pregabalin and Stroke

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N-acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially "repurposable" medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury-treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose-blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecu

Topics: Acetylcysteine; Animals; Anticonvulsants; Antioxidants; Atorvastatin; Brain Injuries, Traumatic; Ceftriaxone; Dibenzazepines; Drug Repositioning; Epilepsy; Epilepsy, Post-Traumatic; Erythropoietin; Fingolimod Hydrochloride; GABA Agents; Gabapentin; Humans; Immunologic Factors; Inflammation; Interleukin 1 Receptor Antagonist Protein; Isoflurane; Levetiracetam; Losartan; Neuroprotective Agents; Oxidative Stress; Pregabalin; Pyrrolidinones; Sirolimus; Stroke; Topiramate; Translational Research, Biomedical; Vigabatrin

Patients with POAG have lower corneal endothelial cell density than healthy controls of the same age. This may be attributed to mechanical damage from elevated IOP and toxicity of glaucoma medications.. Mycophenolic acid was detected in all cats. The dose 10 mg/kg given q12h for 1 week was tolerated (n = 3). The efficacy of MMF as an immunosuppressant and long-term safety in cats of this dosage regimen is unknown.. T

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Central neuropathic pain is a painful condition, often severe, that occurs in a person who is already affected by an injury or disease of the brain or spinal cord. This dual insult is especially threatening to the quality of life of a person and their ability to perform even the most basic of tasks. Despite this high level of suffering there are relatively few trials investigating the management of central neuropathic pain. However, two randomised placebo-controlled studies have recently emerged demonstrating efficacy of pregabalin in reducing central neuropathic pain due to spinal cord injury and central poststroke pain. Pregabalin, an anticonvulsant, has been shown to be efficacious in the management of peripheral neuropathic pain of various causes and now may have a role to play in central neuropathic pain.

Topics: Analgesics; Animals; gamma-Aminobutyric Acid; Humans; Multiple Sclerosis; Neuralgia; Pregabalin; Risk Factors; Spinal Cord Injuries; Stroke; Treatment Outcome

Pregabalin has demonstrated efficacy in several forms of neuropathic pain, but its long-term efficacy in central post-stroke pain (CPSP) is unproven. We evaluated the efficacy and safety of pregabalin versus placebo in patients with CPSP. A 13-week, randomized, double-blind, multicenter, placebo-controlled, parallel group study of 150 to 600 mg/day pregabalin was conducted in patients aged ≥18 years with CPSP. The primary efficacy endpoint was the mean pain score on the Daily Pain Rating Scale over the last 7 days on study drug up to week 12 or early termination visit. Secondary endpoints included other pain parameters and patient-reported sleep and health-related quality-of-life measures. A total of 219 patients were treated (pregabalin n=110; placebo n=109). A mean pain score at baseline of 6.5 in the pregabalin group and 6.3 in the placebo group reduced at endpoint to 4.9 in the pregabalin group and 5.0 in the placebo group (LS mean difference=-0.2; 95% CI=-0.7, 0.4; P=0.578). Treatment with pregabalin resulted in significant improvements, compared with placebo, on secondary endpoints including MOS-sleep, HADS-A anxiety, and clinician global impression of change (CGIC) P<0.05. Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 9 (8.2%) of pregabalin patients versus 4 (3.7%) of placebo patients. Although pain reductions at endpoint did not differ significantly between pregabalin and placebo, improvements in sleep, anxiety, and CGIC suggest some utility of pregabalin in the management of CPSP.

Topics: Adult; Aged; Aged, 80 and over; Analgesics; Dose-Response Relationship, Drug; Double-Blind Method; Female; gamma-Aminobutyric Acid; Humans; Male; Middle Aged; Pain; Pain Measurement; Pregabalin; Stroke; Treatment Outcome

