Risk of chronic arthralgia and impact of pain on daily activities in a cohort of patients with chikungunya virus infection from Brazil.

OBJECTIVES: To investigate risk factors for persistent arthralgia in patients with chikungunya, and describe its impact on daily activities. METHODS: From September 2014 to July 2016, a surveillance study enrolled patients with acute febrile illness in Salvador, Brazil, and detected those with chikungunya virus infection using IgM enzyme-linked immunosorbent assay or reverse transcriptase polymerase chain reaction. Telephone follow-ups were performed to ascertain the progression of disease. RESULTS: Of 153 followed cases, 65 (42.5%) reported chronic arthralgia that lasted >3 months, and 47 (30.7%) were still symptomatic at the time of the interview (approximately 1.5 years after symptom onset). Limitations in daily activities and mental distress were reported by 93.8% and 61.5% of those with chronic arthralgia, respectively. Female sex [risk ratio (RR) 1.79, 95% confidence interval (CI) 1.95-2.69] and age (RR 1.02 for each 1-year increase, 95% CI 1.01-1.03) were independent risk factors for chronic arthralgia. Chronic arthralgia was not associated with co-infection with dengue virus (RR 0.97, 95% CI 0.48-1.94) or chikungunya viral load at diagnosis (median chikungunya virus RNA of 5.60 and 5.52 log10 copies/µL for those with and without chronic arthralgia, respectively; P = 0.75). CONCLUSIONS: These findings reinforce the high frequency of chronic chikungunya arthralgia, and highlight the substantial disability associated with the persistence of pain. Development of novel strategies to mitigate the transmission of chikungunya virus and to provide long-term medical assistance for patients with chikungunya are needed urgently.

Screening, Brief Intervention, and Referral to Treatment for Pain Management for Veterans Seeking Service-Connection Payments for Musculoskeletal Disorders: SBIRT-PM Study Protocol.

BACKGROUND: Veterans with significant chronic pain from musculoskeletal disorders are at risk of substance misuse. Veterans whose condition is the result of military service may be eligible for a disability pension. Department of Veterans Affairs compensation examinations, which determine the degree of disability and whether it was connected to military service, represent an opportunity to engage Veterans in pain management and substance use treatments. A multisite randomized clinical trial is testing the effectiveness and cost-effectiveness of Screening, Brief Intervention, and Referral to Treatment for Pain Management (SBIRT-PM) for Veterans seeking compensation for musculoskeletal disorders. This telephone-based intervention is delivered through a hub-and-spoke configuration. DESIGN: This study is a two-arm, parallel-group, 36-week, multisite randomized controlled single-blind trial. It will randomize 1,100 Veterans experiencing pain and seeking service-connection for musculoskeletal disorders to either SBIRT-PM or usual care across eight New England VA medical centers. The study balances pragmatic with explanatory methodological features. Primary outcomes are pain severity and number of substances misused. Nonpharmacological pain management and substance use services utilization are tracked in the trial. SUMMARY: Early trial enrollment targets were met across sites. SBIRT-PM could help Veterans, at the time of their compensation claims, use multimodal pain treatments and reduce existing substance misuse. Strategies to address COVID-19 pandemic impacts on the SBIRT-PM protocol have been developed to maintain its pragmatic and exploratory integrity.

A preliminary analysis of the association between perceived stigma and HIV-related pain in South Africans living with HIV.

BACKGROUND:  Stigma related to the human immunodeficiency virus (HIV) remains common and has been associated with severity of HIV-related symptoms. Associations between HIV stigma and HIV-related pain, one of the most common symptoms in HIV, have however not been investigated. Data from low back pain populations suggest that stigma is associated with worse pain intensity and so we hypothesised that the same would be the case in HIV. AIM:  The goal of this study was to assess the association between HIV stigma and pain intensity in people living with HIV (PLWH) with chronic pain whilst controlling for depression, a well-established correlate of pain. SETTING:  The study took place at an HIV clinic in Johannesburg, South Africa. METHODS:  Mediation analysis was used to assess the effect of depression on the relationship between stigma and pain intensity in a cross-sectional cohort of 50 PLWH and chronic pain (pain most days of the week for > 3 months). All participants were assessed using the HIV/AIDS Stigma Instrument - PLWA, an 11-point numerical pain rating scale and the Beck Depression Inventory II. RESULTS:  In all, 88% (44/50) of participants reported experiencing some form of HIV stigma (HIV stigma scale score ≥ 1). Worst pain intensity and depressive symptoms individually correlated with total stigma score (Spearman's r = 0.33, p = 0.02 for both). The mediation analysis highlighted that mediation of the relationship by depression was equivocal (b = -0.002, bootstrapped confidence interval -0.02 to 0.00). CONCLUSION:  Whilst these preliminary data are marginal, they do suggest that associations between HIV stigma and HIV-related pain warrant further investigation. Future study should also include potential mechanisms, which may include mediation through depression.

