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The midbrain periaqueductal gray (PAG) plays a central role in pain modulation via descending pathways. Opioids and cannabinoids are thought to activate these descending pathways by relieving intrinsic GABAergic inhibition of PAG neurons which project to the rostroventromedial medulla (RVM), a process known as disinhibition. However, the PAG also receives descending extrinsic GABAergic inputs from the central nucleus of the amygdala (CeA) which are thought to inhibit PAG GABAergic interneurons. It remains unclear how opioids and cannabinoids act at these different synapses to control descending analgesic pathways. We used optogenetics, tract tracing and electrophysiology to identify the circuitry underlying opioid and cannabinoid actions within the PAG of male and female rats. It was observed that both RVM-projection and nonprojection PAG neurons received intrinsic-PAG and extrinsic-CeA synaptic inputs, which were predominantly GABAergic. Opioids acted via presynaptic µ-receptors to suppress both intrinsic and extrinsic GABAergic inputs onto all PAG neurons, although this inhibition was greater in RVM-projection neurons. By contrast, cannabinoids acted via presynaptic CB1 receptors to exclusively suppress the direct descending GABAergic input from the CeA onto RVM-projection PAG neurons. These findings indicate the CeA controls PAG output neurons which project to the RVM via parallel direct and indirect GABAergic pathways. While µ-opioids indiscriminately inhibit GABAergic inputs onto all PAG neurons, cannabinoids selectively inhibit a direct extrinsic GABAergic input from the amygdala onto PAG projection neurons. These differential actions of opioids and cannabinoids provide a flexible system to gate the descending control of analgesia from the PAG. The disinhibition hypothesis of analgesia states that opioids activate the midbrain periaqueductal gray (PAG) descending pathway by relieving the tonic inhibition of projection neurons from GABAergic interneurons. However, the PAG also receives extrinsic GABAergic inputs and is the locus of action of cannabinoid analgesics. Here, we show the relative sensitivity of GABAergic synapses to opioids and cannabinoids within the PAG depends on both the origin of presynaptic inputs and their postsynaptic targets. While opioids indiscriminately inhibit all GABAergic inputs onto all PAG neurons, cannabinoids selectively inhibit a direct extrinsic GABAergic input from the amygdala onto PAG descending projection neurons. These differential actions of opioids and cannabinoids provide a flexible system to gate PAG descending outputs.

In advanced cancer, pain is a poor prognostic factor, significantly impacting patients' quality of life. It has been shown that up to 30% of cancer patients in Southeast Asian countries may receive inadequate analgesia from opioid therapy. This significant under-management of cancer pain is largely due to the inter-individual variability in opioid dosage and relative efficacy of available opioids, leading to unpredictable clinical responses to opioid treatment. Single nucleotide polymorphisms (SNPs) cause the variability in opioid treatment outcomes, yet their association in Asian populations remains unclear. Therefore, this review aimed to evaluate the association of SNPs with variability in opioid treatment responses in Asian populations. A literature search was conducted in Medline and Embase databases and included primary studies investigating the association of SNPs in opioid treatment outcomes, namely pharmacokinetics, opioid dose requirements, and pain control among Asian cancer patients. The results show that *10 has the most clinical relevance in tramadol treatment. Other SNPs such as rs7439366 (), rs1641025 () and rs1718125 () though significant have limited pharmacogenetic implications due to insufficient evidence. rs1799971, rs4680 and (rs1045642, rs1128503, and rs2032582) need to be further explored in future for relevance in Asian populations.

Using a patient-informed regimen, we conducted an exploratory randomized, double-blind, placebo-controlled study to systematically investigate the effects of psilocybin in cluster headache.

The aim of this review is to draw attention to neurosurgical approaches for treating chronic and opioid-resistant pain. In a first chapter, an up-to-date overview of the main pathophysiological mechanisms of pain has been carried out, with special emphasis on the details in which the surgical treatment is based. In a second part, the principal indications and results of different surgical approaches are reviewed. Cordotomy, Myelotomy, DREZ lesions, Trigeminal Nucleotomy, Mesencephalotomy, and Cingulotomy are revisited. Ablative procedures have a limited role in the management of chronic non-cancer pain, but they continues to help patients with refractory cancer-related pain. Another ablation lesion has been named and excluded, due to lack of current relevance. Peripheral Nerve, Spine Cord, and the principal possibilities of Deep Brain and Motor Cortex Stimulation are also revisited. Regarding electrical neuromodulation, patient selection remains a challenge.

The current study evaluated the feasibility and preliminary clinical impact of robot-led distraction during needle procedures in children with chronic diseases on pain-related memories. Participants were 22 children (8-12 years old) diagnosed with a chronic disease (e.g., chronic immune deficiency) and undergoing a needle procedure as part of their routine treatment. Children were randomized to the experimental group (i.e., robot-led distraction) or control group (i.e., usual care). For feasibility, we evaluated study- and needle-procedure-related characteristics, intervention fidelity and acceptability, and nurse perceptions of the intervention. Primary clinical outcomes included children's memory bias for pain intensity and pain-related fear (1 week later). Results indicated that intervention components were >90% successful. Overall, the robot-led distraction intervention was perceived highly acceptable by the children, while nurse perceptions were mixed, indicating several challenges regarding the intervention. Preliminary between-group analyses indicated a medium effect size on memory bias for pain intensity (Hedges' g = 0.70), but only a very small effect size on memory bias for pain-related fear (Hedges' g = 0.09), in favor of the robot-led distraction intervention. To summarize, while feasible, certain challenges remain to clinically implement robot-led distraction during needle procedures. Further development of the intervention while accounting for individual child preferences is recommended.

Migraine, a common neurological disease, is known to impact the quality of life of individuals with this condition. We performed a systematic review with meta-analysis to investigate the abnormalities associated with executive functions of migraineurs as compared with healthy controls. In addition, we investigated the differences between patients with and without aura. A total of 25 studies were included in the systematic review and 19 in the meta-analysis. Meta-analysis was conducted using random effects models, with the unit of analysis as the standardised mean difference (calculated as Hedges'g). Patients with migraine had worse performance in the trail making test A (g = 0.40; 95% confidence interval [CI] 0.05-0.74;  = 0.0271) and B (g = 0.40; 95% CI 0.16-0.64;  = 0.0026), and digit span backward test (g = -0.20; 95% CI – 0.31, – 0.09;  = 0.0105). Subgroup analysis revealed no difference between migraine with and without aura. These results suggest that migraine patients may present worse performance for specific executive functional domains, including attention, working memory, and mental flexibility.

Physiotherapists trained to deliver biopsychosocial interventions for complex musculoskeletal pain problems often report difficulties in confidence and competency at the end of training. Cognitive Functional Therapy (CFT) is an individualized biopsychosocial intervention and understanding the facilitators and barriers to training in CFT will help inform future training programs. This study aimed to explore physiotherapists' and trainers' perceptions of the process of developing competency in CFT.

A-wave is a late response related either to demyelination or early axonal regeneration. It may be helpful in the evaluation of some peripheral neuropathies. In leprosy, previous studies suggested that A-waves could be a neurophysiological marker of pain in patients during reactions. Herein, we attempted to further assess the profile and clinical correlates of A-waves by exploring a large leprosy cohort.

The aim of this review is to characterize headache as a vaccine adverse event (VAE) in clinical trials.

The purpose of this review is to summarize advances in behavioral treatments for pain and headache disorders, as well as recent innovations in telemedicine for behavioral treatments.