Treatment of cholinergic-induced status epilepticus with polytherapy targeting GABA and glutamate receptors.

Despite new antiseizure medications, the development of cholinergic-induced refractory status epilepticus (RSE) continues to be a therapeutic challenge as pharmacoresistance to benzodiazepines and other antiseizure medications quickly develops. Studies conducted by Epilepsia. 2005;46:142 demonstrated that the initiation and maintenance of cholinergic-induced RSE are associated with trafficking and inactivation of gamma-aminobutyric acid A receptors (GABAA R) thought to contribute to the development of benzodiazepine pharmacoresistance. In addition, Dr. Wasterlain's laboratory reported that increased N-methyl-d-aspartate receptors (NMDAR) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) contribute to enhanced glutamatergic excitation (Neurobiol Dis. 2013;54:225; Epilepsia. 2013;54:78). Thus, Dr. Wasterlain postulated that targeting both maladaptive responses of reduced inhibition and increased excitation that is associated with cholinergic-induced RSE should improve therapeutic outcome. We currently review studies in several animal models of cholinergic-induced RSE that demonstrate that benzodiazepine monotherapy has reduced efficacy when treatment is delayed and that polytherapy with drugs that include a benzodiazepine (eg midazolam and diazepam) to counter loss of inhibition, concurrent with an NMDA antagonist (eg ketamine) to reduce excitation provide improved efficacy. Improved efficacy with polytherapy against cholinergic-induced seizure is demonstrated by reduction in (1) seizure severity, (2) epileptogenesis, and (3) neurodegeneration compared with monotherapy. Animal models reviewed include pilocarpine-induced seizure in rats, organophosphorus nerve agent (OPNA)-induced seizure in rats, and OPNA-induced seizure in two mouse models: (1) carboxylesterase knockout (Es1-/- ) mice which, similarly to humans, lack plasma carboxylesterase and (2) human acetylcholinesterase knock-in carboxylesterase knockout (KIKO) mice. We also review studies showing that supplementing midazolam and ketamine with a third antiseizure medication (valproate or phenobarbital) that targets a nonbenzodiazepine site rapidly terminates RSE and provides further protection against cholinergic-induced SE. Finally, we review studies on the benefits of simultaneous compared with sequential drug treatments and the clinical implications that lead us to predict improved efficacy of early combination drug therapies. The data generated from seminal rodent studies of efficacious treatment of cholinergic-induced RSE conducted under Dr. Wasterlain's guidance suggest that future clinical trials should treat the inadequate inhibition and temper the excess excitation that characterize RSE and that early combination therapies may provide improved outcome over benzodiazepine monotherapy.

Stem bark chloroform extract of Bombax costatum Pellegr. & Vuillet exhibit anticonvulsant and neuroprotective effects in pentylenetetrazole-induced seizures in rats.

AIM OF THE STUDY: The study aimed at evaluating the potentials of stem bark extracts of Bombax costatum (B. costatum) on seizure, pentylenetetrazole (PTZ) induced kindling and associated changes in wistar albino rats. MATERIALS AND METHODS: Phase 1 evaluated which extract of B. costatum (chloroform, ethanol and n-hexane) is most effective in preventing seizure in acute PTZ-induced (85mg/kg) seizure in rats. Phase 2 evaluated the potentials of stem bark chloroform extract of B. costatum in PTZ-kindled rats at a dose 250 and 500mg/kg in comparison to diazepam. As its effects on memory, oxidative stress markers, neurotransmitters and brain histology were evaluated. Phase 3 determined the probable curative effects of B. costatum on fully kindled rats. RESULTS: In phase 1, Chloroform extract of B. coststum 500mg/kg is the most effective (P<0.05) in preventing seizure as compared to ethanol and n-hexane extracts. In phase 2, chloroform extract of B. costatum delayed the development of kindling, improved kindling associated cognitive impairment and alterations of glutamate and gamma-aminobutyric acid (GABA). Further, it attenuated oxidative stress besides the maintenance of neuronal architecture of the hippocampus. CONCLUSION: Conclusively, chloroform stem bark extract of B. costatum antagonizes PTZ-induced seizure progression, protects against kindling induced cognitive impairment and oxidative stress. Additionally, it also increases the brain level of GABA at high dose and prevented against kindling-induced hippocampal disruptions. Hence, this justifies its use traditionally in the treatment of epileptic seizures.