Enhanced facilitation and diminished inhibition characterizes the pronociceptive endogenous pain modulatory balance of persons living with HIV and chronic pain.

Chronic pain in persons living with HIV (PLWH) may be related to alterations in endogenous pain modulatory processes (e.g., high facilitation and low inhibition of nociception) that promote exaggerated pain responses, known as hyperalgesia, and central nervous system (CNS) sensitization. This observational study examined differences in endogenous pain modulatory processes between 59 PLWH with chronic pain, 51 PLWH without chronic pain, and 50 controls without HIV or chronic pain. Quantitative sensory testing for temporal summation (TS) of mechanical and heat pain as well as conditioned pain modulation (CPM) were used to assess endogenous pain facilitatory and inhibitory processes, respectively. Associations among TS, CPM, and self-reported clinical pain severity were also examined in PLWH with chronic pain. Findings demonstrated significantly greater TS of mechanical and heat pain for PLWH with chronic pain compared to PLWH without chronic pain and controls. CPM effects were present in controls, but not in either PLWH with or without chronic pain. Among PLWH with chronic pain, greater TS of mechanical pain was significantly associated with greater average clinical pain severity. Results of this study suggest that enhanced facilitation and diminished inhibition characterizes the pronociceptive endogenous pain modulatory balance of persons living with HIV and chronic pain.

Frequency of Chronic Joint Pain Following Chikungunya Virus Infection: A Colombian Cohort Study.

OBJECTIVE: To estimate the frequency of chronic joint pain after infection with chikungunya virus in a Latin American cohort. METHODS: A cross-sectional follow-up of a prospective cohort of 500 patients from the Atlántico Department, Colombia who were clinically diagnosed as having chikungunya virus during the 2014-2015 epidemic was conducted. Baseline symptoms and follow-up symptoms at 20 months were evaluated in serologically confirmed cases. RESULTS: Among the 500 patients enrolled, 485 had serologically confirmed chikungunya virus and reported joint pain status. Patients were predominantly adults (mean ± SD age 49 ± 16 years) and female, had an education level of high school or less, and were of Mestizo ethnicity. The most commonly affected joints were the small joints, including the wrists, ankles, and fingers. The initial virus symptoms lasted a median of 4 days (interquartile range [IQR] 3-8 days). Sixteen percent of the participants reported missing school or work (median 4 days [IQR 2-7 days]). After 20 months, one-fourth of the participants had persistent joint pain. A multivariable analysis indicated that significant predictors of persistent joint pain included college graduate status, initial symptoms of headache or knee pain, missed work, normal activities affected, ≥4 days of initial symptoms, and ≥4 weeks of initial joint pain. CONCLUSION: This is the first report to describe the frequency of chikungunya virus-related arthritis in the Americas after a 20-month follow-up. The high frequency of chronic disease highlights the need for the development of prevention and treatment methods.

Phosphorylated CCAAT/Enhancer Binding Protein ß Contributes to Rat HIV-Related Neuropathic Pain: In Vitro and In Vivo Studies.

Chronic pain is increasingly recognized as an important comorbidity of HIV-infected patients, however, the exact molecular mechanisms of HIV-related pain are still elusive. CCAAT/enhancer binding proteins (C/EBPs) are expressed in various tissues, including the CNS. C/EBPß, one of the C/EBPs, is involved in the progression of HIV/AIDS, but the exact role of C/EBPß and its upstream factors are not clear in HIV pain state. Here, we used a neuropathic pain model of perineural HIV envelope glycoprotein gp120 application onto the rat sciatic nerve to test the role of phosphorylated C/EBPß (pC/EBPß) and its upstream pathway in the spinal cord dorsal horn (SCDH). HIV gp120 induced overexpression of pC/EBPß in the ipsilateral SCDH compared with contralateral SCDH. Inhibition of C/EBPß using siRNA against C/EBPß reduced mechanical allodynia. HIV gp120 also increased TNFα, TNFRI, mitochondrial superoxide (mtO2·-), and pCREB in the ipsilateral SCDH. ChIP-qPCR assay showed that pCREB enrichment on the C/EBPß gene promoter regions in rats with gp120 was higher than that in sham rats. Intrathecal TNF soluble receptor I (functionally blocking TNFα bioactivity) or knockdown of TNFRI using antisense oligodeoxynucleotide against TNFRI reduced mechanical allodynia, and decreased mtO2·-, pCREB and pC/EBPß. Intrathecal Mito-tempol (a mitochondria-targeted O2·-scavenger) reduced mechanical allodynia and decreased pCREB and pC/EBPß. Knockdown of CREB with antisense oligodeoxynucleotide against CREB reduced mechanical allodynia and lowered pC/EBPß. These results suggested that the pathway of TNFα/TNFRI-mtO2·--pCREB triggers pC/EBPß in the HIV gp120-induced neuropathic pain state. Furthermore, we confirmed the pathway using both cultured neurons treated with recombinant TNFα in vitro and repeated intrathecal injection of recombinant TNFα in naive rats. This finding provides new insights in the understanding of the HIV neuropathic pain mechanisms and treatment.SIGNIFICANCE STATEMENT Painful HIV-associated sensory neuropathy is a neurological complication of HIV infection. Phosphorylated C/EBPß (pC/EBPß) influences AIDS progression, but it is still not clear about the exact role of pC/EBPß and the detailed upstream factors of pC/EBPß in HIV-related pain. In a neuropathic pain model of perineural HIV gp120 application onto the sciatic nerve, we found that pC/EBPß was triggered by TNFα/TNFRI-mtO2·--pCREB signaling pathway. The pathway was confirmed by using cultured neurons treated with recombinant TNFα in vitro, and by repeated intrathecal injection of recombinant TNFα in naive rats. The present results revealed the functional significance of TNFα/TNFRI-mtO2·--pCREB-pC/EBPß signaling in HIV neuropathic pain, and should help in the development of more specific treatments for neuropathic pain.

