Anticonvulsant Gabapentin Research Articles

What do ultrasound vocalizations really mean in rats with different origins of pain?

This study is to assess how 22 kHz and 50 kHz spontaneous ultrasound vocalization (USV) calls would be affected by different origins of pain so as to validate the use of USV in pain studies. Five well-established rat models of pain were used to evaluate various parameters of spontaneous 22 kHz and 50 kHz calls in adult male rats in terms of both acute and chronic or inflammatory and neuropathic or somatic and visceral origins. The effects of local lidocaine blockade of the injection site and intraperitoneal administration of antidepressant (amitriptyline) and anticonvulsant (gabapentin) were examined as well in typical inflammatory and neuropathic pain models, respectively. The major new gains were as follows: (1) naive rats staying alone and engaging dyadic social interaction with a naive or a conspecific in pain emitted similar power and amounts of both 22 kHz and 50 kHz spontaneous USV calls; however, rats suffering from various origins of pain emitted significantly less USV calls of both 22 kHz and 50 kHz in terms of both number and time. (2) Local blockade of the injury sites of inflammatory pain could reverse the impaired emission of both 22 kHz and 50 kHz spontaneous calls, so did the treatment of the rats with neuropathic pain by amitriptyline and gabapentin. Emissions of both 22 kHz and 50 kHz spontaneous calls were impaired by acute and chronic pain conditions regardless of inflammatory and neuropathic or somatic and visceral origins.

Biochemical and antioxidant responses of common carp (Cyprinus carpio) exposed to sublethal concentrations of the antiepileptic and analgesic drug gabapentin

Biochemical and antioxidant responses of common carp (Cyprinus carpio) exposed to sublethal concentrations of the antiepileptic and analgesic drug gabapentin

The Voltage-Gated Calcium Channel α2δ Subunit in Neuropathic Pain.

Neuropathic pain (NP) is a chronic pain caused by injury or disease of the somatosensory nervous system, or it can be directly caused by disease. It often presents with clinical features like spontaneous pain, hyperalgesia, and dysesthesia. At present, voltage-gated calcium ion channels (VGCCs) are known to be closely related to the development of NP, especially the α2δ subunit. The α2δ subunit is a regulatory subunit of VGCCs. It exists mainly in the brain and peripheral nervous system, especially in nerve cells, and it plays a crucial part in regulating presynaptic and postsynaptic functions. Furthermore, the α2δ subunit influences neuronal excitation and pain signaling by promoting its expression and localization through binding to VGCC-related subunits. The α2δ subunit is widely used in the management of NP as a target of antiepileptic drugs gabapentin and pregabalin. Although drug therapy is one of the treatments for NP, its clinical application is limited due to the adverse reactions caused by drug therapy. Therefore, further research on the therapeutic target α2δ subunit is needed, and attempts are made to obtain an effective treatment for relieving NP without side effects. This review describes the current associated knowledge on the function of the α2δ subunit in perceiving and modulating NP.

Brazilian Psychiatric Association guidelines for the treatment of Social Anxiety Disorder.

Social anxiety disorder (SAD) is one of the most prevalent anxiety disorders, often not well recognized. In most of the cases, SAD follows an unremitted and chronic course, affecting several areas of the individual functioning (i.e.: relationship, academic, work). Due to its relevance, there is a need for guideline-based treatments for SAD treatment adapted to the Brazilian social and economic reality. A systematic review was produced by our group assessing several treatment modalities for SAD. The Medical Subject Headings term used was Social Anxiety Disorder or Social Phobia. PubMed, Cochrane, Scielo, ClinicalTrials.gov were searched resulting in 438 articles screened, of which 20 were selected. Selective serotonin reuptake inhibitors are considered first line choices for the treatment of SAD, with great effects and a large database of evidence. Monoamine oxidase inhibitors (MAOIs), benzodiazepines and the anticonvulsants pregabalin and gabapentin are also effective. The serotonin noradrenaline reuptake inhibitor (SNRI) venlafaxine shows divergent results. With regards to psychological interventions, robust data offered evidence for cognitive behavioral therapy (CBT) as a first line option (individual, group and internet delivered). Psychodynamic psychotherapy, exposure and social skills therapy, self-help (with and without support) therapies, cognitive bias modification, virtual reality exposure therapy and mindfulness-based therapy are also effective techniques. Compared to pharmacological agents, psychological interventions are better tolerated and show evidence of long-term benefits. Patient's access to treatments (considering the Brazilian socioeconomic context), adherence, response rates (short and long-term treatment) and side effects must be considered when choosing the best strategy for the treatment of SAD.