[Hepatotoxicity probably associated with gabapentin]. / Hepatotoxicidad probablemente asociada a gabapentina.

BACKGROUND: Gabapentin is an anticonvulsant medication used as an adjuvant in the treatment of neuropathic pain; few cases have been reported in which it causes acute liver injury. CLINICAL CASE: 56-year-old male patient with a history of chronic kidney disease on hemodialysis and narrowing of the spinal canal under treatment with gabapentin, who presented acute liver injury probably secondary to a dose of gabapentin; however, it remitted with the suspension of said drug. CONCLUSION: Gabapentin lacks liver metabolism; the mechanism by which it produces liver injury is still unknown; however, there are reports of hepatotoxicity associated with its administration, so its use must be individualized for each patient.

INTRODUCCIÓN: la gabapentina es un fármaco anticonvulsivante utilizado como adyuvante en el tratamiento del dolor neuropático; se han reportado pocos casos en los cuales es causa de lesión hepática aguda. CASO CLÍNICO: paciente masculino de 56 años de edad con antecedente de enfermedad renal crónica en hemodiálisis y diagnóstico de canal lumbar estrecho en tratamiento con gabapentina, quien presentó lesión hepática aguda, probablemente secundaria a la dosis de gabapentina; sin embargo, remitió posterior a la suspensión de dicho fármaco. CONCLUSIÓN: la gabapentina carece de metabolismo hepático; el mecanismo por el cual produce lesión hepática aún es desconocido; sin embargo, existen reportes de hepatotoxicidad asociada a su administración, por lo que su utilización deberá individualizarse para cada paciente.

Evaluation of Gamma Amino Butyric Acid (GABA) and Glibenclamide Combination Therapy in Streptozotocin Induced Diabetes.

BACKGROUND: Type 1-diabetes (T1D) is characterized by autoimmune destruction of ß-cells and loss of endogenous insulin. A lifelong dependency on exogenous supply of insulin presents a great challenge in the pharmacotherapy of T1D that elicits a quest for alternative therapies, which can protect ß-cells and revive their insulinogenic functions. GABA (γ-aminobutyric acid) has immunoprotective and ß-cell regenerative capabilities. Co-administration of an insulin secretagogue, such as glibenclamide (Glib), along with GABA may enhance the pancreatic insulin output in T1D. OBJECTIVE: The present study evaluated the possible mechanism of GABA in the improvement of glucose tolerance and its effects in streptozotocin (STZ) induced T1D along with Glib. METHODS: Wistar rats (180-220 g) were administered a single dose of STZ (55 mg/kg, i.p.). GABA (100 mg/kg, i.p.) and Glib (5 or 10 mg/kg, i.p.) alone or in combination were administered for 28 days. Body weight (b.w.), water consumption, fasting blood glucose (FBG), oral glucose tolerance, plasma lipids, insulin, and muscle GLUT-4 (glucose transporters) protein level were assessed. RESULTS: T1D significantly decreased b.w. and increased water-intake in rats. An increase in FBG and a decrease in plasma insulin and muscle GLUT-4 indicated STZ-triggered destruction of ß-cells in diabetic rats accompanied with dyslipidemia. GABA or Glib (10 mg/kg) significantly improved b.w., plasma insulin and GLUT-4 levels, and ameliorated FBG and blood lipid profile in diabetic rats. GABA and Glib (5 mg/kg) combination therapy achieved far better control over hyperglycemia and related pathogenic conditions (b.w., water-intake, insulin, GLUT-4, lipids). The anti-diabetic effect of combination therapy was significantly more pronounced in comparison to individual drug treatments. Histopathological analysis revealed an increase in the number of functional pancreatic-islets by combination therapy. CONCLUSION: GABA revitalized ß-cells against STZ-toxicity. GABA and Glib synergistically augmented insulin secretion that can be used to manage T1D and its complications. GABA has the potential to remarkably enhance the therapeutic outcome in diabetic patients and reduce the dose of existing anti-diabetic drugs such as Glib.

Phenibut (ß-Phenyl-γ-Aminobutyric Acid): an Easily Obtainable "Dietary Supplement" With Propensities for Physical Dependence and Addiction.

