-
Journal of Addiction MedicineThis narrative review summarizes literature on pharmaceutical fentanyl's absorption, distribution, metabolism, and excretion patterns to inform research on illicitly... (Review)
Review
OBJECTIVES
This narrative review summarizes literature on pharmaceutical fentanyl's absorption, distribution, metabolism, and excretion patterns to inform research on illicitly manufactured fentanyl (IMF).
RESULTS
Fentanyl is highly lipophilic, lending itself to rapid absorption by highly perfused tissues (including the brain) before redistributing from these tissues to muscle and fat. Fentanyl is eliminated primarily by metabolism and urinary excretion of metabolites (norfentanyl and other minor metabolites). Fentanyl has a long terminal elimination, with a documented secondary peaking phenomenon that can manifest as "fentanyl rebound." Clinical implications in overdose (respiratory depression, muscle rigidity, and "wooden chest syndrome") and opioid use disorder treatment (subjective effects, withdrawal, and buprenorphine-precipitated withdrawal) are discussed. The authors highlight research gaps derived from differences in medicinal fentanyl studies and IMF use patterns, including that medicinal fentanyl studies are largely conducted with persons who were opioid-naive, anesthetized, or had severe chronic pain and that IMF use is characterized by supratherapeutic doses and frequent and sustained administration patterns, as well as adulteration with other substances and/or fentanyl analogs.
CONCLUSIONS
This review reexamines information yielded from decades of medicinal fentanyl research and applies elements of the pharmacokinetic profile to persons with IMF exposure. In persons who use drugs, peripheral accumulation of fentanyl may be leading to prolonged exposure. More focused research on the pharmacology of fentanyl in persons using IMF is warranted.
Topics: Humans; Analgesics, Opioid; Chronic Pain; Clinical Relevance; Drug Overdose; Fentanyl
PubMed: 37788600
DOI: 10.1097/ADM.0000000000001185 -
Journal of Integrative Neuroscience Oct 2023Parkinson's disease (PD) is a common neurodegenerative disorder characterized by misfolding of α-synuclein. Clinical manifestations include slowly developing resting... (Review)
Review
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by misfolding of α-synuclein. Clinical manifestations include slowly developing resting tremor, muscle rigidity, bradykinesia and abnormal gait. The pathological mechanisms underlying PD are complex and yet to be fully elucidated. Clinical studies suggest that the onset of gastrointestinal symptoms may precede motor symptoms in PD patients. The microbiota-gut-brain axis plays a bidirectional communication role between the enteric nervous system and the central nervous system. This bidirectional communication between the brain and gut is influenced by the neural, immune and endocrine systems related to the gut microbiome. A growing body of evidence indicates a strong link between dysregulation of the gut microbiota and PD. In this review, we present recent progress in understanding the relationship between the microbiota-gut-brain axis and PD. We focus on the role of the gut microbiota, the unique changes observed in the microbiome of PD patients, and the impact of these changes on the progression of PD. Finally, we evaluate the role of current treatment strategies for PD, including probiotics, fecal microbial transplants, dietary modifications, and related drug therapies.
Topics: Humans; Parkinson Disease; Brain-Gut Axis; Gastrointestinal Microbiome; Probiotics; Brain
PubMed: 38176929
DOI: 10.31083/j.jin2206157 -
Brain : a Journal of Neurology Sep 2023Although rigidity is a cardinal motor sign in patients with Parkinson's disease (PD), the instrumental measurement of this clinical phenomenon is largely lacking, and...
Although rigidity is a cardinal motor sign in patients with Parkinson's disease (PD), the instrumental measurement of this clinical phenomenon is largely lacking, and its pathophysiological underpinning remains still unclear. Further advances in the field would require innovative methodological approaches able to measure parkinsonian rigidity objectively, discriminate the different biomechanical sources of muscle tone (neural or visco-elastic components), and finally clarify the contribution to 'objective rigidity' exerted by neurophysiological responses, which have previously been associated with this clinical sign (i.e. the long-latency stretch-induced reflex). Twenty patients with PD (67.3 ± 6.9 years) and 25 age- and sex-matched controls (66.9 ± 7.4 years) were recruited. Rigidity was measured clinically and through a robotic device. Participants underwent robot-assisted wrist extensions at seven different angular velocities randomly applied, when ON therapy. For each value of angular velocity, several biomechanical (i.e. elastic, viscous and neural components) and neurophysiological measures (i.e. short and long-latency reflex and shortening reaction) were synchronously assessed and correlated with the clinical score of rigidity (i.e. Unified Parkinson's Disease Rating Scale-part III, subitems for the upper limb). The biomechanical investigation allowed us to measure 'objective rigidity' in PD and estimate the neuronal source of this phenomenon. In patients, 'objective rigidity' progressively increased along with the rise of angular velocities during robot-assisted wrist extensions. The neurophysiological examination disclosed increased long-latency reflexes, but not short-latency reflexes nor shortening reaction, in PD compared with control subjects. Long-latency reflexes progressively increased according to angular velocities only in patients with PD. Lastly, specific biomechanical and neurophysiological abnormalities correlated with the clinical score of rigidity. 'Objective rigidity' in PD correlates with velocity-dependent abnormal neuronal activity. The observations overall (i.e. the velocity-dependent feature of biomechanical and neurophysiological measures of objective rigidity) would point to a putative subcortical network responsible for 'objective rigidity' in PD, which requires further investigation.
Topics: Humans; Parkinson Disease; Muscle Rigidity; Reflex, Stretch; Reflex, Abnormal; Electromyography
PubMed: 37018058
DOI: 10.1093/brain/awad114