Binding and occupancy properties of gabapentin in mixed surfactant systems

AbstractThis research highlights the efficacy of mixed micellar systems as an innovative chemical formulation for improving the binding properties of active pharmaceutical drugs. The formulations based on the mole fraction were utilized for preparing mixed micelles with anionic sodium dioctyl sulfosuccinate (AOT) and sodium dodecyl sulphate (SDS). DLS measurements demonstrated the formation of small micelles and mixed micelles in SDS‐AOT combinations. A UV absorbance investigation demonstrated the effectiveness of the SDS‐AOT mixed micelles for determining the binding constant (Kb) and mean ion occupancy (i0) of the anticonvulsant gabapentin (GBP) drug. Kb values increased, but the occupancy (i) of GBP per micelle decreased by decreasing the mole fraction (α) of SDS from αSDS 0.9 to 0.1, predicting a shift in occupancy of drugs from the Palisade to the Stern layer. To get a better comprehension of micellization behavior and preferential interaction of the drugs under study, molecular docking studies were performed. According to the docking studies, the GBP displayed significant binding in the presence of SDS‐AOT when compared to pure SDS and AOT molecules. Ultimately, in pharmaceutical applications, mixed micelle played an important role in enhancing the binding and encapsulation efficiency of drugs.

The association between sociodemographic, clinical, and potentially preventive therapies with oxaliplatin-induced peripheral neuropathy in colorectal cancer patients.

The purpose of this retrospective cohort study was to evaluate whether several potentially preventive therapies reduced the rate of oxaliplatin-induced peripheral neuropathy (OIPN) in colorectal cancer patients and to assess the relationship of sociodemographic/clinical factors with OIPN diagnosis. Data were obtained from the Surveillance, Epidemiology, and End Results database combined with Medicare claims. Eligible patients were diagnosed with colorectal cancer between 2007 and 2015, ≥ 66years of age, and treated with oxaliplatin. Two definitions were used to denote diagnosis of OIPN based on diagnosis codes: OIPN 1 (specific definition, drug-induced polyneuropathy) and OIPN 2 (broader definition, additional codes for peripheral neuropathy). Cox regression was used to obtain hazard ratios (HR) with 95% confidence intervals (CI) for the relative rate of OIPN within 2years of oxaliplatin initiation. There were 4792 subjects available for analysis. At 2years, the unadjusted cumulative incidence of OIPN 1 was 13.1% and 27.1% for OIPN 2. For both outcomes, no therapies reduced the rate of OIPN diagnosis. The anticonvulsants gabapentin and oxcarbazepine/carbamazepine were associated with an increased rate of OIPN (both definitions) as were increasing cycles of oxaliplatin. Compared to younger patients, those 75-84years of age experienced a 15% decreased rate of OIPN. For OIPN 2, prior peripheral neuropathy and moderate/severe liver disease were also associated with an increased hazard rate. For OIPN 1, state buy-in health insurance coverage was associated with a decreased hazard rate. Additional studies are needed to identify preventive therapeutics for OIPN in cancer patients treated with oxaliplatin.

A Narrative Review of the Lesser Known Medications for Treatment of Restless Legs Syndrome and Pathogenetic Implications for Their Use.