PURPOSE OF REVIEW: Phenibut (ß-phenyl-γ-aminobutyric acid) is a psychoactive GABA analogue currently being marketed online as an anxiolytic and nootropic dietary supplement. Its use is growing in popularity, but its pharmacological activity is well beyond that of a conventional nutritional supplement, and similar to that of a prescription strength sedative. This review will focus on the potential adversities of phenibut use and will discuss what treatment options may be beneficial to afflicted patients. RECENT FINDINGS: Over the last several years, multiple case reports have highlighted phenibut's potential to produce the conditions of physical dependence, withdrawal, and addiction. In cases involving intoxication, patients have presented with a varying degree of mental status changes, from being minimally responsive to manifesting symptoms of an agitated delirium. Phenibut is a potent psychoactive substance with GABAB agonist properties, which is emerging as a drug of misuse through growing internet sales. Its marketing as a "dietary supplement" is inaccurate and misleading, given its pharmacological profile and ability to induce the physiological changes associated with withdrawal and physical dependence.

Gabapentin dose and the 30-day risk of altered mental status in older adults: A retrospective population-based study.

Gabapentin is an effective treatment for chronic neuropathic pain but may cause dizziness, drowsiness, and confusion in some older adults. The goal of this study was to assess the association between gabapentin dosing and adverse outcomes by obtaining estimates of the 30-day risk of hospitalization with altered mental status and mortality in older adults (mean age 76 years) in Ontario, Canada initiated on high dose (>600 mg/day; n = 34,159) compared to low dose (≤600 mg/day; n = 76,025) oral gabapentin in routine outpatient care. A population-based, retrospective cohort study assessing new gabapentin use between 2002 to 2014 was conducted. The primary outcome was 30-day hospitalization with an urgent head computed tomography (CT) scan in the absence of evidence of stroke (a proxy for altered mental status). The secondary outcome was 30-day all-cause mortality. The baseline characteristics measured in the two dose groups were similar. Initiation of a high versus low dose of gabapentin was associated with a higher risk of hospitalization with head CT scan (1.27% vs. 1.06%, absolute risk difference 0.21%, adjusted relative risk 1.29 [95% CI 1.14 to 1.46], number needed to treat 477) but not a statistically significant higher risk of mortality (1.25% vs. 1.16%, absolute risk difference of 0.09%, adjusted relative risk of 1.01 [95% CI 0.89 to 1.14]). Overall, the risk of being hospitalized with altered mental status after initiating gabapentin remains low, but may be reduced through the judicious use of gabapentin, use of the lowest dose to control pain, and vigilance for early signs of altered mental status.

Efficacy and safety of combined low doses of either diclofenac or celecoxib with gabapentin versus their single high dose in treatment of neuropathic pain in rats.

Neuropathic pain is a worldwide health problem with no consensus regarding its optimal therapy. This study compared the analgesic effect and gastric, hepatic, and renal safety of combined low doses of diclofenac and celecoxib with gabapentin versus their individual high doses in the treatment of neuropathic pain in rats. Left sciatic nerve ligation was used as neuropathic pain model. Rats were allocated into 7 groups (7 rats for each): sham control; model group (received vehicle); Gaba-group (received gabapentin (100 mg/kg /day); Diclo 10-group (received diclofenac (10 mg/kg); Cele 10-group (received celecoxib (10 mg/kg/day); Gaba + Diclo 5 (receivedgabapentin(100 mg/kg /day) plus diclofenac (5 mg/kg); Gaba + Cele 5 (received gabapentin (100 mg/kg/day) plus celecoxib (5 mg/kg)). The analgesic effect was assessed using both hot plate and acetone tests. The impact of the used drugs on peptic ulcer index, liver enzymes, and serum urea and creatinine was evaluated, along with histopathological examination and oxidative stress parameters. Combination therapy of low dose of either diclofenac or celecoxib, with gabapentin showed higher analgesic effect compared with their individual high doses as indicated by prolonged response time in hot plate test and decreased frequency of paw withdrawal in acetone test. Their effect was associated with gentle effect on gastric mucosa, renal and hepatic integrity and oxidative stress parameters. In conclusion, the use of combined low doses of either diclofenac or celecoxib with gabapentin is better than high dose monotherapy regarding both the efficacy and safety.

