Human Studies

Persistent pain is a leading cause of disability worldwide yet implementation of clinical guidelines that recommend a biopsychosocial approach remains a challenge in clinical practise. Limited pain understanding amongst clinicians may be partly responsible for this.

Increased glucocorticoids characterise acute pain responses, but not the chronic pain state, suggesting specific modifications to the hypothalamic-pituitary-adrenal (HPA)-axis preventing the persistent nature of chronic pain from elevating basal glucocorticoid levels. Individuals with chronic pain mount normal HPA-axis responses to acute stressors, indicating a rebalancing of the circuits underpinning these responses. Preclinical models of chronic neuropathic pain generally recapitulate these clinical observations, but few studies have considered that the underlying neuroendocrine circuitry may be altered. Additionally, individual differences in the behavioural outcomes of these pain models, which are strikingly similar to the range of behavioural subpopulations that manifest in response to stress, threat and motivational cues, may also be reflected in divergent patterns of HPA-axis activity, which characterises these other behavioural subpopulations. We investigated the effects of sciatic nerve chronic constriction injury (CCI) on adrenocortical and hypothalamic markers of HPA-axis activity in the subpopulation of rats showing persistent changes in social interactions after CCI (Persistent Effect) and compared them with rats that do not show these changes (No Effect). Basal plasma corticosterone did not change after CCI and did not differ between groups. However, adrenocortical sensitivity to adrenocorticotropic hormone (ACTH) diverged between these groups. No Effect rats showed large increases in basal plasma ACTH with no change in adrenocortical melanocortin 2 receptor (MC R) expression, whereas Persistent Effect rats showed modest decreases in plasma ACTH and large increases in MC R expression. In the paraventricular nucleus of the hypothalamus of Persistent Effect rats, single labelling revealed significantly increased numbers of corticotropin releasing factor (CRF) +ve and glucocorticoid receptor (GR) +ve neurons. Double-labelling revealed fewer GR +ve CRF +ve neurons, suggesting a decreased hypothalamic sensitivity of CRF neurons to circulating corticosterone in Persistent Effect rats. We suggest that in addition to rebalancing the HPA-axis, the increased CRF expression in Persistent Effect rats contributes to changes in complex behaviours, and in particular social interactions.

To examine changes in the occurrence, severity, and symptoms of headache episodes in patients with chronic migraine following eptinezumab treatment.

The validity of current tools for intraoperative objective assessment of nociception/antinociception balance during anesthesia in young and very young surgery children is unknown.

Fibromyalgia (FM) is a chronic pain disorder characterized by chronic widespread musculoskeletal pain (CWP), resting pain, movement-evoked pain (MEP), and other somatic symptoms that interfere with daily functioning and quality of life. In clinical studies, this symptomology is assessed, while preclinical models of CWP are limited to nociceptive assays. The aim of the study was to investigate the human-to-model translatability of clinical behavioral assessments for spontaneous (or resting) pain and MEP in a preclinical model of CWP. For preclinical measures, the acidic saline model of FM was used to induce widespread muscle pain in adult female mice. Two intramuscular injections of acidic or neutral pH saline were administered following baseline measures, five days apart. An array of adapted evoked and spontaneous pain measures and functional assays were assessed for three weeks. A novel paradigm for MEP assessment showed increased spontaneous pain following activity. For clinical measures, resting and movement-evoked pain and function were assessed in adult women with FM. Moreover, we assessed correlations between the preclinical model of CWP and in women with fibromyalgia to examine whether similar relationships between pain assays that comprise resting and MEP existed in both settings. For both preclinical and clinical outcomes, MEP was significantly associated with mechanical pain sensitivity. Preclinically, it is imperative to expand how the field assesses spontaneous pain and MEP when studying multi-symptom disorders like FM. Targeted pain assessments to match those performed clinically is an important aspect of improving preclinical to clinical translatability of animal models.

A significant proportion of patients with short-lasting unilateral neuralgiform headache attacks (SUNHA) are refractory to medical treatments. Neuroimaging studies have suggested a role for ipsilateral trigeminal neurovascular conflict with morphological changes in the pathophysiology of this disorder. We present the outcome of an uncontrolled open-label prospective single centre study conducted between 2012 and 2020, to evaluate the efficacy and safety of trigeminal microvascular decompression in refractory chronic SUNHA with magnetic resonance imaging evidence of trigeminal neurovascular conflict ipsilateral to the pain side. Primary endpoint was the proportion of patients who achieved an "excellent response", defined as 90-100% weekly reduction in attack frequency, or "good response", defined as a reduction in weekly headache attack frequency between 75% and 89% at final follow-up, compared to baseline. These patients were defined as responders. The study group consisted of 47 patients of whom 31 had SUNCT and 16 had SUNA (25 females, mean age ± SD 55.2 years ± 14.8). Participants failed to respond or tolerate a mean of 8.1 (±2.7) preventive treatments pre-surgery. Magnetic resonance imaging of the trigeminal nerves (n = 47 patients, n = 50 symptomatic trigeminal nerves) demonstrated ipsilateral neurovascular conflict with morphological changes in 39/50 (78.0%) symptomatic nerves and without morphological changes in 11/50 (22.0%) symptomatic nerves. Post-operatively, 37/47 (78.7%) patients obtained either an excellent or a good response. Ten patients (21.3%, SUNCT = 7 and SUNA = 3) reported no post-operative improvement. The mean post-surgery follow-up was 57.4 ± 24.3 months (range 11-96 months). At final follow-up, 31 patients (66.0%) were excellent/good responders. Six patients experienced a recurrence of headache symptoms. There was no statistically significant difference between SUNCT and SUNA in the response to surgery (p = 0.463). Responders at the last follow-up were however more likely not to have interictal pain (77.42% vs 22.58%, p = 0.021) and to show morphological changes on the magnetic resonance imaging (78.38% vs 21.62%, p = 0.001). The latter outcome was confirmed in the Kaplan Meyer analysis, where patients with no morphological changes were more likely to relapse overtime compared to those with morphological changes (p = 0.0001). All but one patient who obtained an excellent response without relapse, discontinued their preventive medications. Twenty-two post-surgery adverse events occurred in 18 patients (46.8%) but no mortality or severe neurological deficit was seen. Trigeminal microvascular decompression may be a safe and effective long-term treatment for short-lasting unilateral neuralgiform headache attacks patients with magnetic resonance evidence of neurovascular conflict with morphological changes.