Bidirectional Neuronal Control of Epileptiform Activity by Repetitive Transcranial Focused Ultrasound Stimulations.

Repetitive stimulation procedures are used in neuromodulation techniques to induce persistent excitatory or inhibitory brain activity. The directivity of modulation is empirically regulated by modifying the stimulation length, interval, and strength. However, bidirectional neuronal modulations using ultrasound stimulations are rarely reported. This study presents bidirectional control of epileptiform activities with repetitive transcranial-focused ultrasound stimulations in a rat model of drug-induced acute epilepsy. It is found that repeated transmission of elongated (40 s), ultra-low pressure (0.25 MPa) ultrasound can fully suppress epileptic activities in electro-encephalography and cerebral blood volume measurements, while the change in bursting intervals from 40 to 20 s worsens epileptic activities even with the same burst length. Furthermore, the suppression induced by 40 s long bursts is transformed to excitatory states by a subsequent transmission. Bidirectional modulation of epileptic seizures with repeated ultrasound stimulation is achieved by regulating the changes in glutamate and γ-Aminobutyric acid levels, as confirmed by measurements of expressed c-Fos and GAD65 and multitemporal analysis of neurotransmitters in the interstitial fluid obtained via microdialysis.

Gabapentin for Pain in Pediatric Palliative Care.

OBJECTIVE: Gabapentin is commonly used to treat pain in children receiving pediatric palliative care. This study describes the real-world use of gabapentin and the associated benefits and adverse effects/events (AEs). METHODS: A prospective, multicenter cohort of standardized data collection after a clinical decision was made to use gabapentin for managing neuropathic or nociplastic pain in children attended on by a pediatric palliative care service. It was conducted across 11 sites in seven countries including hospital, inpatient, and outpatient services. Clinical outcomes were graded using pain scales validated for age and cognitive ability and the National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) at baseline, 14 days, 28 days, six weeks and 12 weeks after initiation of gabapentin. Ad-hoc safety reporting continued throughout the study. RESULTS: Data were collected from 127 children with a median age of 4.7 years (IQR 0.1-17.9); 61% had a neurological disorder, 21% advanced cancer and the cohort had a high level of disability (Lansky/Karnofsky performance score 37.1). Gabapentin was prescribed at standard pediatric doses. On average, 76% of children had a reduction in pain and 42% experienced a potential AE. The mean pain score decreased from 6.0 (SD 2.6) at baseline to 3.3 (SD 2.4) at 14 days and 1.8 (SD 1.8) after 12-weeks of gabapentin therapy. Ten percent had increased pain at each time point. AEs did not increase when individual changes over time were accounted for except for somnolence (7%). Serious AEs attributable to gabapentin were possible or probable in 3% of children. CONCLUSIONS: Gabapentin prescribed at standard doses for advanced cancer and severe neurological injury in children under a pediatric palliative care service was associated with generally improved pain intensity at previously described levels of adverse effects.

Signal detection of adverse events associated with gabapentinoid use for chronic pain.

INTRODUCTION: Gabapentinoids (GABA) prescribing as a potential and conceivably safer substitute for opioids has substantially increased. Understanding all potential adverse drug events (ADEs) associated with GABA will guide clinical decision-making for pain management. METHODS: A 20% sample of Medicare enrollees with new chronic pain diagnoses in 2017-2018 was selected. GABA users were those with >=30 consecutive days prescription in a year without opioid prescription. Opioid users were similarly defined. The control group used neither of these drugs. Propensity score match across three groups based on demographics and comorbidity was performed. We used proportional reporting ratio (PRR), Gamma Poisson Shrinker, and tree-based scan statistic (TBSS) to detect ADEs within 3, 6, and 12 months of follow-up. RESULTS: Immunity disorder was detected within 3 months of follow-up by PRR compared to opioid use (PRR:2.33), and by all three methods compared to controls. Complications of transplanted organs/tissues and schizophrenia spectrum/other psychotic disorders were consistently detected by PRR and TBSS within 3 months. Skin disorders were detected by TBSS; and stroke was detected by PRR within 3 months compared to opioid use (PRR:4.74). Some malignancies were detected by PRR within 12 months. Other signals detected in GABA users were neuropathy and nerve disorders. CONCLUSIONS: Our study identified expected and unexpected ADE signals in GABA users. Neurological signals likely related to indications for GABA use. Signals for immunity, mental/behavior, and skin disorders were found in the FDA adverse event reporting system database. Unexpected signals of stroke and cancer require further confirmatory analyses to verify.