Benefits and safety of gabapentinoids in chronic low back pain: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND OBJECTIVE: Chronic Low Back Pain (CLBP) is very common, with a lifetime prevalence between 51% and 80%. In majority, it is nonspecific in nature and multifactorial in etiology. Pregabalin (PG) and Gabapentin (GB) are gabapentinoids that have demonstrated benefit in neuropathic pain conditions. Despite no clear rationale, they are increasingly used for nonspecific CLBP. They necessitate prolonged use and are associated with adverse effects and increased cost. Recent guidelines from the National Health Service (NHS), England, expressed concerns on their off-label use, in addition to the risk of misuse. We aimed to assess the effectiveness and safety of gabapentinoids in adult CLBP patients. METHODS: Electronic databases of MEDLINE, EMBASE, and Cochrane were searched from their inception until December 20th, 2016. We included randomized control trials reporting the use of gabapentinoids for the treatment of CLBP of >3 months duration, in adult patients. Study selection and data extraction was performed independently by paired reviewers. Outcomes were guided by Initiative on Methods, Measurement and Pain Assessment in Clinical Trials guidelines, with pain relief and safety as the primary outcomes. Meta-analyses were performed for outcomes reported in 3 or more studies. Outcomes were reported as mean differences (MDs) or risk ratios (RRs) with their corresponding 95% confidence intervals (CIs), and I2 in percentage representing the percentage variability in effect estimates that could be explained by heterogeneity. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was used to assess the quality of evidence. RESULTS: Out of 1,385 citations, eight studies were included. Based on the interventions and comparators, studies were analyzed in 3 different groups. GB compared with placebo (3 studies, n = 185) showed minimal improvement of pain (MD = 0.22 units, 95% CI [-0.5 to 0.07] I2 = 0%; GRADE: very low). Three studies compared PG with other types of analgesic medication (n = 332) and showed greater improvement in the other analgesic group (MD = 0.42 units, 95% CI [0.20 to 0.64] I2 = 0; GRADE: very low). Studies using PG as an adjuvant (n = 423) were not pooled due to heterogeneity, but the largest of them showed no benefit of adding PG to tapentadol. There were no deaths or hospitalizations reported. Compared with placebo, the following adverse events were more commonly reported with GB: dizziness-(RR = 1.99, 95% CI [1.17 to 3.37], I2 = 49); fatigue (RR = 1.85, 95% CI [1.12 to 3.05], I2 = 0); difficulties with mentation (RR = 3.34, 95% CI [1.54 to 7.25], I2 = 0); and visual disturbances (RR = 5.72, 95% CI [1.94 to 16.91], I2 = 0). The number needed to harm with 95% CI for dizziness, fatigue, difficulties with mentation, and visual disturbances were 7 (4 to 30), 8 (4 to 44), 6 (4 to 15), and 6 (4 to 13) respectively. The GRADE evidence quality was noted to be very low for dizziness and fatigue, low for difficulties with mentation, and moderate for visual disturbances. Functional and emotional improvements were reported by few studies and showed no significant improvements. CONCLUSIONS AND RELEVANCE: Existing evidence on the use of gabapentinoids in CLBP is limited and demonstrates significant risk of adverse effects without any demonstrated benefit. Given the lack of efficacy, risks, and costs associated, the use of gabapentinoids for CLBP merits caution. There is need for large high-quality trials to more definitively inform this issue. TRIAL REGISTRATION: PROSPERO CRD42016034040.

Clostridium difficile infection induced by pregabalin-associated agranulocytosis.

A 33-year-old man who had recently undergone surgery for cervical spondylotic myelopathy was prescribed pregabalin for neuralgia, and the dose was increased to 600 mg/day during hospitalization. However, the patient was diagnosed with a Clostridium difficile infection on day 34 after admission. A complete blood count showed agranulocytosis (neutrophil count: 105/µL). We did not observe any changes in vital signs, a relative increase in band cells, or intestinal edema. The patient's agranulocytosis resolved after withdrawing pregabalin. This is the first reported case of agranulocytosis associated with pregabalin. Periodic monitoring of the white blood cell count is therefore considered to be useful in patients receiving high-dose pregabalin therapy.

Analgesia for the cirrhotic patient: a literature review and recommendations.

