Human Studies

While several studies have found that chronic pain is characterized by increased cross-network connectivity between salience, sensorimotor, and default mode (DMN) networks, a large sample-size investigation allowing a more reliable evaluation of somatotopic specificity and subgroup analyses with linkage to clinical pain intensity has been lacking. We enrolled healthy adults and a large cohort of patients (N=181) suffering from chronic low back pain (cLBP). To specifically link brain connectivity with clinical pain intensity, patients were scanned at baseline and after performing physical maneuvers that exacerbated pain. Compared to healthy adults, cLBP patients demonstrated increased connectivity between the functionally-localized back representation in primary somatosensory cortex (S1back) and both salience and DMN networks. Pain exacerbation maneuvers increased S1back connectivity to salience network regions, but decreased connectivity to DMN, with greater pain intensity increase associated with greater shifts in these connectivity patterns. Furthermore, only in cLBP patients reporting high pain catastrophizing, DMN connectivity was increased to a cardinal node of the salience network, anterior insula cortex, which was correlated with increased post-maneuver pain in this cLBP subgroup. Hence, increased information transfer between salience processing regions, particularly anterior insula, and DMN may be strongly influenced by pain catastrophizing. Increased information transfer between salience network and S1 likely plays an important role in shifting nociceptive afference away from self-referential processing, re-allocating attentional focus and affective coding of nociceptive afference from specific body areas. These results demonstrate S1 somatotopic specificity for cross-network connectivity in encoding clinical back pain, and moderating influence of catastrophizing for DMN/insula connectivity.

The opioid risk tool (ORT) is a commonly employed measure of risk of aberrant drug related behaviors (ADRB) in patients with chronic pain prescribed opioid therapy. In this study the discriminant predictive validity of the ORT was evaluated in a unique cohort of patients with chronic nonmalignant pain (CNMP) on long-term opioid therapy (LTOT) that displayed no evidence of developing an opioid use disorder (OUD) and a sample of patients with CNMP that developed an OUD after commencing opioid therapy. Results revealed that the original ORT was able to discriminate between patients with and without OUDs (OR=1.624; CI 95%: 1.539-1.715, p< 0.001). A weighted ORT eliminating the gender specific history of preadolescent sexual abuse item revealed comparable results (OR= 1.648; CI 95%: 1.539-1.742, p< 0.001). A revised unweighted ORT (ORT-OUD) removing the history of preadolescent sexual abuse item was notably superior in predicting the development of OUD in patients with CNMP on LTOT (OR= 3.085; CI 95%: 2.725-3.493, p< 0.001) with high specificity (0.851; CI 95%: 0.811-0.885), sensitivity (0.854; 95% CI: 0,799-0.898), positive (0.757; CI 95%: 0.709-0.799) and negative (0.914; CI 95%: 0.885-0.937) predictive values. Perspective: The revised ORT (ORT-OUD) is the first tool developed on a unique cohort to predict the risk of developing an OUD in patients with CNMP receiving opioid therapy, as opposed to ADRB that can reflect a number of other issues. The ORT-OUD has clinical utility in providing clinicians a simple, validated method to rapidly screen for the risk of developing OUD in patients on or being considered for opioid therapy.

Fabry disease (FD) is an X-linked lysosomal storage disorder associated with pain triggered by heat or febrile infections. We modelled this condition by measuring the cytokine expression of peripheral blood mononuclear cells (PBMC) from FD patients in vitro upon stimulation with heat and lipopolysaccharide (LPS). We enrolled 67 FD patients and 37 healthy controls. We isolated PBMC, assessed their gene expression of selected pro- and anti-inflammatory cytokines, incubated them with heat, LPS, globotriaosylceramide (Gb3), and tumor necrosis factor-α (TNF), and measured TNF secretion in the supernatant and intracellular Gb3 accumulation, respectively. We found increased TNF, interleukin (IL-)1β, and toll-like receptor 4 (TLR4) gene expression in FD men (p < .05 to p < .01). TNF and IL-10 were higher, and IL-4 was lower in the subgroup of FD men with pain compared to controls (p < .05 to p < .01). Hereby, TNF was only increased in FD men with pain and classical mutations (p < .05) compared to those without pain. PBMC from FD patients secreted more TNF upon stimulation with LPS (p < .01) than control PBMC. Incubation with Gb3 and an additional α-galactosidase A inhibitor did not further increase TNF secretion, but incubation with TNF greatly increased the Gb3 load in FD PBMC compared to controls (p < .01). Also, LPS incubation and heat challenge (40 °C) increased Gb3 accumulation in PBMC of patients compared to baseline (p < .05 each), while no alterations were observed in control PBMC. Our data show that TNF holds a crucial role in the pathophysiology of FD associated pain, which may open a novel perspective for analgesic treatment in FD pain.

Chronic pain patients managed with opioids are at an increased risk of opioid misuse or opioid use disorder (OUD). In recent years, there has seen a stark increase in abuse, misuse, and diversion of prescription opioid medications. The aim of this study is to investigate trends in changing rates of opioid use disorder amongst chronic pain patients.

The present study aimed to: (1) better understand physical activity levels in youth with chronic abdominal pain and (2) investigate the relationship between day-level physical activity related to next day pain intensity to identify any intra-individual heterogeneity.

Persistent postsurgical pain (PPP) is defined as the discomfort that lasts >3 months postoperatively. The primary aim of this retrospective study was to estimate the risk of developing moderate-to-severe PPP after primary total knee arthroplasty (TKA). The secondary goal was to explore potential predictors of this outcome.Data were collected via hospital arthroplasty registry and chart review. The risk of moderate-to-severe PPP, defined as ≥4 on the numerical rating scale (NRS) at minimum of 3 months post-surgery, was calculated. Multivariable logistic regression was used to estimate the association of patient demographics, diagnoses, length of hospital stay, and preoperative NRS with the odds of developing PPP. Exploratory, simple logistic regression was used to estimate the association of perioperative factors with the odds of developing PPP on a subset of patients (n = 72).The risk of PPP after TKA was 31.3% (95% confidence interval [CI]: 27.5-35.0) (n = 578). Every 2-point increase in baseline NRS was associated with 1.66 (95% CI: 1.37-2.03) times the odds of developing PPP (P < .001). African-Americans (vs whites) had 1.82 (95% CI: 1.03-3.22) times the odds of developing PPP (P = .040). Exploratory analysis suggested that the adductor canal saphenous nerve (vs femoral nerve) blocks were associated with 2.87 (95% CI: 1.00-8.26) times the odds of developing PPP (P = .049).This study estimated a high risk (31.3%) of moderate-to-severe PPP after primary TKA. This study suggested that higher preoperative pain scores might be associated with greater odds of developing PPP. Moreover, this study suggested the possibility that racial differences and types of peripheral nerve blocks might be associated with greater odds of developing moderate-to-severe PPP after TKA surgery. However, the evidence obtained from our exploratory analysis of limited data certainly requires further exploration in large-scale studies.