Luyanduthando Mqadi

Acute pain in hospitalised patients is common, yet African data are scarce. We conducted a prospective point-prevalence study of hospitalised adult patients across Africa to determine acute pain prevalence and severity and investigate associations of pain with critical illness and 7-day mortality. On a single day, investigators assessed patients' worst pain in the preceding 24 hours using a 0 to 10 visual-numerical scale and recorded vital signs. Critical illness was defined as ≥1 vital sign out of range, in line with an international consensus definition. In-hospital mortality was assessed at day 7. Data are presented as median [interquartile range], n (%), and odds ratios with 95% confidence intervals. Between September and December 2023, 19,438 patients from 180 hospitals in 22 African nations were included (age 40 [29; 59] years; 10,874 [56%] female). Pain prevalence [95% CI] was 67.9% [67.9-68.5], with 2795 (14.4%) patients reporting severe pain (≥7/10). Pain was more common among patients admitted for emergency or trauma care and in surgical and high-care wards. Pain severity did not differ meaningfully between sexes. There was no evidence of an association between pain severity and critical illness; however, increasing pain severity was associated with a higher likelihood of 7-day mortality. These findings are comparable to data from high-income countries despite substantial differences in healthcare resources, suggesting that acute pain remains a persistent and underaddressed problem globally. This study provides the first large-scale evidence of acute pain burden in African hospitals and lays a foundation for future research aimed at comprehensively characterising in-hospital pain.

Social factors are consequences and determinants of chronic pain, yet little is known about how informal social support operates for people with chronic pain and HIV. The overlapping burdens of emotional distress and chronic pain in people living with HIV raise the need to identify targets for culturally resonant treatments. This qualitative study explored how people living with chronic or recurrent pain and HIV seek informal social support for pain and distress from their social networks, how these networks operate, and how social support is influenced by socio-ecological factors. Adults with virally suppressed HIV who endorsed pain over repeated weeks were purposively sampled (n=18). Semi-structured, individual in-depth interviews explored individuals’ experiences of living with HIV and chronic pain, distress and its relationship to pain, and help-seeking behaviours for chronic pain and distress. Codebook thematic analysis was used within an interpretivist epistemological approach. Support for pain involved more tangible actions by fewer people than support for distress. Disruptions in social support were more likely when the person with pain was irritable, socially withdrawn, or unable to fulfil social roles. Interpersonal conflict could also cause or increase pain and distress. Current pain assessments rarely identify the social interference of pain identified here. This work identified potential targets for individual-level interventions to sustain informal social support: individuals’ abilities to cope with daily stressors, pain self-management strategies to facilitate socialisation and engagement in valued life activities, and strategies to prevent support fatigue in informal social networks.

Longitudinal pain studies present an opportunity to understand intra-individual variations in pain. However, current methods to quantify the anatomical extent of pain fail to capture variations across multiple body sites over time. Our aims were to (1) describe patterns of intra-individual variation in pain sites over time, (2) develop a metric that quantifies intra-individual variation in pain sites over time, and (3) determine whether this metric is related to other indicators of pain burden. We used data from a longitudinal cohort of 72 participants (51 female; median (IQR) age 43 (37-51) years) living with virally suppressed HIV, who provided weekly reports of pain severity, pain site(s), and distress over 49 weeks. Participant reports showed noteworthy intra-individual changes in pain sites over time. The pain sites variation metric, based on 727 consecutive reports from 53 participants, reflected intra-individual temporal variation in pain sites, and distinguished participants with consistent pain sites from participants with high temporal variation in pain sites. The metric was positively associated with pain severity and emotional distress, but only when unadjusted for the count of painful sites. Thus, using a longitudinal cohort, we developed a metric that quantifies individual temporal variability in pain sites and demonstrated its relationship to two frequently used metrics of pain burden, namely pain severity and distress. This metric provides an opportunity to study whether the number of, and variability in, pain sites contributes to pain burden and clinical outcomes.