The choice of analgesic agent in cirrhotic patients is problematic and must be individualized taking into account several factors including severity of liver disease, history of opioid dependence, and potential drug interactions. With a cautious approach including slow dose up-titration and careful monitoring, effective analgesia can be achieved in most cirrhotic patients without significant side effects or decompensation of their liver disease. Paracetamol is safe in patients with chronic liver disease but reduced doses of 2-3 grams daily is recommended for long-term use. Non-steroidal anti-inflammatory drugs are best avoided because of risk of renal impairment, hepatorenal syndrome, and gastrointestinal hemorrhage. Opioids have an increased risk of toxicity particularly in patients with hypoalbuminaemia, and immediate-release as opposed to controlled-release formulations are advised. Co-prescription of laxatives is mandatory to avoid constipation and encephalopathy. Adjuvant analgesics such as tricyclic antidepressants and anti-convulsants may be used cautiously for cirrhotic patients with neuropathic pain. Gabapentin or pregabalin may be better tolerated in cirrhosis because of non-hepatic metabolism and a lack of anti-cholinergic side effects.

Perverted head-shaking and positional downbeat nystagmus in pregabalin intoxication.

Dizziness and ataxia are known adverse effects of pregabalin, but characteristic oculomotor signs in pregabalin intoxication have not been reported. Here we describe a patient who displayed perverted head-shaking and positional downbeat nystagmus after prescription of a high dosage of pregabalin. Since pregabalin reduces excitatory neurotransmitter secretion in the central nervous system, decreased excitatory inputs from the brainstem may lead to cerebellar dysfunction, causing perverted head-shaking and positional downbeat nystagmus.

Donepezil provides positive effects to patients treated with gabapentin for neuropathic pain: an exploratory study.

BACKGROUND: The first-line medication gabapentin and the acetylcholinesterase inhibitor donepezil represent a new promising combination to improve treatment outcomes for patients with severe neuropathic pain. The drugs have previously shown synergism following co-administration in nerve-injured rats. METHODS: The clinical relevance of adding donepezil to existing gabapentin treatment in patients with post-traumatic neuropathic pain was explored in this open-label study. The study comprised two consecutive periods of minimum 6 weeks: (1) titration of gabapentin to the highest tolerable dose or maximum 2400 mg daily, and (2) addition of donepezil 5 mg once daily to the fixed gabapentin dose. Efficacy and tolerability were assessed by ratings of pain intensity, questionnaires for pain and health-related quality of life, and reporting of adverse events. Pain scores were also analysed using mixed-effects analysis with the software NONMEM to account for intersubject variability. RESULTS: Eight patients commenced treatment with donepezil, of which two withdrew because of adverse events. Addition of donepezil resulted in clinically relevant reductions of pain (> 11 units on a 0-100 scale) and improved mental wellness in three of six patients. The remaining three patients had no obvious supplemental effect. Mixed-effects analysis revealed that pain scores were significantly lower during co-administration (P < 0.0001 combination vs. monotherapy). CONCLUSION: Donepezil may provide additional analgesia to neuropathic pain patients with insufficient pain relief from gabapentin as monotherapy. The promising results support controlled clinical trials of the drug combination. The usefulness of mixed-effects analysis in small-scale trials and/or for data with high intersubject variability was also demonstrated.

[Promising effects of pregabalin in the treatment of oxaliplatin-induced sensory neuropathy in patients with colorectal carcinoma].

Thirteen patients with metastatic colorectal cancer who suffered from oxaliplatin-induced sensory neuropathy were evaluated to determine the neuropathy Grade before and after the administration of pregabalin. All patients received oxaliplatin as adjuvant or first-line chemotherapy. The mFOLFOX6 and CapeOX groups included 3 and 10 cases, respectively, and the average treatment regimens were 8 and 5 doses, respectively. Before receiving pregabalin, sensory neuropathy was classified as Grade 3 in 2 patients, as Grade 2 in 8 patients, and as Grade 1 in 3 patient. The average amount of pregabalin administered to patients was 237 (range: 150-450) mg. After administering pregabalin, we observed improvements in 8 neuropathy cases (61. 5%)within approximately 2 weeks. All side effects were mild. In this study, pregabalin was shown to positively impact sensory neuropathy resulting from oxaliplatin treatment and to enable the long-term use of oxaliplatin-based chemotherapy.

Randomised phase II trial (NCT00637975) evaluating activity and toxicity of two different escalating strategies for pregabalin and oxycodone combination therapy for neuropathic pain in cancer patients.