Gabapentin and pregabalin are commonly prescribed medications to treat pain in patients with diabetic neuropathy. Gabapentin and pregabalin can cause fluid retention, which is hypothesized to be associated with cardiovascular diseases. However, whether long-term use of gabapentin and pregabalin is associated with adverse cardiovascular diseases remains unknown. This study aims to examine the association between gabapentin use, pregabalin use and several adverse cardiovascular events.. This retrospective cohort study used propensity score matching within patient electronic health records (EHRs) from a multicenter database with 106 million patients from 69 health care organizations in the US. The study population comprised 210,064 patients who had a diagnosis of diabetic neuropathy and were prescribed diabetic neuropathy medications in their EHRs. The exposure cohort comprised patients who were prescribed gabapentin or pregabalin to treat diabetic neuropathy. The comparison cohort comprised patients who were not prescribed either gabapentin or pregabalin but were prescribed other drugs to treat diabetic neuropathy. The outcomes of interest were myocardial infarcts, strokes, heart failure, peripheral vascular disease, and venous thromboembolic events. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for 3-month and 5-year risk for adverse cardiovascular events between the propensity score-matched cohorts.. Both gabapentin and pregabalin were associated with increased risk of 5-year adverse cardiovascular events compared with the comparison group. In patients prescribed gabapentin, the highest risk was observed for deep venous thrombosis (HR: 1.58, 95% CI 1.37-1.82), followed by pulmonary embolism (HR: 1.5, 95% CI 1.27-1.76), peripheral vascular disease (HR: 1.37, 95% CI 1.27-1.47), stroke (HR: 1.31, 95% CI 1.2-1.43), myocardial infarction (HR: 1.25, 95% CI 1.14-1.38) and heart failure (HR: 1.14, 95% CI 1.07-1.21). In patients prescribed pregabalin, the highest risk was observed for deep venous thrombosis (HR: 1.57, 95% CI 1.31-1.88), followed by peripheral vascular disease (HR: 1.35, 95% CI 1.22-1.49), myocardial infarction (HR: 1.29, 95% CI 1.13-1.47), pulmonary embolism (HR: 1.28, 95% CI 1.04-1.59), stroke (HR: 1.26, 95% CI 1.12-1.42), and heart failure (HR: 1.2, 95% CI 1.11-1.3). There were significant associations between short-term (3 month) gabapentin use and heart failure, myocardial infarction, peripheral vascular disease, deep venous thrombosis, and pulmonary embolism. Short-term (3 month) pregabalin use was associated with deep venous thrombosis, peripheral vascular disease.. In patients with diabetic neuropathy who were prescribed gabapentin and pregabalin, there is an increased risk for heart failure, myocardial infarction, peripheral vascular disease, stroke, deep venous thrombosis, and pulmonary embolism with long-term use. Our findings suggest that increased risk for adverse cardiovascular events, along with other side effects, the efficacy of pain control and the degree of tolerance of the patient, should be considered when prescribing gabapentin and pregabalin long-term in patients with diabetic neuropathy.

Topics: Amines; Analgesics; Cardiovascular Diseases; Cyclohexanecarboxylic Acids; Diabetic Neuropathies; Gabapentin; gamma-Aminobutyric Acid; Heart Disease Risk Factors; Heart Failure; Humans; Myocardial Infarction; Pain; Peripheral Vascular Diseases; Pregabalin; Pulmonary Embolism; Retrospective Studies; Risk Factors; Stroke

Contralateral C7 nerve transfer is a new surgical treatment for stroke patients with unilateral upper extremity paralysis, but neuropathic pain in the nonparalyzed side is the common complication after surgery. We report a stroke patient with neuropathic pain after C7 nerve transfer who received combination treatment of transcutaneous electrical nerve stimulation(TENS) and pregabalin.. A 53-year old, 6 months post-stroke patient with right hemiplegia after contralateral C7 nerve transfer was admitted in our department with a significant neuropathic pain in his left upper extremity. The treatment of pregabalin and TENS were used for patient. The visual analogue scale(VAS), medical outcomes study sleep scale(. This report suggests that the combination of pregabalin and TENS have prominent clinical effects on neuropathic pain of nonparalyzed side in stroke patients after contralateral C7 nerve transfer.

Topics: Analgesics; Combined Modality Therapy; Humans; Middle Aged; Nerve Transfer; Neuralgia; Paralysis; Pregabalin; Stroke; Transcutaneous Electric Nerve Stimulation; Upper Extremity

Hyperglycemia, which reduces the efficacy of treatments and worsens clinical outcomes, is common in stroke. Ability of pregabalin to reduce neuroexcitotoxicity may provide protection against stroke, even under hyperglycemia. We investigated its protective effect against hyperglycemic stroke and its possible molecular mechanisms. Male Wistar rats administered dextrose to cause hyperglycemia, underwent middle cerebral artery occlusion for 1 h and subsequent reperfusion. Rats were treated with an intraperitoneal injection of 30 mg/kg pregabalin or an equal amount of normal saline at the onset of reperfusion (n = 16 per group). At 24 h after reperfusion, neurological deficit, infarct volume, and apoptotic cell count were assessed. Western blot analysis was performed to determine protein expression of high-mobility group box 1 (HMGB1), toll-like receptor-4 (TLR-4), phosphorylated nuclear factor-kappa B (p-NF-κB), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α), phosphorylated inducible and endothelial nitric oxide synthase (p-iNOS, p-eNOS), Bcl-2, Bax, Cytochrome C, and caspase-3 in the brain. Pregabalin-treated rats showed significantly improved neurological function (31% decrease in score), reduced infarct size (by 33%), fewer apoptotic cells (by 63%), and lower expression levels of HMGB1, TLR4, p-NF-κB, IL-1β, and TNF- α, compared with control rats. Decreased p-iNOS and increased p-eNOS expressions were also observed. Expression of Bax, Cytochrome C, and cleaved caspase-3/caspase3 was significantly downregulated, while Bcl-2 expression was increased by pregabalin treatment. Pregabalin administration upon reperfusion decreased neuronal death and improved neurological function in hyperglycemic stroke rats. Cogent mechanisms would include attenuation of HMGB1/TLR-4-mediated inflammation and favorable modulation of the NOS.

