however, it is inaccessible to most patients. We aimed to evaluate the effect of a 12-week, self-guided, smartphone-delivered digital ACT programme on fibromyalgia management. METHODS: In the PROSPER-FM randomised clinical trial conducted at 25 US community sites, adult participants aged 22-75 years with fibromyalgia were recruited and randomly assigned (1:1) to the digital ACT group or an active control group that offered daily symptom tracking and monitoring and access to health-related and fibromyalgia-related educational materials. Randomisation was done with a web-based system in permuted blocks of four at the site level. We used a blind-to-hypothesis approach in which participants were informed they would be randomly assigned to one of two potentially effective therapies under evaluation. Research staff were not masked to group allocation, with the exception of a masked statistics group while preparing statistical programming for the interim analysis. The primary endpoint was patient global impression of change (PGIC) response rate at week 12. Analyses were by intention to treat. The trial was registered with ClinicalTrials.gov, NCT05243511 (now fully closed). FINDINGS: Between Feb 8, 2022, and Feb 2, 2023, 590 individuals were screened, of whom 275 (257 women and 18 men) were randomly assigned to the digital ACT group (n=140) and the active control group (n=135). At 12 weeks, 99 (71%) of 140 ACT participants reported improvement on PGIC versus 30 (22%) of 135 active control participants, corresponding to a difference in proportions of 48·4% (95% CI 37·9-58·9; p<0·0001). No device-related safety events were reported. INTERPRETATION: Digital ACT was safe and efficacious compared with digital symptom tracking in managing fibromyalgia in adult patients. FUNDING: Swing Therapeutics.

Nutrients and Nocioception: Diet in the management of pain.

Nutrition can play a pivotal role in the management of pain associated with chronic rheumatic diseases. There is a growing body of research linking certain nutrients from the diet to inflammation. Certain nutrients have been shown to improve pain associated with inflammation. Furthermore, certain dietary patterns have been shown to improve pain across multiple rheumatic conditions. Finally, maintaining a low body mass is associated with improved pain associated with chronic rheumatic diseases.

Health Care Use for Eye Pain.

Importance: National estimates regarding the frequency of presentations and patterns of care for eye pain are unknown. This information could guide research and clinical efforts to optimize outcomes. Objective: To estimate eye pain visits in the US in the outpatient and emergency department (ED) settings. Design, Setting, and Participants: This retrospective cross-sectional study of National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey data (2008-2019) analyzed a population-based sample of visits to outpatient clinics and EDs. The sample consisted of patients presenting with eye pain. Data were analyzed from September 2023 to April 2024. Main Outcomes and Measures: Weighted sample data estimated outpatient and ED eye pain presentations including patient and clinician characteristics, diagnoses (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10]), and disposition. Results: From 2008 through 2019, 4.6 million (95% CI, 3.9 million to 5.3 million) outpatient and 1.0 million (95% CI, 0.8 million to 1.1 million) ED eye pain visits occurred annually. Patients were predominantly women (63.2% [95% CI, 59.4%-67.0%]) and older than 60 years (46.6% [95% CI, 42.4%-51.0%]) in the outpatient setting. Patients presenting to the ED were more often men (51.8% [95% CI, 48.7%-55.0%]) and aged younger than 45 years (aged <15 years: 16.4% [95% CI, 13.9%-18.8%]; 15-24 years: 19.2% [95% CI, 16.6%-21.7%]; and 25-44 years: 35.6% [95% CI, 32.7%-38.5%]). In nearly half of outpatient eye pain visits, the major problem was classified as nonacute (2.0 million [95% CI, 1.6 million to 2.3 million]). Eye pain was the primary reason for the visit (RFV) in 42.0% (95% CI, 37.8%-46.2%) of outpatient visits and 66.9% (95% CI, 62.9%-70.9%) of ED eye pain visits. It was the only RFV in 18.3% (95% CI, 15.0%-21.7%) of outpatient and 32.7% (95% CI, 29.0%-36.4%) of ED eye pain encounters. Ophthalmologists evaluated the largest number of outpatient visits (45.3% [95% CI, 38.8%-51.7%). The primary diagnosis was non-vision threatening for most outpatient (78.5% [95% CI, 56.8%-100%]) and ED (69.9% [95% CI, 62.1%-77.7%]) visits when eye pain was the primary RFV. Additional follow-up was scheduled in 89.4% (95% CI, 86.2%-92.6%) of visits. Conclusions and Relevance: More than 5 million eye pain visits occur annually; the largest percentage are outpatient with ophthalmologists. Most diagnoses were non-vision threatening in both the outpatient and ED setting and resulted in additional care. Expanding therapeutic approaches to treat the causes of eye pain may reduce the burden on the health care system and optimize outcomes.

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.

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.

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.

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.

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.

Is fibromyalgia an autoimmune disorder?

Fibromyalgia (FM) is a multifactorial syndrome which includes not only widespread pain and stiffness, now recognized as major symptoms, but also numerous other somatic, emotional, and neuropsychic manifestation. The lack of specific validated biological and instrumental biomarkers has made FM a condition of unexplained medical significance, and its pathophysiology remains controversial and subject to debate. The current hypothesis regarding the pathogenesis of FM proposes that its development is influenced by various mechanism, including genetic predisposition, stressful life events, inflammatory processes, and cognitive-emotional factors. However, despite the extensive research conducted to date, the available data do not provide a clear understanding of the pathogenesis of FM. In this article, we report the opposing viewpoints of two leading experts who debate the question of whether FM is an autoimmune disease, based on scientific data regarding this condition. Both perspectives are discussed and the latest evidence on the pathophysiology of FM is reported to provide a comprehensive understanding of this complex syndrome.

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.

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.