There are several well-known treatments for Restless Legs Syndrome (RLS), including dopamine agonists (pramipexole, ropinirole, rotigotine), anticonvulsants (gabapentin and its analogs, pregabalin), oral or intravenous iron, opioids and benzodiazepines. However, in clinical practice, treatment is sometimes limited due to incomplete response or side effects and it is necessary to be aware of other treatment options for RLS, which is the purpose of this review. We performed a narrative review detailing all of the lesser known pharmacological treatment literature on RLS. The review purposefully excludes well-established, well-known treatments for RLS which are widely accepted as treatments for RLS in evidence-based reviews. We also have emphasized the pathogenetic implications for RLS of the successful use of these lesser known agents. Alternative pharmacological agents include clonidine which reduces adrenergic transmission, adenosinergic agents such as dipyridamole, glutamate AMPA receptor blocking agents such as perampanel, glutamate NMDA receptor blocking agents such as amantadine and ketamine, various anticonvulsants (carbamazepine/oxcarbazepine, lamotrigine, topiramate, valproic acid, levetiracetam), anti-inflammatory agents such as steroids, as well as cannabis. Bupropion is also a good choice for the treatment of co-existent depression in RLS because of its pro-dopaminergic properties. Clinicians should first follow evidence-based review recommendations for the treatment of RLS but when the clinical response is either incomplete or side effects are intolerable other options can be considered. We neither recommend nor discourage the use of these options, but leave it up to the clinician to make their own choices based upon the benefit and side effect profiles of each medication. Clinicians should first follow evidence-based reviews for RLS but when response is incomplete and side effects intolerable, other medications can be considered. We do not make a recommendation on these options but leave it up to the clinician to make their own choice based upon the benefit and side effect profiles of each medication.

Pharmacological interventions for reducing catheter-related bladder discomfort in patients undergoing elective surgeries under general anaesthesia: A systematic review and meta-analysis.

Catheter-related bladder discomfort (CRBD) is identified as a major concern after surgery as it can lead to increased morbidity and prolonged hospital stay. A suitable agent to prevent and treat postoperative CRBD is not yet established, and the literature is scarce in this regard. So, we aimed to find the efficacy of various drugs in preventing CRBD after elective surgery. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed for the study, and electronic databases like PubMed Central, Cochrane database and Embase were searched. The methodological quality of selected studies was assessed by the Cochrane Collaboration risk of bias tool. Review Manager 5.4.1 was used for statistical analysis. The meta-analysis revealed that antimuscarinic agents were able to lower the incidence of CRBD significantly at 0 hour, 1 hour, 2 hours and 6 hours (P < 0.01) after the surgery. Tramadol was effective at 1 hour, 2 hours and 6 hours postoperatively (P < 0.01), whereas ketamine was effective at 2 and 6 hours (P < 0.01) postoperatively. Antiepileptic drugs (pregabalin and gabapentin) were able to lower the incidence of CRBD at 0 hour (P < 0.01), 1 hour (P < 0.05), 2 hours (P < 0.05) and 6 hours (P < 0.01) postoperatively while dexmedetomidine at 0 hour (P < 0.01) and 2 hours (P < 0.01) after the surgery. Injections paracetamol, amikacin and diphenhydramine were also shown to reduce the incidence of CRBD in separate randomised controlled trials. The current meta-analysis showed that antimuscarinic agents, tramadol, pregabalin, gabapentin, paracetamol and dexmedetomidine are effective in significantly reducing the incidence of postoperative CRBD.

Painful diabetic polyneuropathy: modern approaches to diagnosis and treatment

Diabetes mellitus is one of the most common chronic diseases, the incidence of which is steadily increasing. Approximately 1 in 11 adults in the world today has diabetes. Diabetic polyneuropathy is a common complication of diabetes mellitus and leads to a decrease in the quality and life expectancy of patients, increases the risk of disability. The pain form of diabetic polyneuropathy has a particularly negative effect on the quality of life. It includes both acute (Ellenberg’s neuropathy and acute insulin-induced neuropathy) and chronic forms. The article discusses modern ideas about the pathogenesis of pain diabetic polyneuropathy, as well as risk factors, clinical symptoms and diagnostic methods (electroneuromyography, quantitative sensory testing, sudomotor function, skin biopsy, confocal biopsy of the cornea) of the disease. In most patients, the pain form of diabetic polyneuropathy is accompanied by autonomic disorders. Treatment of painful diabetic polyneuropathy is a difficult task, including the correction of risk factors (glycemia level, patient lifestyle), as well as pathogenetic and symptomatic therapy. As symptomatic therapy, adjuvant analgesics are used, namely drugs from the group of anticonvulsants (gabapentin, pregabalin) and antidepressants (duloxetine). The use of alpha-lipoic acid is the basis of pathogenetic therapy. As a universal antioxidant, alpha-lipoic acid is an absolutely safe drug with a proven effect in the treatment of painful diabetic polyneuropathy and can be recommended for use in clinical practice.