Topics: Animals; Apoptosis; Brain; Brain Infarction; Cytokines; Disease Models, Animal; HMGB1 Protein; Hyperglycemia; Injections, Intraperitoneal; Male; Neuroprotective Agents; NF-kappa B; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Pregabalin; Rats; Rats, Wistar; Reperfusion Injury; Stroke; Toll-Like Receptor 4

In view of the paucity of studies on central poststroke pain (CPSP), in this hospital-based prospective study, we evaluated the frequency, the spectrum, imaging, and quantitative sensory testing in a cohort of stroke patients with CPSP.. Stroke patients who developed CPSP at onset or during follow-up were included. Patients were subjected to clinical evaluation and sensory testing. The severity of stroke was defined by the Modified Rankin Scale and disability by the Barthel Index. Quantitative sensory testing included monofilament testing and evaluation for static and dynamic mechanical allodynia, punctuate hyperalgesia, temporal summation, cold allodynia, and cold hyperalgesia. Sleep, anxiety, and depression were also evaluated. Patients were treated with pregabalin 150 to 600 mg/d and good response was defined as >50% improvement in the VAS score. CPSP symptoms were correlated with demographic information, sensory findings, and imaging findings.. A total of 319 patients with stroke were evaluated. CPSP occurred in 66 (20.7%) of them. The median age of the CPSP patients was 55 years (range, 25 to 80 y). About 31.8% patients were female. The onset, the duration, and the distribution of pain were variable. The severity of symptoms did not correlate with demographic variables and the site of lesion. Spinothalamic sensations were normal in 42.3% patients. On treatment with pregabalin (150 to 600 mg), half of the patients had a good response.. CPSP was present in 20.7% of the stroke patients. Spinothalamic tract dysfunction may not be necessary for the development of CPSP, and it can also be seen with normal spinothalamic sensation. The location of the stroke, its type and quality, and the severity of CPSP were not related.

Topics: Adult; Aged; Aged, 80 and over; Analgesics; Anxiety; Brain Ischemia; Cold Temperature; Depression; Female; Follow-Up Studies; Humans; Hyperalgesia; Intracranial Hemorrhages; Male; Middle Aged; Pain Measurement; Pregabalin; Prospective Studies; Severity of Illness Index; Sleep; Stroke; Touch

To analyze the results of examination and treatment of patients with poststroke shoulder pain.. The study included 213 patients who have had a stroke, including 16.4% patients with poststroke shoulder pain in early recovery period and 35.9% patients with poststroke shoulder pain in late recovery period. Therapeutic efficacy of amitriptyline, lidocaine (intravenously), pregabalin, tizanidine and non-steroid anti-inflammatory drugs was assessed.. Dysfunction of nervous system plays the main role in this pain syndrome. The efficacy of the drugs in the early/late recovery period was estimated as follows: nonsteroidal anti-inflammatory drugs - 33%/12%, amitriptyline - 24%/42%, gabapentin - 10%/13%, lidocaine - 95%/100%, tizanidine - 29%/33%. Seventy-six percent of patients were free of pain after treatment using a regimen suggested by the authors.. Цель исследования - изучение случаев постинсультной боли в области плеча (ПИБОП). Были обследованы и лечились 213 пациентов, перенесших церебральный инсульт. ПИБОП имелась у 16,4% пациентов в раннем восстановительном периоде и 35,9% - в позднем. Установлено, что ведущую роль в ее возникновении играет дисфункция нервной системы, проявляющаяся наличием нейропатического болевого синдрома. Оценивали терапевтическую эффективность применения амитриптилина, лидокаина (внутривенно), прегабалина, тизанидина и нестероидных противовоспалительных препаратов. Их эффективность в раннем и позднем восстановительном периодах была следующей: нестероидные противовоспалительные средства - 33 и 12% соответственно, амитриптилин - 24 и 42%, габапентин - 10 и 13%, лидокаин - 95 и 100%, тизанидин - 29 и 33%. Полное устранение боли при использовании предложенного алгоритма лечения отмечено у 76% пациентов.