Pain self-management in HIV-infected individuals with chronic pain: a qualitative study.

OBJECTIVE: Chronic pain in individuals with HIV is a common, impairing condition. Behavioral interventions for chronic pain specifically tailored to this population have yet to be developed. We assert that understanding self-management strategies already used by persons living with these conditions is an essential first step, and is the objective of this investigation. DESIGN: We conducted a thematic analysis of qualitative data from 25 in-depth interviews with individuals with HIV and chronic pain. RESULTS: The primary pain self-management strategies articulated by participants were: physical activity; cognitive and spiritual strategies; spending time with family and friends and social support; avoidance of physical/social activity; medication-centric pain management; and substance use. CONCLUSIONS: Some of these strategies may be viewed as beneficial and overlap with known HIV self-management strategies (cognitive strategies), whereas others may have negative health consequences (substance use). Interventions that incorporate healthy self-management strategies may be particularly effective in improving both HIV and pain outcomes.

Chronic-pain-associated astrocytic reaction in the spinal cord dorsal horn of human immunodeficiency virus-infected patients.

Studies with animal models have suggested that reaction of glia, including microglia and astrocytes, critically contributes to the development and maintenance of chronic pain. However, the involvement of glial reaction in human chronic pain is unclear. We performed analyses to compare the glial reaction profiles in the spinal dorsal horn (SDH) from three cohorts of sex- and age-matched human postmortem tissues: (1) HIV-negative patients, (2) HIV-positive patients without chronic pain, and (3) HIV patients with chronic pain. Our results indicate that the expression levels of CD11b and Iba1, commonly used for labeling microglial cells, did not differ in the three patient groups. However, GFAP and S100ß, often used for labeling astrocytes, were specifically upregulated in the SDH of the "pain-positive" HIV patients but not in the "pain-negative" HIV patients. In addition, proinflammatory cytokines, TNFα and IL-1ß, were specifically increased in the SDH of pain-positive HIV patients. Furthermore, proteins in the MAPK signaling pathway, including pERK, pCREB and c-Fos, were also upregulated in the SDH of pain-positive HIV patients. Our findings suggest that reaction of astrocytes in the SDH may play a role during the maintenance phase of HIV-associated chronic pain.

Variables associated with decreasing pain among persons living with human immunodeficiency virus: a longitudinal follow-up study.

BACKGROUND: Pain is common among persons with human immunodeficiency virus (HIV); however, there are minimal data on its natural history, or the long-term efficacy of analgesic therapies. METHODS: We performed an observational study between 2001 and 2009. Pain was defined on a 0 to 10 scale; 0=no pain; 10=worst pain possible. Patients were included if they were HIV positive, had a chronic pain diagnosis, a median pain score during the first year of observation of ≥1.0, ≥2 years of follow-up, and ≥3 recorded pain scores. Two models were used to describe decreasing pain. Model 1 defined decreasing pain as a negative slope to the best fit line through all recorded pain scores. Model 2 defined decreasing pain as a median pain score of zero during the last year of follow-up. RESULTS: Using model 1, decreasing pain was negatively associated with a history of being abused (odds ratio=0.29) and positively associated with peripheral neuropathy (3.54). Using model 2, decreasing pain was positively associated with highly active antiretroviral therapy (3.71) and negatively associated with opioid analgesic use (0.24). CONCLUSIONS: We found social and HIV-related variables associated with decreasing pain. We failed to show a positive association between analgesic use and decreasing pain.