Transdermal Pharmacologic Treatment of Peripheral Pain: An Alternative to Systemic Treatment Using Opioids, High Dose NSAIDs and Psychoactive Drugs-A Health Policy Review

Background: The national crisis resulting from the wide-spread abuse of opioids and other psychoactive drugs and its relationship to the prescribing practices of physicians has led to governmental and public pressure for clinicians to consider alternative therapies to pain treatment. Unfortunately, while the need for alternatives is widely recognized, there is little consensus regarding the appropriate substitutes. Objectives: The authors challenge the current pain treatment paradigm and its focus on the systemic treatment of pain, in particular peripheral pain, by the oral administration of opioids, high dose NSAIDS, anti-convulsants, and psychotropic drugs. The authors report that patients suffering from acute and chronic peripheral pain have benefitted in the physician’s practice from the transdermal delivery of a combination of an anti-convulsant (gabapentin) and an anti-inflammatory (naproxen). Study Design: A narrative review Methods: Literature search was conducted. Results: In this report the authors summarize how patients suffering from acute and chronic peripheral pain have benefitted in the physician’s practice from the transdermal delivery of combination of an anti-convulsant (gabapentin) and an anti-inflammatory (naproxen) in a 10% to 5% ratio. This compounded transdermal combination drug therapy, in that ratio, is intended to target the pain at its source while avoiding the adverse systemic effects commonly associated with the oral administration of either drug. Conclusion(s): The authors urge clinicians to consider local targeted transdermal pharmacologic treatment for a multitude of peripheral pain conditions, before implementing a systemic approach. Also, they raise concern that the insurance industry and their Pharmacy Benefit Managers (PBMs) are interfering with the ability of prescribers to provide their patients with less dangerous and less expensive alternatives to opioids and other systemic drugs by automatically denying reimbursement claims for transdermal medications and imposing pre-textual and burdensome demands for Prior Authorization (PA). These unnecessary barriers to care interfere with the doctor-patient relationship and the physician’s solemn duty to “first do no harm.” They prevent the patient from receiving pain treatment that has the best chance to restore well-being and function while minimizing or avoiding the deleterious effects to body and mind resulting from the systemic delivery of opioids, high dose NSAIDs, or powerful psychoactive drugs.

Pathophysiological Roles of Auxiliary Calcium Channel α2δ Subunits.

α2δ proteins serve as auxiliary subunits of voltage-gated calcium channels, which are essential components of excitable cells such as skeletal and heart muscles, nerve cells of the brain and the peripheral nervous system, as well as endocrine cells. Over the recent years, α2δ proteins have been identified as critical regulators of synaptic functions, including the formation and differentiation of synapses. These functions require signalling mechanisms which are partly independent of calcium channels. Hence, in light of these features it is not surprising that the genes encoding for the four α2δ isoforms have recently been linked to neurological and neurodevelopmental disorders including epilepsy, autism spectrum disorders, schizophrenia, and depressive and bipolar disorders. Despite the increasing number of identified disease-associated mutations, the underlying pathophysiological mechanisms are only beginning to emerge. However, a thorough understanding of the pathophysiological role of α2δ proteins ideally serves two purposes: first, it will contribute to our understanding of general pathological mechanisms in synaptic disorders. Second, it may support the future development of novel and specific treatments for brain disorders. In this context, it is noteworthy that the antiepileptic and anti-allodynic drugs gabapentin and pregabalin both act via binding to α2δ proteins and are among the top sold drugs for treating neuropathic pain. In this book chapter, we will discuss recent developments in our understanding of the functions of α2δ proteins, both as calcium channel subunits and as independent regulatory entities. Furthermore, we present and summarize recently identified and likely pathogenic mutations in the genes encoding α2δ proteins and discuss potential underlying pathophysiological consequences at the molecular and structural level.