Topics: Amines; Amitriptyline; Anti-Inflammatory Agents; Clonidine; Cyclohexanecarboxylic Acids; Drug Therapy, Combination; Female; Gabapentin; gamma-Aminobutyric Acid; Humans; Lidocaine; Male; Pregabalin; Shoulder Pain; Stroke

The study was designed to compare the efficacy of pregabalin, an anticonvulsant on pain behavior of stroke patients with shoulder pain in a comparative study with ultrasound therapy and ultimately to recommend a better treatment option to improve pain and function in post stroke shoulder pain. This study was carried out in a private neurology Hospital in Dhaka during January to December 2010. Data were collected from 70 post stroke patients with shoulder pain and were divided into two groups. The patients in Group A were treated with pregabalin 100mg twice daily along with therapeutic ultrasound 10 minutes daily and group B were treated with therapeutic ultrasound alone for the same dose and duration. Pain free range of motion exercise was given to both groups as the therapeutic exercise. Pain parameters in the form of VAS were measured at one and two weeks and were compared. Seventy one percent of the patients were male with 80% were above 60 years old. Pain scoring in VAS of 100 was 21.32±6.01 in group A and 41±4.58 in groups B at the end of two weeks assuming the pretreatment VAS of all patients as 100. Marked improvement in shoulder pain were observed in both groups and Group A had better improvement in pain than group B. Therapeutic ultrasound when given with pregabalin found to have added benefit over therapeutic ultrasound alone in post stroke shoulder pain. Differences were statistically significant.

Topics: Adult; Aged; Analgesics; Female; gamma-Aminobutyric Acid; Humans; Male; Middle Aged; Pregabalin; Shoulder Pain; Stroke; Ultrasonic Therapy; Visual Analog Scale

Pregabalin, a Ca(2+) channel α(2)δ-subunit antagonist with analgesic and antiepileptic activity, reduced neuronal loss and improved functional outcome in a mouse model of focal ischemic stroke. Pregabalin administration (5-10mg/kg, i.p.) 30-90 min after transient middle cerebral artery occlusion/reperfusion reduced infarct volume, neuronal death in the ischemic penumbra and neurological deficits at 24h post-stroke. Pregabalin significantly decreased the amount of Ca(2+)/calpain-mediated α-spectrin proteolysis in the cerebral cortex measured at 6h post-stroke. Together with the extensive clinical experience with pregabalin for other neurological indications, our findings suggest the potential for a therapeutic benefit of pregabalin in stroke patients.

Topics: Animals; Calcium; Dose-Response Relationship, Drug; gamma-Aminobutyric Acid; Male; Mice; Mice, Inbred C57BL; Pregabalin; Proteolysis; Stroke; Treatment Outcome

Topics: Analgesics; gamma-Aminobutyric Acid; Humans; Pain; Pregabalin; Stroke

In nonlinear mixed effects modeling using NONMEM, mixture models can be used for multimodal distributions of parameters. The fraction of individuals belonging to each of the subpopulations can be estimated, and the most probable subpopulation for each patient is output (MIXEST(k)). The objective function value (OFV) that is minimized is the sum of the OFVs for each patient (OFV(i)), which in turn is the sum across the k subpopulations (OFV(i,k)). The OFV(i,k) values can be used together with the total probability in the population of belonging to subpopulation k to calculate the individual probability of belonging to the subpopulation (IP(k)). Our objective was to explore the information gained by using IP(k) instead of or in addition to MIXEST(k) in the analysis of mixture models. Two real data sets described previously by mixture models as well as simulations were used to explore the use of IP(k) and the precision of individual parameter values based on IP(k) and MIXEST(k). For both real data-based mixture models, a substantial fraction (11% and 26%) of the patients had IP(k) values not close to 0 or 1 (IP(k) between 0.25 and 0.75). Simulations of eight different scenarios showed that individual parameter estimates based on MIXEST were less precise than those based on IP(k), as the root mean squared error was reduced for IP(k) in all scenarios. A probability estimate such as IP(k) provides more detailed information about each individual than the discrete MIXEST(k). Individual parameter estimates based on IP(k) should be preferable whenever individual parameter estimates are to be used as study output or for simulations.

Topics: Algorithms; Anticonvulsants; Chlormethiazole; Computer Simulation; Decision Making; Decision Support Techniques; Epilepsy; gamma-Aminobutyric Acid; Humans; Hypnotics and Sedatives; Likelihood Functions; Monitoring, Physiologic; Nonlinear Dynamics; Patients; Poisson Distribution; Pregabalin; Probability; Randomized Controlled Trials as Topic; Software; Stroke

Topics: Animals; Antiparkinson Agents; Carbazoles; gamma-Aminobutyric Acid; Humans; Indoles; Neuroprotective Agents; Pain; Peripheral Nervous System Diseases; Pregabalin; Prodrugs; Stroke