Safety and Efficacy of Gabapentin for Pain in Pediatric Patients: A Systematic Review.

CONTEXT: Gabapentin has shown benefits for a variety of pain etiologies in adult patients, with off-label use as an adjunctive agent in pediatric patients occurring more frequently. OBJECTIVES: To summarize the studies which evaluate safety and efficacy of gabapentin for the treatment of pediatric pain. DATA SOURCES: A systematic review of the literature was conducted via PubMed query with controlled vocabulary and key terms using indexed medical subject heading. STUDY SELECTION: Prospective studies published between January 1, 2000, and July 1, 2023, were selected utilizing a predetermined exclusion criteria independently by 2 authors, with a third independent author available for discrepancies. DATA EXTRACTION: Data extraction was performed by 2 authors independently to include study design, patient population and characteristics, drug dosing, and outcomes. Studies were then assessed for their independent risk of bias utilizing the Grading of Recommendations, Assessment, Development, and Evaluations approach to risk of bias. RESULTS: A total of 11 studies describing 195 pediatric patients who received gabapentin were included. Of the 11 studies, 9 were randomized controlled trials, 1 was a prospective multicenter study, and 1 was an open-label pilot study. CONCLUSIONS: Heterogeneity of pain type and gabapentin dosing regimens within the included studies made conclusions difficult to quantify. Efficacy likely depends significantly on etiology of pain; however, per these studies, gabapentin is likely safe to use for a variety of pediatric patient populations as a multimodal agent.

Effectiveness of oral clonidine and gabapentin on peripheral neuropathy in diabetic patients in southwestern Iran: a randomized clinical trial.

BACKGROUND: Peripheral neuropathy is not only the most prevalent consequence of diabetes but also the main reason for foot ulceration, disability, and amputation. Therefore, the current study aims to determine the effectiveness of oral clonidine and gabapentin on peripheral neuropathy in diabetic patients. METHODS: This 12-week, randomized, and parallel-group trial was conducted to compare the efficacy of oral clonidine and gabapentin with gabapentin alone in diabetic patients in southwest Iran during the first half of 2021. Thirty patients with type 2 diabetes with peripheral neuropathy as assessed by a visual analog scale (VAS) and divided into two groups of 15 patients, treated for up to three months. The data were analyzed using SPSS-21 software. In order to report the results, descriptive indices, independent t-test, one-way analysis of covariance (ANCOVA) and analysis of variance with repeated measures were used. RESULTS: The mean and standard deviation of the age of the participants in the clonidine + gabapentin group was equal to 50.20 ± 7.44, and in the gabapentin group was equal to 50.47 ± 7.57 (t = 0.10, P-value = 0.923). This research showed a significant difference between the clonidine + gabapentin group and with gabapentin group in terms of neuropathic pain and the severity of neuropathic pain (P < 0.001). CONCLUSIONS: According to this research results, clonidine + gabapentin can reduce neuropathic pain and the severity of neuropathic pain in diabetic patients. Therefore, it is recommended that healthcare professionals with diabetes expertise prescribe these medications to reduce neuropathic pain and its severity. TRIAL REGISTRATION: This study was registered in the Iranian Clinical Trials System with the ID (IRCT20211106052983N1) on 14/01/2022.

Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia.

Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist 3,4-dihydroxy-L-phenylalanine (L-DOPA) to treat Parkinson's disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we search for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identify the enlarged axon terminals of striatal medium spiny neurons in LID and TD model mice. Striatal overexpression of the vesicular gamma-aminobutyric acid transporter (VGAT) is necessary and sufficient for modeling these structural changes; VGAT levels gate the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation.

Flumazenil Pretreatment Reduces Mefenamic Acid-Induced Central Nervous System Toxicity in Mice.

BACKGROUND: Mefenamic acid (MFA), a common analgesic, causes central nervous system (CNS) toxicity at high doses with a proposed activity on the Gamma-aminobutyric acid (GABA) system. However, it remains unknown whether flumazenil (FMZ), a GABA type A receptor (GABAAR) antagonist, can reverse MFA toxicity. METHODS: The behavioral and neurophysiological effects of MFA were investigated in mice with and without FMZ pre-treatment. The elevated zero maze (EZM) and marble burying tests were used to assess anxiety-like behaviors and burying activities, respectively. The standard bar test was used to evaluate catalepsy, while the actophotometer test was used to measure locomotor activity. Seizure intensity was scored, and fatalities were counted. RESULTS: Without FMZ pre-treatment, MFA induced behavioral and neurophysiological effects in a dose-dependent manner as follows: At a dose of 20 mg/kg, i.p, MFA-treated mice exhibited anxiety-like behaviors, which was determined by a significant increase in the time spent in the closed areas and a significant decrease in the number of entries to the open areas of the EZM apparatus. These mice also showed a significant decrease in the burying activity, manifested as a significant decrease in the number of buried marbles. At 40 mg/kg, i.p., MFA-treated mice showed catalepsy that was associated with a significant decrease in locomotor activity. At a dose of 80 mg/kg, i.p., mice developed fatal tonic-clonic seizures (seizure score = 4). Pre-treatment with FMZ (5 mg/kg, i.p.) significantly reversed the anxiety-like behaviors and restored marble-burying activity. Additionally, FMZ prevented catalepsy, significantly restored locomotor activity, reduced seizure intensity (seizure score = 0.3) and significantly reduced mortalities. CONCLUSIONS: The present study's findings indicate that activation of the GABAAR is involved in the CNS toxicity of MFA, and FMZ reverses MFA toxicity by interfering with this receptor.

Abuse and addiction in gabapentinoid drug users for neuropathic pain.

OBJECTIVE: Gabapentinoids are gamma-aminobutyric acid analogue agents used in the treatment of neuropathic pain. They are increasingly being abused to achieve euphoric and dissociative effects. This study aimed to determine drug misuse/abuse and related factors in patients who used gabapentinoids for neuropathic pain. PATIENTS AND METHODS: This study included 140 patients over the age of 18. Patients were excluded from the study if they had aphasia, dementia, or diseases that led to aphasia or cooperative and cognitive dysfunction. They were also excluded if they lacked sufficient information about how long or at what dosage they had been using the drug. The Beck Depression Inventory and Beck Anxiety Inventory were used to evaluate depression and anxiety states. The patients' levels of drug abuse were determined according to the definitions provided in the terminology for misuse, abuse, and related events. RESULTS: The mean age of the patients was 56.78 ± 14.45 years, and 52.1% of them were females. While 57.9% of the patients used pregabalin, 42.1% of the patients used gabapentin. For the median (min-max) of the dataset, the pregabalin dose was 300 (50-600) mg/day, and the gabapentin dose was 900 (300-2,400) mg/day. Abuse was present in 17.9% of the patients. Risk factors for gabapentinoid abuse were smoking, alcohol, and antidepressant use, anxiety and depression, living alone, and drug dose and duration of use. CONCLUSIONS: Before prescribing drugs and managing the treatment process in a controlled manner, questioning patients about their risk factors can reduce the rate of abuse.

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.

The safety and efficacy of gabapentinoids in the management of neuropathic pain: a systematic review with meta-analysis of randomised controlled trials.

