Human Studies

Patients with complex regional pain syndrome (CRPS) report cognitive difficulties, affecting the ability to represent, perceive and use their affected limb. Moseley, Gallace & Spence (2009) observed that CRPS patients tend to bias the perception of tactile stimulation away from the pathological limb. Interestingly, this bias was reversed when CRPS patients were asked to cross their arms, implying that this bias is embedded in a complex representation of the body that takes into account the position of body-parts. Other studies have failed to replicate this finding (Filbrich et al., 2017) or have even found a bias in the opposite direction (Sumitani et al., 2007). Moreover, perceptual biases in CRPS patients have not often been compared to these of other chronic pain patients. Chronic pain patients are often characterized by an excessive focus of attention for bodily sensations. We might therefore expect that non-CRPS pain patients would show a bias towards instead of away from their affected limb. The aim of this study was to replicate the study of Moseley, Gallace & Spence (2009) and to extend it by comparing perceptual biases in a CRPS group with two non-CRPS pain control groups (i.e., chronic unilateral wrist and shoulder pain patients). In a temporal order judgment (TOJ) task, participants reported which of two tactile stimuli, one applied to either hand at various intervals, was perceived as occurring first. TOJs were made, either with the arms in a normal (uncrossed) position, or with the arms crossed over the body midline. We found no consistent perceptual biases in either of the patient groups and in either of the conditions (crossed/uncrossed). Individual differences were large and might, at least partly, be explained by other variables, such as pain duration and temperature differences between the pathological and non-pathological hand. Additional studies need to take these variables into account by, for example, comparing biases in CRPS (and non-CRPS) patients in an acute versus a chronic pain state.

Synovitis is one of the possible pain generators in osteoarthritis (OA) and is associated with upregulation of proinflammatory cytokines, which can lead to worsening of the postoperative pain. This exploratory study aimed to investigate the association between perioperative synovitis and self-reported pain 12 months after total knee arthroplasty (TKA) in patients with OA.

Oral sucrose is commonly used to provide analgesia to neonates during painful procedures, such as venepuncture. The additional benefits of reducing pain during venepuncture when oral sucrose is combined with nonpharmacological strategies have not been extensively studied. This randomized controlled trial compared the efficacy of oral sucrose with nonnutritive sucking vs. oral sucrose with nonnutritive sucking plus "holding-cuddling" for pain management during venepuncture in term infants from birth to 3 months of life. Seventy-eight infants were equally randomized to receive 24% oral sucrose with nonnutritive sucking (control group) or 24% oral sucrose with nonnutritive sucking plus "holding-cuddling" (being held in a secure, cuddling position; experimental group) before venepuncture. Behavioral response to pain was measured by the 0-10 ranking scale "acute pain for neonates (APN)" at 30 and 60 s after venepuncture. Within the study sample, APN scores were ≥ 2 for 32/68 (47%) infants. "Holding-cuddling" did not significantly reduce mean APN scores at 30 and 60 s, but the rate of infants experiencing a high pain score (APN ≥ 8) at 60 s after the venepuncture was significantly lower in the experimental group compared to controls [4/34 vs. 12/34 ( = 0.04)]. Venepuncture is a painful procedure in newborn and young infants. The implementation of behavioral strategies in association with oral sucrose may mitigate pain during this procedure. This trial was registered at http://clinicaltrials.gov/ (NCT number 02803723).

Although transcranial direct current stimulation (tDCS) and mirror therapy (MT) have benefits in combating chronic pain, there is still no evidence of the effects of the simultaneous application of these techniques in patients with neuropathic pain. This study aims to assess the efficacy of tDCS paired with MT in neuropathic pain after brachial plexus injury. In a sham controlled, double-blind, parallel-group design, 16 patients were randomized to receive active or sham tDCS administered during mirror therapy. Each patient received 12 treatment sessions, 30 min each, during a period of 4 weeks over M1 contralateral to the side of the injury. Outcome variables were evaluated at baseline and post-treatment using the McGill questionnaire, Brief Pain Inventory, and Medical Outcomes Study 36-Item Short-Form Health Survey. Long-term effects of treatment were evaluated at a 3-month follow-up. An improvement in pain relief and quality of life were observed in both groups ( ≤ 0.05). However, active tDCS and mirror therapy resulted in greater improvements after the endpoint ( ≤ 0.02). No statistically significant differences in the outcome measures were identified among the groups at follow-up ( ≥ 0.12). A significant relationship was found between baseline pain intensity and outcome measures ( ≤ 0.04). Moreover, the results showed that state anxiety is closely linked to post-treatment pain relief ( ≤ 0.05). Active tDCS combined with mirror therapy has a short-term effect of pain relief, however, levels of pain and anxiety at the baseline should be considered. www.ClinicalTrials.gov, identifier NCT04385030.

Spinal manipulative therapy (SMT) helps to reduce chronic low back pain (cLBP). However, the underlying mechanism of pain relief and the neurological response to SMT remains unclear. We utilized brain functional magnetic resonance imaging (fMRI) upon the application of a real-time spot pressure mechanical stimulus to assess the effects of SMT on patients with cLBP. Patients with cLBP (Group 1, = 14) and age-matched healthy controls without cLBP (Group 2, = 20) were prospectively enrolled. Brain fMRI was performed for Group 1 at three time points: before SMT (TP1), after the first SMT session (TP2), and after the sixth SMT session (TP3). The healthy controls (Group 2) did not receive SMT and underwent only one fMRI scan. During fMRI scanning, a real-time spot pressure mechanical stimulus was applied to the low back area of all participants. Participants in Group 1 completed clinical questionnaires assessing pain and quality of life using a visual analog scale (VAS) and the Chinese Short Form Oswestry Disability Index (C-SFODI), respectively. Before SMT (TP1), there were no significant differences in brain activity between Group 1 and Group 2. After the first SMT session (TP2), Group 1 showed significantly greater brain activity in the right parahippocampal gyrus, right dorsolateral prefrontal cortex, and left precuneus compared to Group 2 ( < 0.05). After the sixth SMT session (TP3), Group 1 showed significantly greater brain activity in the posterior cingulate gyrus and right inferior frontal gyrus compared to Group 2 ( < 0.05). After both the first and sixth SMT sessions (TP2 and TP3), Group 1 had significantly lower VAS pain scores and C-SFODI scores than at TP1 ( < 0.001). We observed alterations in brain activity in regions of the default mode network in patients with cLBP after SMT. These findings suggest the potential utility of the default mode network as a neuroimaging biomarker for pain management in patients with cLBP. Chinese Clinical Trial Registry, identifier ChiCTR1800015620.

Chronic pain, particularly that following nerve injury, can occur in the absence of external stimuli. Although the ongoing pain is sometimes continuous, in many individuals the intensity of their pain fluctuates. Experimental animal studies have shown that the brainstem contains circuits that modulate nociceptive information at the primary afferent synapse and these circuits are involved in maintaining ongoing continuous neuropathic pain. However, it remains unknown if these circuits are involved in regulating fluctuations of ongoing neuropathic pain in humans.