Comparison of Mean Analgesia Consumption for Postoperative Pain with Single Dose of Preoperative Oral Gabapentin versus Placebo in Patients Undergoing Surgery Under General Anesthesia

Background: Postoperative pain management aims to alleviate discomfort, promote early recovery from surgery, shorten hospital stays, and increase patient satisfaction. Multimodal treatment is the best method for perioperative pain management since it reduces the requirement for opioids. For postoperative pain, the anticonvulsant medicine gabapentin is safe and effective. Objective: To compare mean analgesia consumption for postoperative pain with single dose of preoperative oral gabapentin versus placebo in patients undergoing surgery under general anesthesia. Design of the Study: Descriptive case series. Place and Duration of Study: This study was carried out at Department of Anesthesia, Combined Military Hospital, Muzaffarabad from 6-1-2018 to 6-7-2018. Patients and Methods: From the operation theatre, 60 patients who met the criteria for selection were selected. Patients were then divided into two groups at random using the lottery method. Patients in group A received gabapentin. Oral placebo capsules were administered to group B one hour prior to surgery. All patients received anaesthesia. The post-anesthesia care unit was transferred with the patients. During the first 12 hours, pain and total morphine consumption were noted. This entire data was entered into a proforma. The SPSS version 21 application was used to enter and analyze the data. Using an independent sample t-test, the mean analgesia consumption of the two groups was compared. P-values lower than 0.05 were considered significant. Results of the Study: Patients in the gabapentin group have mean age of 42.30±6.90 yrs compared to 43.50±8.48 yrs in the placebo group. In the gabapentin group, there were 16 (53.3%) males and 14 (46.7%) women, while in the placebo group, there were 50% males and 50% women. In the gabapentin group, the mean BMI was 26.80±4.26 g/m2, while in the placebo group, it was 26.97±2.37 g/m2. After 12 hours, the mean pain score was 2.43 0.82 in the gabapentin group and 3.97±1.56 in the placebo group. The difference was statistically significant (p 0.05).The mean analgesia consumed in a 12-hour period was 10.53±1.96mg/kg in the gabapentin group versus 13.10±2.25mg/kg in the placebo group. The difference was significant statistically (p&lt;0.05).. Conclusion: It was shown that a single dose of gabapentin was effective in reducing the postoperative pain and amount of analgesic consumption required during the postoperative period. Keywords: General Anesthesia, Gabapentin, Postoperative Pain, Placebo, Opioids, Morphine, Analgesia Consumption,

A miniaturized electrothermal array for rapid analysis of temperature preference behaviors in ecology and ecotoxicology

Due to technical limitations, there have been minimal studies performed on thermal preferences and thermotactic behaviors of aquatic ectotherm species commonly used in ecotoxicity testing. In this work, we demonstrate an innovative, purpose-built and miniaturized electrothermal array for rapid thermal preference behavioral tests. We applied the novel platform to define thermal preferences in multiple invertebrate and vertebrate species. Specifically, Dugesia notogaea (freshwater planarians), Chironomus tepperi (nonbiting midge larvae), Ostracoda (seed shrimp), Artemia franciscana (brine shrimp), Daphnia carinata (water flea), Austrochiltonia subtenuis (freshwater amphipod), Physa acuta (freshwater snail), Potamopyrgus antipodarum (New Zealand mud snail) and larval stage of Danio rerio (zebrafish) were tested. The Australian freshwater water fleas, amphipods, snail Physa acuta as well as zebrafish exhibited the most consistent preference to cool zones and clear avoidance of zones >27 °C out of nine species tested. Our results indicate the larval stage of zebrafish as the most responsive species highly suitable for prospective development of multidimensional behavioral test batteries. We also showcase preliminary data that environmentally relevant concentrations of pharmaceutical pollutants such as non-steroidal anti-inflammatory drug (NSAID) ibuprofen (9800 ng/L) and insecticide imidacloprid (4600 ng/L) but not anti-depressant venlafaxine (2200 ng/L) and (iv) anticonvulsant medications gabapentin (400 ng/L) can perturb thermal preference behavior of larval zebrafish. Collectively our results demonstrate the utility of simple and inexpensive thermoelectric technology in rapid exploration of thermal preference in diverse species of aquatic animals. We postulate that more broadly such technologies can also have added value in ecotoxicity testing of emerging contaminants.

