Human Studies

Post-traumatic headache (PTH) is commonly reported after concussion. Calcitonin gene-related peptide (CGRP) is implicated in the pathogenesis of migraine. We explored how single nucleotide polymorphisms (SNPs) from CGRP-alpha (CALCA) and the receptor activity modifying protein-1 (RAMP1) related to headache burden during the first week after concussion.

Pain is thought to be influenced by the threat value of the particular context in which it occurs. However, the mechanisms by which a threat achieves this influence on pain are unclear. Here, we explore how threat influences experimentally-induced secondary hyperalgesia, which is thought to be a manifestation of central sensitization. We developed an experimental study to investigate the effect of a manipulation of threat on experimentally-induced secondary hyperalgesia in 26 healthy human adults (16 identifying as female; 10 as male). We induced secondary hyperalgesia at both forearms using high-frequency electrical stimulation. Prior to the induction, we used a previously successful method to manipulate threat of tissue damage at one forearm (threat site). The effect of the threat manipulation was determined by comparing participant-rated anxiety, perceived threat, and pain during the experimental induction of secondary hyperalgesia, between the threat and control sites. We hypothesized that the threat site would show greater secondary hyperalgesia (primary outcome) and greater surface area (secondary outcome) of induced secondary hyperalgesia than the control site. Despite a thorough piloting procedure to test the threat manipulation, our data showed no main effect of site on pain, anxiety, or threat ratings during high-frequency electrical stimulation. In the light of no difference in threat between sites, the primary and secondary hypotheses cannot be tested. We discuss reasons why we were unable to replicate the efficacy of this established threat manipulation in our sample, including: (1) competition between threats, (2) generalization of learned threat value, (3) safety cues, (4) trust, and requirements for participant safety, (5) sampling bias, (6) sample-specific habituation to threat, and (7) implausibility of (sham) skin examination and report. Better strategies to manipulate threat are required for further research on the mechanisms by which threat influences pain.

Chronic pain in multiple sclerosis is common and difficult to treat. Its mechanisms remain incompletely understood. Dysfunction of the descending pain modulatory system is known to contribute to human chronic pain conditions. However, it is not clear how alterations in executive function influence this network, despite healthy volunteer studies linking function of the descending pain modulatory system, to cognition. In adults with multiple sclerosis-associated chronic neuropathic limb pain, compared to those without pain, we hypothesized altered functional connectivity of the descending pain modulatory system, coupled to executive dysfunction. Specifically we hypothesized reduced mental flexibility, because of potential importance in stimulus reappraisal. To investigate these hypotheses, we conducted a case-control cross-sectional study of 47 adults with relapsing remitting multiple sclerosis (31 with chronic neuropathic limb pain, 16 without pain), employing clinical, neuropsychological, structural, and functional MRI measures. We measured brain lesions and atrophy affecting descending pain modulatory system structures. Both cognitive and affective dysfunctions were confirmed in the chronic neuropathic limb pain group, including reduced mental flexibility (Delis Kaplan Executive Function System card sorting tests  < 0.001). Functional connectivity of rostral anterior cingulate and ventrolateral periaqueductal gray, key structures of the descending pain modulatory system, was significantly lower in the group experiencing chronic neuropathic pain. There was no significant between-group difference in whole-brain grey matter or lesion volumes, nor lesion volume affecting white matter tracts between rostral anterior cingulate and periaqueductal gray. Brainstem-specific lesion volume was higher in the chronic neuropathic limb pain group ( = 0.0017). Differential functional connectivity remained after correction for brainstem-specific lesion volume. Gabapentinoid medications were more frequently used in the chronic pain group. We describe executive dysfunction in people with multiple sclerosis affected by chronic neuropathic pain, along with functional and structural MRI evidence compatible with dysfunction of the descending pain modulatory system. These findings extend understanding of close inter-relationships between cognition, function of the descending pain modulatory system, and chronic pain, both in multiple sclerosis and more generally in human chronic pain conditions. These findings could support application of pharmacological and cognitive interventions in chronic neuropathic pain associated with multiple sclerosis.

Spinal fusion surgery is a common and painful musculoskeletal surgery performed in the adolescent population. Despite the known risk for developing chronic postsurgical pain, few perioperative psychosocial interventions have been evaluated in this population, and none have been delivered remotely (via the Internet) to improve accessibility.

The direction and the magnitude of verbal suggestions have been shown to be strong modulators of nocebo hyperalgesia, while little attention has been given to the role of their temporal content. Here, we investigate whether temporal suggestions modulate the timing of nocebo hyperalgesia in an experimental model of sustained pain.

Opioid receptors are expressed not only by neural cells in the central nervous system, but also by many solid tumor cancer cells. Whether perioperative opioids given for analgesia after tumor resection surgery might inadvertently activate tumor cells, promoting recurrence or metastasis, remains controversial. We analysed large public gene repositories of solid tumors to investigate differences in opioid receptor expression between normal and tumor tissues and their association with long-term oncologic outcomes.

Myofascial pain syndrome (MPS) is one of the most common causes of chronic skeletal muscle pain, which is closely related to skeletal muscle myofascial trigger point (MTRP). Since there is no first-line treatment for MPS, we investigated Loxoprofen Sodium Cataplasm combined with physiotherapy as a non-invasive therapy in patients at different levels to a protocol with superior efficacy that is safe and easy to promote. Moreover, this treatment could represent an alternative therapeutic strategy for low-income patients to a safer, more convenient, and more economical treatment scheme.

Vagus nerve innervation electrical stimulation and meditative-based diaphragmatic breathing may be promising treatment avenues for fibromyalgia.

While factors contributing to between-subjects differences in pain have been studied extensively, factors contributing to the within-subjects variability of pain reports are yet unexplored. The aim of this investigation was to assess possible associations between short-term memory and the within-subjects variability of pain reports in healthy and chronic pain patients. Healthy participants were recruited at the University of Haifa, Israel, and Fibromyalgia patients were recruited at a rheumatology department in a central hospital in Lisbon, Portugal. Following consent, both cohorts underwent the same procedures, including the digit-span test, assessing short-term memory, and the FAST procedure, assessing within-subject variability of pain intensity reports in response to experimental pain. One-hundred twenty-one healthy volunteers and 29 Fibromyalgia patients completed the study. While a significant correlation was found between the within-subjects variability and the total score of the short-term memory task (Spearman's r = 0.394, P = 0.046) in the Fibromyalgia group, a marginal correlation emerged in the healthy cohort (r = 0.174, P = 0.056). A possible interpretation of these results is that in the patients' group, at least some of the within-subjects variability of pain intensity reports might be due to error measurement derived by poorer short-term memory, rather than true fluctuations in perception.