pregabalin and Central-Nervous-System-Diseases

Pregabalin is a specific ligand of the alpha2-delta (α2-δ) auxiliary subunit of voltage-gated calcium channels. A growing body of evidence from studies of anxiety and pain indicate that the observed responses with pregabalin may result from activity at the α2-δ auxiliary protein expressed presynaptically, in several different circuits of the central nervous system (CNS). The disorders that appear to be effectively treated with pregabalin are thematically linked by neuronal dysregulation or hyperexcitation within the CNS. This review proposes how binding to the α2-δ protein target in different regions of the CNS may contribute to the observed clinical activity of pregabalin, as well as to the adverse event profile of the compound. Whether this compound regulates synaptic function via α2-δ in additional conditions is yet to be discovered. The potential of pregabalin to regulate neuronal hyperactivity involving other CNS circuits will require further exploration.

Topics: Animals; Calcium Channel Blockers; Central Nervous System Diseases; gamma-Aminobutyric Acid; Humans; Pregabalin; Synaptic Transmission

The effective treatment of patients suffering from central neuropathic pain remains a clinical challenge, despite a standard pharmacological approach in combination with anticonvulsants and antidepressants. A randomized, double-blinded, placebo-controlled trial evaluated the effects of pregabalin on pain relief, tolerability, health status, and quality of life in patients with central neuropathic pain caused by brain or spinal cord injuries. At baseline and 4 weeks after the start of treatment subjects were evaluated with standard measures of efficacy: pain intensity measured by visual analog scale, health status (Pain Disability Index and EQ-5D) and quality of life (SF-36). Forty patients received escalating doses of either pregabalin (150, 300, and 600mg/day) or matching placebo capsules. In both groups, patients started with 1 capsule per day (either 150mg of pregabalin or placebo). If pain relief was insufficient, patients were titrated to a higher dose. There was a statistically significant decrease in mean pain score at endpoint for pregabalin treatment, compared with placebo (P=0.016). Follow-up observation showed no significant difference in Pain Disability Index scores between the two groups. The pregabalin group, however, showed a statistically significant improvement for the EQ-5D. Pregabalin treatment led to a significant improvement in the bodily pain domain of the SF36. In the other domains, more favorable scores were reported without reaching statistical significance. Pregabalin, in a flexible-dose regime, produced clinically significant reductions in pain, as well as improvements in health status in patients suffering from severe central neuropathic pain.

Topics: Central Nervous System Diseases; Double-Blind Method; Female; gamma-Aminobutyric Acid; Humans; Male; Middle Aged; Pain; Pain Measurement; Pregabalin; Quality of Life

Patients with cancer receiving pregabalin potentially have a high incidence of central nervous system (CNS) symptoms. The purpose of this study was to explore clinical factors influencing the incidence of CNS symptoms, including plasma pregabalin exposure, cancer cachexia, and opioid analgesic cotreatment.. Sixty-eight patients with cancer receiving twice-daily pregabalin were enrolled. Plasma concentrations of pregabalin, clinical laboratory data, opioid analgesic cotreatment, and the Glasgow Prognostic Score, which is an inflammation-based cachexia score, were considered as clinical factors. The incidence of CNS symptoms was collected from the patients' medical records. The predose plasma concentrations of pregabalin at steady state were determined by ultra-high-performance liquid chromatography.. The steady-state trough plasma pregabalin concentrations showed a large variability with an interquartile range of 0.43-1.2 mg/L per mg/kg and were negatively correlated with an estimated glomerular filtration rate (eGFR). C-reactive protein (standardized partial regression coefficient, β = 0.31) and opioid analgesic cotreatment (β = 0.24) were also identified in addition to eGFR (β = -0.60) in the multiple regression analysis. The incidence of CNS symptoms was significantly increased with opioid analgesic cotreatment and a higher Glasgow Prognostic Score but not with the absolute value of plasma pregabalin concentrations, eGFR, or other clinical laboratory data.. In patients with cancer, steady-state trough plasma pregabalin concentrations were altered with renal function, systemic inflammation, and opioid analgesic cotreatment. However, a higher incidence of CNS symptoms observed in patients with cancer on pregabalin was more related to cachexia and opioid analgesic cotreatment than to altered pregabalin concentrations.

Topics: Adult; Aged; Analgesics, Opioid; C-Reactive Protein; Cachexia; Central Nervous System Diseases; Female; Glomerular Filtration Rate; Humans; Male; Middle Aged; Neoplasms; Nervous System; Pain Measurement; Pregabalin

Neuropathic pain is a chronic pain condition resulting from neuronal damage, and is usually treated with pregabalin or gabapentin, which are structurally related to γ-aminobutyric acid (GABA) and are originally developed as anticonvulsant drugs. Here, we report the synthesis and pharmacology of (R)- and (S)-4-amino-3-(trimethylsilyl)methylbutanoic acids (1a and 1b), which showed analgesic activity as potent as that of pregabalin in the Chung spinal nerve ligation model. However, unlike pregabalin, 1a and 1b do not have antiepileptic effects, and they are therefore promising candidates for selective therapeutic agents to treat neuropathic pain without central nervous system-related side effects.

Topics: Analgesics; Animals; Anticonvulsants; Butyrates; Central Nervous System Diseases; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Molecular Structure; Neuralgia; Rats; Stereoisomerism; Trimethylsilyl Compounds