Childhood adversity is linked to persistent pain in adulthood. Nociceptive upregulation may play a role in this relationship. We investigated whether childhood adversity is associated with measures of nociceptive processing, and whether these associations differ by sex. In this experimental observational study, we enrolled pain-free adults with varying severity of childhood adversity, scored on the Childhood Trauma Questionnaire-Short Form. Measures of nociceptive processing included the surface area and magnitude of induced secondary hyperalgesia, temporal summation, and conditioned pain modulation. We used linear regression to investigate whether childhood adversity was associated with increased surface area or magnitude of secondary hyperalgesia, increased temporal summation, or reduced conditioned pain modulation, and whether these relationships differed by sex. Ninety-five participants (61 female; median age 23 [IQR: 9] years) completed the study. Childhood adversity was positively associated with the surface area of secondary hyperalgesia (β=0.32 [95%CI: 0.01; 0.62], p = 0.04), with no evidence of an interaction effect of sex. Childhood adversity was unrelated to the magnitude of secondary hyperalgesia, temporal summation, or conditioned pain modulation. These data suggest that childhood adversity may influence the distribution rather than the magnitude of evoked ascending nociception. Perspective

Psychological distress predicts the onset and worsening of persistent pain, but the mechanisms that underpin this influence are poorly understood. Proinflammatory signalling is a plausible link, given its known connections to distress, pain, and neural upregulation. Sustained distress may prime the inflammatory system to respond more strongly to a phasic noxious challenge, supporting neuroimmune upregulation of central nociceptive signalling and persistent pain. This cross-sectional study tested the hypotheses that in vitro endotoxin-provoked expression of typically proinflammatory cytokines (IL1β, IL6) is a partial mediator between distress and persistent pain, and that it is associated with experimentally induced secondary hyperalgesia, in people with suppressed HIV. Study participants were 99 adults (mean [range] age: 43 [28-64 y/o; 72 females]) with either no pain (n = 54) or persistent pain (n = 45), mostly of black South African ethnicity, low socio-economic status, and with high social support. The results replicated previous reports that distress is associated with persistent pain status and pain severity, and distress was associated with the anatomical extent of pain. However, distress was not associated with provoked cytokine expression, nor was provoked cytokine expression associated with secondary hyperalgesia. The conflict between our findings and prior evidence could reflect the influence of differentially trained immune systems or a more complex relationship arising from diverse psychoneuroimmunological interactions in this sample. This sample's combination of HIV status, African genetic ancestry, financial impoverishment, and rich social interconnectedness is poorly represented in current research and provides an opportunity to deepen insight into psychoneuroimmunological interactions in persistent pain.

Adversity in childhood elevates the risk of persistent pain in adulthood. Neuroimmune interactions are a candidate mechanistic link between childhood adversity and persistent pain. We aimed to clarify whether immune reactivity is associated with provoked differences in nociceptive processing in adults with a range of childhood adversity. Pain-free adults (n = 96; 61 female; median [range] age: 23 [18-65] years old) with a history of mild to severe childhood adversity underwent psychophysical assessments before and after in vivo neural provocation (high-frequency electrical stimulation) and, separately, before and after in vivo immune provocation (influenza vaccine administration). Psychophysical assessments included the surface area of secondary hyperalgesia after neural provocation and change in conditioned pain modulation (test stimulus: pressure pain threshold; conditioning stimulus: cold water immersion) after immune provocation. Immune reactivity was operationalised as interleukin-6 and tumour necrosis factor-α expression after in vitro lipopolysaccharide provocation of whole blood. We hypothesised associations between immune reactivity and (1) childhood adversity, (2) induced secondary hyperalgesia, and (3) vaccine-associated change in conditioned pain modulation. We found that provoked expression of proinflammatory cytokines was not statistically associated with childhood adversity, induced secondary hyperalgesia, or vaccine-associated change in conditioned pain modulation. The current findings from a heterogenous sample cast doubt on 2 prominent ideas: that childhood adversity primes the inflammatory system for hyper-responsiveness in adulthood and that nociceptive reactivity is linked to inflammatory reactivity. This calls for the broader inclusion of heterogeneous samples in fundamental research to investigate the psychoneuroimmunological mechanisms underlying vulnerability to persistent pain.