PURPOSE: Neuropathic pain is commonly associated with cancer. Current treatments include combination opioid and adjuvant therapies, but no guidelines are available for dose escalation strategies. This phase II study compared the efficacy and tolerability of two dose escalation strategies for oxycodone and pregabalin combination therapy. METHODS: Patients (N = 75) with oncological neuropathic pain, previously untreated with pregabalin, were recruited in 5 Italian institutions between 2007 and 2010. Patients were randomised to two different dose escalation strategies (arm A; N = 38) oxycodone at a fixed dose with increasing pregabalin doses; (arm B; N = 37) pregabalin at a fixed dose with increasing oxycodone doses. Patients were evaluated from daily diaries and follow-ups at 3, 7, 10, and 14 days after beginning treatment with a numerical rating scale (NRS), neuropathic pain scale (SDN), and well-being scale (ESAS). The primary endpoint was a ≥1/3 reduction in pain (NRS); secondary endpoints included the time to analgesia and adverse effects. The study had a 90% probability of detecting the best strategy for a true difference of at least 15%. RESULTS: More patients in arm A (76%) than arm B (64%) achieved ≥1/3 overall pain reduction even after controlling for baseline factors (gender, baseline pain). Group A reported fewer side effects than group B; constipation 52.8% vs. 66.7%; nausea: 27.8% vs. 44.4%; drowsiness: 44.4% vs. 55.6%; confusion: 16.7% vs. 27.8%; itching: 8.3% vs. 19.4%. CONCLUSIONS: Both strategies effectively controlled neuropathic pain, but according to the adopted selection design arm A is preferable to arm B for pain control. TRIAL REGISTRATION: ClinicalTrials.gov NCT00637975.

Real-world treatment of post-herpetic neuralgia with gabapentin or pregabalin.

BACKGROUND AND OBJECTIVES: There are limited data examining the real-world use of gabapentin and pregabalin for the treatment of post-herpetic neuralgia (PHN). This study examines dosing patterns, therapy outcomes, healthcare utilization and costs of patients with PHN who initiate treatment with gabapentin or pregabalin. METHODS: This was a retrospective administrative claims data analysis from July 2005 to February 2010. Patients with PHN initiating gabapentin or pregabalin (index therapy) from January 2006 to February 2009 were identified and were observed for 12 months after index therapy initiation. Outcomes were mean daily dosages of the index therapy, attainment of minimally effective dosages of gabapentin (≥ 1,800 mg/day) or pregabalin (≥ 150 and ≥ 300 mg/day) persistence, discontinuation, index therapy switching, addition of neuropathic pain medications to index therapy, and healthcare resource use and costs. RESULTS: 1,645 patients were identified. The mean daily dosage was 826 mg for gabapentin and 187 mg for pregabalin. Only 52.6 % of patients initiating gabapentin and 56.9 % initiating pregabalin obtained a refill during the post-index period. Approximately 14 % of patients treated with gabapentin reached the target dosage (1,800 mg/day). For pregabalin, 87 % reached ≥ 150 mg/day and 27 % reached ≥ 300 mg/day. On average, patients took 10 weeks to reach 1,800 mg/day gabapentin, and 5.0 and 9.2 weeks to reach ≥ 150 mg/day and ≥ 300 mg/day pregabalin, respectively. Approximately one-third of patients in both index therapy cohorts added a pain medication; more than half added opioids. The percentage of patients switching from either drug (57 %) or adding a therapy (34 %) were similar between index therapy cohorts; opioids were the most common therapy patients switched to or added. CONCLUSION: It appears that gabapentin and pregabalin are not used effectively to treat PHN. Suboptimal dosing and discontinuation may be associated with supplementary use of other analgesics, especially opioids.

[Efficacy of vision correcting system "focus" for prevention and treatment of dry form of age macular degeneration].

The results of comparative study of efficacy and safety of vision correcting system "Focus" and Picamilon in patients with dry form of age macular degeneration are presented. 60 patients were enrolled into the study, follow-up was 3 months. Routine examination revealed positive impact of "Focus" on dynamics of main visual functions (visual acuity and field). In terms of impact on dynamics of main visual functions "Focus" is comparable with Picamilon, though it is better tolerated. Intake of vision correcting system "Focus" promotes visual functions improvement and prevents progressing of retinal degenerations.

A double-blind randomized crossover study to evaluate the timing of pregabalin for third molar surgery under local anesthesia.

