Background: Chronic cocaine exposure is increasingly associated with persistent brain alterations, yet it remains unclear whether these changes reflect reversible neuroadaptation, accelerated brain ageing, or a degeneration-like trajectory in a vulnerable subgroup. This Perspective proposes a neuroprogressive vulnerability framework—referred to as cocaine-specific encephalopathy/cerebropathy only in a heuristic sense—to organise heterogeneous evidence without implying a distinct neurodegenerative disease entity. Methods: We conducted a structured, critical synthesis of peer-reviewed human and preclinical literature (PubMed, Scopus, Web of Science; inception to December 2025), integrating neuroimaging (MRI/DTI/fMRI/PET/SPECT), neuropathology/post-mortem findings, neurochemical and molecular mechanisms, and neuropsychological outcomes, with explicit attention to confounders (polysubstance use, psychiatric and medical comorbidity, HIV, vascular risk, abstinence duration). Results: Convergent evidence supports a multi-hit vulnerability model in which chronic stimulant exposure may weaken neural resilience through dopaminergic dysregulation, oxidative stress, mitochondrial dysfunction, neuroinflammatory signalling, and putative α-synuclein–related mechanisms. Human imaging studies consistently implicate fronto–striato–limbic circuits and suggest possible cerebellar involvement, but findings are heterogeneous and often cross-sectional; direct evidence of progressive neuronal loss or disease-defining proteinopathies attributable to cocaine remains limited. Conclusions: Rather than asserting cocaine-induced classic neurodegeneration, we outline an exploratory framework in which chronic cocaine exposure may increase susceptibility to neuroprogressive impairment in a subset of biologically vulnerable individuals. Longitudinal multimodal studies combining advanced imaging, biomarkers, and phenotypic stratification are needed to clarify causality, temporal progression, and reversibility with sustained abstinence.

Background: Chronic pain, opioid use, and mental health disorders frequently co-occur in older adults, forming a complex and mutually reinforcing triad. Neurobiological ageing processes—such as neuroinflammation, dopaminergic decline, and impaired top-down regulation—may increase vulnerability to maladaptive coping strategies, including opioid misuse. This review aims to integrate neurobiological, affective, and clinical evidence to propose a unified neuropsychiatric framework for understanding the intersection between chronic pain, emotional distress, and opioid vulnerability in later life, while highlighting implications for integrated treatment and opioid stewardship. Methods: This structured narrative review synthesised interdisciplinary evidence from neuroscience, geriatric psychiatry, and pain medicine. The literature was thematically organised to examine shared neurobiological and psychosocial mechanisms underlying chronic pain, affective disorders, and opioid use disorder (OUD) in older adults, with attention to treatment strategies and stewardship principles. Results: Converging evidence suggests a neuroprogressive continuum linking chronic pain, emotional distress, opioid misuse, and cognitive decline. Key mechanisms include frontolimbic dysfunction, impaired reward processing, and chronic allostatic load. Therapeutic approaches that integrate analgesia with emotional regulation—such as buprenorphine, serotonin–noradrenaline reuptake inhibitors (SNRIs), and multimodal tapering strategies—may offer neuroprotective benefits. Effective opioid stewardship appears to require integrated functional, cognitive, and affective monitoring. Conclusions: Pain management in older adults may benefit from moving beyond symptom-focused approaches toward a neuropsychiatric model of care aimed at preserving homeostatic balance across sensory, emotional, and motivational domains. Within this framework, opioid therapy can be conceptualised as a potential means of functional and neuroaffective restoration, rather than solely as a strategy for risk reduction.