The 0.7% likelihood of approval for novel analgesics from Phase I represents a systemic crisis hindering resolution of the global opioid epidemic and economic burden. This study identifies causes of this stagnation through a dual–faceted analysis of regulatory trends in Japan and global clinical trial failures between 2015 and 2025. Analysis of the Pharmaceuticals and Medical Devices Agency (PMDA) database revealed approximately 95% of primary endpoints in successful applications rely on unidimensional subjective pain intensity scores, whereas multi–faceted functional indicators represent approximately 5%. Concurrently, global data from Pharmaprojects identified an "Efficacy Wall", with failure rates of 63.4% in Phase II and 56.3% in Phase III. The predominant cause of late–stage discontinuation was a lack of efficacy, suggesting that subjective metrics are insufficient to distinguish therapeutic signals from variable placebo responses amidst high intra–individual variability. To revitalize the pipeline, we propose a paradigm shift focused on four strategic pillars: prioritizing multi–faceted functional outcomes aligned with international bio–psycho–social guidelines, integrating objective biomarkers, such as those monitored via electroencephalography (EEG), to mitigate subjective noise, implementing precision medicine through phenotyping utilizing frameworks such as the ICD–11 to identify high–responder populations, and utilizing real–world data (RWD) to manage the prohibitive costs of extended trials. Furthermore, we emphasize redefining the placebo effect as an endogenous pharmacological mechanism, particularly for evaluating digital therapeutics. Harmonizing these objective and multi–dimensional approaches with regulatory science is essential to bridge the gap between biological innovation and clinical approval, ensuring transformative non–opioid treatments reach patients worldwide.

Background: Neuropathic pain is associated with changes in motor cortical representation and corticospinal excitability. Transcranial magnetic stimulation (TMS), a noninvasive method to stimulate the cortex, allows for detailed evaluation of motor cortical function. TMS–based motor mapping offers insights into alterations in motor cortical representations, but their relationship with pain severity remains unclear. Purpose: This study aimed to investigate the correlation between pain intensity and motor cortical representation in individuals with neuropathic pain through TMS motor mapping. Methods: Fourteen patients with chronic neuropathic pain in the upper limbs underwent TMS motor mapping. Parameters measured included resting motor threshold (RMT), mapped area (area eliciting motor evoked potentials ≥50 µV), and Distance50 (distance from the center of gravity to the estimated location of a 50 µV response). The ratio of the affected to unaffected hemispheres (AH/UH) was calculated. Pain intensity was assessed using the visual analog scale (VAS), numerical rating scale, and short–form McGill pain questionnaire 2. Results: A substantial negative correlation was identified between VAS scores and the AH/UH ratio of the map area (rs = –0.68, p = 0.01), suggesting that increased pain was linked to a reduced motor representation in the affected hemisphere. Conversely, no significant interhemispheric variances or associations with pain intensity were noted for the RMT or Distance50. Conclusions: The findings indicate that alterations in corticospinal excitability play a role in the pathophysiology of neuropathic pain. TMS motor mapping holds promise as a valuable biomarker for comprehending the pathophysiology of neuropathic pain and assessing treatment effectiveness.

Intrathecal analgesia (ITA) is often administered to patients with cancer receiving high–dose systemic opioids. However, in some patients, opioid escalation is challenging even at relatively low doses owing to adverse effects, despite inadequate analgesia. This retrospective study evaluated the effectiveness of neuraxial analgesia and subsequent clinical outcomes in patients with cancer pain who had difficulty tolerating systemic opioid therapy. Among 158 patients who underwent ITA between January 2021 and March 2025, 53 patients with oral morphine equivalents (OME) <200 mg/day were included and followed until death. Pain scores (numerical rating scale [NRS] scores), medication dose changes, home discharge outcomes, survival after ITA, and adverse events were analyzed. Epidural analgesia (EPI) preceded ITA in 52 patients. Median NRS significantly improved from 8 (6–10) before neuraxial analgesia to 1 (0–2) at 2 weeks after ITA (P < 0.001). Median systemic OME decreased from 40 mg/day to 0 mg/day (P < 0.001). Overall, 66% of patients returned home at least once, and 47% died at home. Survival after ITA tended to be shorter in patients with gastrointestinal cancers, whereas greater variability was observed in patients with urinary tract cancers. In patients with cancer pain that was difficult to manage with systemic opioid therapy, stepwise neuraxial analgesia with epidural and intrathecal approaches was associated with substantial pain reduction. Neuraxial analgesia may be considered a therapeutic option in selected patients who are unable to achieve adequate pain control with conventional systemic therapy.

To elucidate the roles of α4β2 nicotinic acetylcholine receptors (nAChRs) in nociceptive somatosensory processing, we examined the localization and expression of α4β2 nAChR subunits in neurons of the superficial spinal dorsal horn (SDH) in mice. Among the nAChR subunits, α4 (Chrna4) and β2 (Chrnb2) exhibited the highest mRNA expression levels in the SDH. In Chrna4–enhanced green fluorescent protein (EGFP) mice, EGFP reflecting α4 subunit expression was abundantly detected in both excitatory and inhibitory SDH neurons. Further functional validation of α4β2 nAChRs expressed across distinct neuronal populations may clarify their novel roles in the regulation of pain and itch processing.