Fate of trace organic compounds in the hyporheic zone: Influence of microbial metabolism

The hyporheic zone (HZ) is considered a hydrodynamically-driven bioreactor with significant pollutant removal capacities and can therefore not only improve wholestream water quality but also preserve human and ecosystem health. Microbial metabolism is hypothesized to play a key role in pollutant transformation in hyporheic sediments of natural streams. However, previous work investigating the influence of microbial metabolism on pollutant transformation has been predominantly laboratory studies. The key challenge for field studies is the appropriate determination of net microbial metabolism, i.e. information on the actual exposure times to specific microbial processes in the investigated system. The present study uses reactive fluorescent tracers to determine microbial metabolism and ultimately its influence on pollutant transformation, e.g. for trace organic compounds, in hyporheic sediments under natural conditions. In particular, the reactive fluorescent tracers resazurin and its main transformation product resorufin were used to determine the microbial metabolism of facultative or obligate aerobes. The influence of the derived microbial metabolism on the transformation of 20 trace organic compounds, such as pharmaceuticals, including 3 parent–daughter pairs, was examined. The present findings validate laboratory results on the microbially-mediated transformation of the anticonvulsant gabapentin to its main transformation product gabapentin lactam under natural conditions. All other TrOCs investigated did not show a clear link between TrOC reactivity to the microbial metabolism informed by the resazurin–resorufin-system. Overall, the present study not only demonstrates the use of the fluorescent tracer-system resazurin and resorufin for determining microbial metabolism of facultative or obligate aerobes but also generally highlights the potential of reactive fluorescent tracers to disentangle specific reactive properties and ultimately their influence on the fate of pollutants in natural HZs.

Sensory-Motor Perturbations in Larval Zebrafish (Danio rerio) Induced by Exposure to Low Levels of Neuroactive Micropollutants during Development.

Due to increasing numbers of anthropogenic chemicals with unknown neurotoxic properties, there is an increasing need for a paradigm shift toward rapid and higher throughput behavioral bioassays. In this work, we demonstrate application of a purpose-built high throughput multidimensional behavioral test battery on larval stages of Danio rerio (zebrafish) at 5 days post fertilization (dpf). The automated battery comprised of the established spontaneous swimming (SS), simulated predator response (SPR), larval photomotor response (LPR) assays as well as a new thermotaxis (TX) assay. We applied the novel system to characterize environmentally relevant concentrations of emerging pharmaceutical micropollutants including anticonvulsants (gabapentin: 400 ng/L; carbamazepine: 3000 ng/L), inflammatory drugs (ibuprofen: 9800 ng/L), and antidepressants (fluoxetine: 300 ng/L; venlafaxine: 2200 ng/L). The successful integration of the thermal preference assay into a multidimensional behavioral test battery provided means to reveal ibuprofen-induced perturbations of thermal preference behaviors upon exposure during embryogenesis. Moreover, we discovered that photomotor responses in larval stages of fish are also altered by the as yet understudied anticonvulsant gabapentin. Collectively our results demonstrate the utility of high-throughput multidimensional behavioral ecotoxicity test batteries in prioritizing emerging risks associated with neuroactive drugs that can perturb neurodevelopment. Moreover, we showcase the added value of thermotaxis bioassays for preliminary screening of emerging contaminants.