Understanding the physiology of specific clinical features of persistent pain, such as secondary hypersensitivity, is crucial for developing effective treatments. This systematic review and meta-analysis investigated the effects of pharmacological manipulations on the magnitude (primary outcome) and surface area (secondary outcome) of experimentally induced secondary hypersensitivity. Following Cochrane Collaboration guidelines and a published and registered protocol, we conducted an electronic search on February 7, 2024. After screening articles in duplicate, we included 117 articles, consisting of 222 datasets. Risk of bias assessments identified potential flaws in methodological quality. Datasets were pooled by the mechanism of action of the manipulation and by outcome. Effect sizes were estimated using standardised mean difference (SMD). Most datasets (207 of 222) had an unclear risk of performance and detection bias for inadequate reporting of blinding procedures. Thirteen different methods were used to induce, and 23 different drug classes were used to manipulate secondary hypersensitivity. The pooled SMDs [95% CI] suggested that alpha-2-delta subunit of voltage-gated calcium channel ligands reduced both the magnitude (−0.24 [−0.39; −0.08]) and surface area (−0.38 [−0.59; −0.18]) of secondary hypersensitivity, and that both N-methyl-D-aspartate receptor antagonists (−0.36 [−0.55; −0.17]) and voltage-gated sodium channel blockers (−1.02 [−1.63; −0.42]) reduced only the surface area of secondary hypersensitivity. These results suggest a need to understand and compare the physiological underpinnings of magnitude and area of secondary hypersensitivity, and to clarify the relative importance of magnitude vs anatomical spread (ie, surface area) of secondary hypersensitivity to people living with pain.

Pain and symptoms of depression and anxiety (here, ‘psychological distress’) are frequently reported by people with HIV. Although pain is widely acknowledged to contribute to distress, distress may also contribute to pain and its persistence. Facilitation of nociceptive signalling is one pathway by which distress could exacerbate pain. The current study investigated the relationships between symptoms of depression and anxiety, secondary hyperalgesia (SH), and persistent pain in people with HIV, reporting pain (n=19) or no pain (n=26). We hypothesised that self-reported distress would be positively associated with the surface area (primary measure) and magnitude (secondary measure) of induced SH, and that participants reporting persistent pain would display greater induced SH than those reporting no pain. We found that distress was positively associated with the surface area (p=0.02) and the magnitude (p=0.01) of induced SH. However, participants with persistent pain showed no difference in the surface area of SH compared to pain-free participants (p=0.87), and those with pain displayed a marginally lower magnitude of SH (p=0.05). These findings position SH as a potentially useful mechanistic outcome for interventions that aim to address pain by reducing symptoms of depression and anxiety. Perspective: Symptoms of depression and anxiety were positively associated with induced secondary hyperalgesia in people with suppressed HIV.

Psychological distress predicts the onset and worsening of persistent pain, but the mechanisms that underpin this influence are poorly understood. Pro-inflammatory signalling is a plausible mechanistic link, given its known connections to distress, pain, and neural upregulation. Sustained distress may prime the inflammatory system to respond more strongly to a phasic noxious challenge, supporting neuroimmune upregulation of central nociceptive signalling and persistent pain. This cross-sectional study tested the hypotheses that in vitro endotoxin-provoked expression of typically pro-inflammatory cytokines (IL1β, IL6) is a partial mediator between distress and persistent pain, and that it is associated with the secondary hyperalgesia response to an experimental noxious challenge, in people with suppressed HIV. Study participants were 99 adults (mean (range) age: 43(28-64y/o; 72 females) with either no pain (n=54) or persistent pain (n=45), mostly of black South African ethnicity, low socio-economic status, and with high social support. The results replicated previous reports that distress is associated with persistent pain status and pain severity, and also showed an association between distress and the anatomical extent of pain. However, distress was not associated with provoked cytokine expression, nor was provoked cytokine expression associated with secondary hyperalgesia. The conflict between our findings and the evidence on which our hypotheses were based could reflect masking of an effect by differentially trained immune systems or a more complex relationship arising from diverse psychoneuroimmunological interactions in this sample. Our sample’s combination of HIV status, African genetic ancestry, financial impoverishment, and rich social interconnectedness is poorly represented in current research and represents an opportunity to deepen insight into psychoneuroimmunological interactions related to distress and persistent pain.