PURPOSE: This double-blind randomized crossover study compared the analgesic efficacy of pre- and postoperative administration of oral pregabalin 75 mg using a postsurgical dental pain model. MATERIALS AND METHODS: Patients requiring third molar surgery in 2 separate stages under local anesthesia were recruited. They were given pregabalin 75 mg either 1 hour before or after their first surgical extraction. They then received the same dose of pregabalin at their second surgical extraction, but those who received it before surgery received it postsurgery, and vice versa. Postoperative analgesic effects were assessed at postoperative hours 2, 4, 8, 12, 24, 48, and 72. Time to first analgesic, analgesic consumption and adverse events were also evaluated. RESULTS: Forty patients were recruited, and 34 completed the study. The area under curves for numerical rating scale pain scores 1 to 24 hours were significantly lower at rest but not during mouth opening for patients receiving postoperative pregabalin (P < .048). Pain relief was similar for the period of 24 to 72 hours. No significant difference was found in time to first analgesic, total analgesic consumption, and side effects between preoperative and postoperative groups. No difference in the incidence of adverse events was noticed in relation to the timing of pregabalin administration. CONCLUSIONS: Postoperative administration of oral pregabalin 75 mg appears to offer better analgesic efficacy than preoperative administration after third molar surgery under local anesthesia.

An open-label, add-on study of pregabalin in patients with partial seizures: a multicenter trial in Greece.

INTRODUCTION: Pregabalin efficacy and safety as an adjunctive treatment for partial seizures was evaluated using an open-label, flexible-dose. STUDY DESIGN: In 98 adults with refractory partial epilepsy taking 1-3 anti-epileptic drugs with ≥2 seizures during an 8-week baseline period. METHODS: Pregabalin was increased to ≤600 mg/day during a 9-week dose optimization period with dosage maintained for 12 additional weeks. Primary endpoint was the percentage change in partial seizure frequency between the 8-week baseline and 12-week observation period. RESULTS: Pregabalin treatment was associated with a significant reduction in partial seizure frequency: median percent change in partial seizure frequency from baseline to 12 weeks was -33% and -22% in patients with a baseline seizure frequency of ≤3 and >3 per 28 days, respectively. The 50% and 75% responder rates were 41.94% (95% CI: 31.91-51.96) and 30.11% (95% CI: 20.78-39.43), respectively. Nineteen percent of subjects were seizure-free throughout the last 12 weeks. Pregabalin administration resulted in a significant reduction in anxiety (mean reduction in Hospital Anxiety and Depression Scale scores of 1.68 units, 95% CI: -2.60 to -0.76). Most patients were much improved or very much improved on Patient Global Impression of Change (53.8%) and Clinical Global Impression of Change (53.8%). The most frequently self-reported adverse events (AEs) were mild or moderate somnolence (20.4%) and dizziness (5.1%) with a low AE discontinuation rate (5.1%). CONCLUSIONS: The efficacy and side-effect profile of pregabalin were similar to previous pregabalin double-blind, controlled studies. Additionally, pregabalin, as an add-on treatment for partial epilepsy, exhibits significant anti-anxiety properties.

Pregabalin reduces pain in patients with chronic pancreatitis in a randomized, controlled trial.

BACKGROUND & AIMS: Pain is a disabling symptom for patients with chronic pancreatitis (CP) and difficult to treat. Evidence from basic science and human studies indicates that pain processing by the central nervous system is abnormal and resembles that observed in patients with neuropathic pain disorders. We investigated whether agents used to treat patients with neuropathic pain are effective in CP. METHODS: We conducted a randomized, double-blind, placebo-controlled trial to evaluate the effects of the gabapentoid pregabalin as an adjuvant analgesic. We measured pain relief, health status, quality of life, and tolerability in 64 patients with pain from CP; they were randomly assigned to groups given increasing doses of pregabalin or placebo (control) for 3 consecutive weeks. The primary end point was pain relief, based on a visual analogue scale documented by a pain diary. Secondary end points included Patients' Global Impression of Change (PGIC) score, changes in physical and functional scales, pain character, quality of life, and tolerability. RESULTS: Pregabalin, compared with placebo, caused more effective pain relief after 3 weeks of treatment (36% vs 24%; mean difference, 12%; 95% confidence interval, 22%-2%; P = .02). The percentage of patients with much or very much improved health status (PGIC score) at the end of the study was higher in the pregabalin than the control group (44% vs 21%; P = .048). Changes in physical and functional scales, pain character, quality of life, and number of serious adverse events were comparable between groups. CONCLUSIONS: In a placebo-controlled trial, pregabalin is an effective adjuvant therapy for pain in patients with CP.