Diabetes: how to manage diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a major complication of diabetes mellitus. Tight glycaemic management focused on lowering haemoglobin A1C and increasing time in the target glucose range along with metabolic risk factor management form the cornerstone of DPN prevention. However, there is limited evidence supporting the efficacy of glycaemic and metabolic control in reducing the symptoms and complications of DPN, including pain once painful DPN develops. DPN treatments include pharmacological agents and non-pharmacological interventions such as foot care and lifestyle modifications. Pharmacological agents primarily address pain symptoms, which affect 25–35% of people with DPN. First-line agents include the anticonvulsants pregabalin and gabapentin, the serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine, and secondary amine tricyclic antidepressants, including nortriptyline and desipramine. All agents have unique pharmacological, safety and clinical profiles, and agent selection should be guided by the presence of comorbidities, potential for adverse effects, drug interactions and costs. Even with the current treatment options, people are commonly prescribed less than the recommended dose of medications, leading to poor management of DPN symptoms and treatment discontinuation. By keeping up with the latest therapy algorithms and treatment options, healthcare professionals can improve the care for people with DPN.

Exploring the Therapeutic Potential of Targeting Purinergic and Orexinergic Receptors in Alcoholic Neuropathy.

Alcoholic neuropathy emerges following the persistent alcohol imbibing, and triggers nerve damage through de-escalating the receptors situated in the central nervous system (CNS), which consecutively evolves into debilitating neuropathic state and further precipitates hyperalgesia, allodynia, dysesthesia, ataxia, numbness, immobility, and decline in certain body functions. Existing pharmacotherapy, such as anticonvulsants (gabapentin and topiramate), and antidepressant drugs (duloxetine, and venlafaxine) render short-lasting benefits; however, their continual use is not favoured nowadays because of their detrimental outcomes and habit-forming behaviour. Consequently, the research is being shifted towards exploring novel propitious targets which entirely assist in the cessation of the disease. This review discloses the multitudinous pathways implicated in the pathogenesis of alcoholic neuropathy, with special emphasis on purinergic and orexinergic receptors. Moreover, the review focuses on targeting purinergic (P2X3, P2X2/3, P2X4, P2X7, and P2Y12), and orexinergic (OX1 and OX2) receptors associated with the evolution of alcoholic neuropathy, and to incentivize further investigation to attain novel propitious strategy in alcoholic neuropathy treatment. The mechanisms implicated in the progression of alcoholic neuropathy comprises malnourishment (B vitamins scarcity), direct pernicious outcomes of alcohol, increased oxidative-nitrosative stress, protein kinase C epsilon (PKCε), and extracellular signal-regulated kinase (ERK)/mitogen activated protein kinase (MAPK) functioning, abnormalities in the axonal transport and cytoskeleton system, activation of nuclear factor-kappa B (NF-κB) and caspase pathway, stimulation of the sympathoadrenal and hypothalamo-pituitary-adrenal (HPA) axis, and microglial cells of spinal column. The purinergic receptor antagonists, orexins/orexinergic receptor antagonists eliminate/modulate hyperalgesia, allodynia, inflammatory pain, liberation of inflammatory mediators, NF-κB signalling pathway, ROS formation, nerve cell deterioration, and craving for alcohol consumption, thereby ceasing the evolution of alcoholic neuropathy. The authors focus to highlight the importance of this alternative strategy as a novel target in alcoholic neuropathy, and to incentivize researchers to scrutinize the possible benefits of purinergic and orexins/orexinergic receptors in the therapy of alcoholic neuropathy.

Prognosis of adenosine triphosphate infusion for anticonvulsants efficacy in patients with intensive cancer pain: a prospective observational study

INTRODUCTION: Pain is a common symptom in cancer patients even when analgesics were given. OBJECTIVE: To assess the prognostic value of intravenous infusion of non-selective purine receptors agonist adenosine triphosphate for effectiveness of anticonvulsant gabapentin in cancer patients with moderate and severe pain who received non-selective inhibitor of cyclooxygenase plus weak opioid tramadol. MATERIALS AND METHODS: Thirty-four cancer patients with intensive pain were scheduled for the study. The intravenous infusion of adenosine triphosphate 35–45 mg∙kg–1∙min–1 was performed within the period from 100 to 160 minutes. Then all patients were taken gabapentin (900 mg in three times daily). Pain was estimated 30 minutes before infusion, 30 minutes after infusion, and after taking 900 mg/day gabapentin for 4 days. Moreover, we studied prognostic significance of adenosine triphosphate infusion for the effectiveness of gabapentin administration. RESULTS: We revealed significant reduction of pain intensity after adenosine triphosphate infusion (Z = 4.0; р &lt; 0.0001 — Wilcoxon signed rank test). The same result was obtained after taking of gabapentin for 4 days (Z = 4.9; р &lt; 0.0001 — Wilcoxon signed rank test). Moreover, we found statistically moderate correlation link (t(N – 2) = 3.94; closeness correlation = 0.57; р &lt; 0.0004 — Spearman’s rank correlation coefficient) between pain intensity value after adenosine triphosphate infusion and taking of gabapentin. Regression analysis demonstrated satisfactory predictive ability of the resulting model (R2 = 0.55 (corrected R2 = 0.53); F = 38.74; р &lt; 0.0001). CONCLUSIONS: 1. Intravenous infusion of adenosine triphosphate may has significance for prognosis of taking anticonvulsant gabapentin effectiveness in cancer patients with moderate and severe pain who received non-selective cyclooxygenase inhibitor plus weak opioid tramadol. 2. Intravenous infusion of adenosine triphosphate or taking anticonvulsant gabapentin may significantly reduce pain intensity in cancer patients who had weak effect of administration of non-selective inhibitor of cyclooxygenase plus weak opioid tramadol.

Forced normalization in epilepsy: Myth or reality?

It was Landolt working in the Swiss Epilepsy Centre who first described the phenomenon of Forced Normalization in 1953. He observed that in patients with intractable epilepsy exposed to the then new drug, ethosuximide, the seizures became controlled, but there emerged a range of psychiatric symptoms. The EEG at this time was relatively or completely normal, leading Landolt to comment on the “paradoxical nature” of the relationship between seizures and behaviour. Tellenbach, described this phenomenon as “the alternative psychosis of epilepsy”. Wolf in his extensive review described how Forced Normalization was reported with every anti-epileptic drug developed, the condition being reviewed extensively in the eponymous book edited by Trimble & Schmitz. Forced Normalization has been described in the last two decades with novel AEDs, levetiracetam, lacosamide; however, the risk of alternative psychosis and forced normalization seems to be particularly low with the new anticonvulsants oxcarbazepine, eslicarbazepine, gabapentin and pregabalin. Despite many years of research, Forced Normalization remains a controversial entity in neuropsychiatry. Many case series and reports point to its presence as a phenomenon in clinical practice when a new AED is introduced in patient management and seizures cease. Yet, very little by way of prospective research or clinical trial attention as been paid to this condition, which indeed could help one distinguish, perhaps, strong from weak AEDs. In this talk we will examine the myth and reality of Forced Normalization in epilepsy, the contemporary relevance of the phenomenon in drug development and clinical practice, and indeed its future application.

Medical Cannabinoid in Pain Management after Spinal Cord Injury

After spinal cord injuries pain remains chronically in many cases and it and its secondary complcations delay their recovery and induce poor prognosis in them. Some drugs such as anticonvulsants (gabapentin, pregabalin), tricyclic antidepressants (amitriptyline, desipramine) and serotonin–noradrenaline reuptake inhibitors (duloxetine) are recommended as the first-line treatment for chronic pain and topical lidocaine (which only acts locally), opioids are additionally recommended as second options. However, chronic pain syndrom remains as a common compaint and non-manageable status in many SCI-patients. In recent years several alternative approaches such as Botulinum toxin A therapy and medical cannabinoids have been studied and recommended more in clinical practice. Actuelly medical use of cannabinoids are allowed in some countries and applied wiedely. Medical cannabinoids have been known as a safe and effective therapy and showed the positive effets in pain reduction and improvement of life quality in SCI patients from previous clinical studies. Further discussion is necessary for the safety and effetive application of medical cannabinoids.