BACKGROUND: There are increasing concerns regarding the abusive potential of gabapentinoids putting at risk patients with neuropathic pain requiring long-term pain management. The evidence to support this is rather inconcusive. AIM: This systematic review aimed to evaluate the safety and efficacy of gabapentinoids in the management of neuropathic pain with a focus on randomised controlled trials (RCTs) and categorising the side effects according to the body systems they were affecting. METHOD: Searches were conducted in MEDLINE (PubMed), EMBASE, Web of Science, PsycoINFO, and CINAHL (EBSCO), and included RCTs to identify and critically appraise studies investigating safety and therapeutic effects of gabapentionoids in adults with neuropathic pain. Data extraction was conducted using an established Cochrane form and the risk-of-bias tool was used in the assessment of quality. RESULTS: 50 studies (12,398 participants) were included. The majority of adverse events pertained to the nervous system (7 effects) or psychiatric (3 effects) disorders. There were more adverse effects reported with pregabalin (36 effects) than with gabapentin (22 effects). Six pregabalin studies reported euphoria as a side effect, while no studies reported euphoria with gabapentin. This was the only side effect that may correlate with addictive potential. Gabapentioids were reported to significantly reduce pain compared to placebo. CONCLUSION: Despite RCTs documenting the adverse events of gabapentionoids on the nervous system, there was no evidence of gabapentinoid use leading to addiction, suggesting an urgent need to design studies investigating their abusive potential.

Misuse of gabapentinoids (pregabalin and gabapentin) in patients with neuropathic pain related to spinal cord injury.

OBJECTIVE: To investigate the misuse of gabapentinoids (pregabalin and gabapentin) in patients with neuropathic pain related to spinal cord injury. STUDY DESIGN: Cross-sectional study. SETTING: Outpatient clinic in a physical therapy and rehabilitation hospital. PARTICIPANTS: 127 patients, aged 18-70 years, who had neuropathic pain related to spinal cord injury (SCI) and disease duration of at least 12 months. OUTCOME MEASURES: Gabapentinoid use disorder of the patients was determined based on the DSM-5 diagnostic criteria for substance-related disorders. Patients were divided into 2 groups as those with drug misuse and those without drug misuse. Demographic and clinical information of the patients were compared between the groups. Factors associated with drug misuse were analyzed. RESULTS: The misuse rate was 81.9% in patients using pregabalin and 69.69% in patients using gabapentin. Duration of disease and the Leeds assessment of neuropathic symptoms and signs (LANSS) score were statistically significantly higher in the drug misuse group. A statistically significant difference was found between the groups in terms of marital status, education and income level, and smoking and alcohol use. A statistically significant relationship was observed between drug misuse and duration of disease and LANSS score. CONCLUSION: Misuse of gabapentinoids is prevalent in patients with neuropathic pain related to spinal cord injury. The duration of disease and the severity of NP are associated with misuse. Clinicians should exercise caution when prescribing gabapentinoids to patients with SCI.

Gabapentin Use During Pregnancy and Lactation With and Without Concurrent Opioid Exposure: Considerations and Future Directions.

Gabapentin is a γ-aminobutyric acid analog formally indicated for the treatment of epilepsy and neuropathic pain that is gaining increased popularity. Gabapentin has been historically considered a safe medication, including during pregnancy and lactation, with low reported concerns for misuse and use disorders. However, new empirical efforts are revealing concerns regarding the safety of widespread gabapentin use, particularly in pregnancy and for individuals with a propensity toward substance misuse. The Food and Drug Administration's full prescribing information report on gabapentin provides concerning preclinical data and then states that gabapentin is potentially "developmentally toxic" and has an unknown risk of birth impacts. Concerns have also been raised surrounding in utero exposure to gabapentin due to the onset and presentation of atypical and/or difficult to control withdrawal signs and symptoms in neonates, including those dually exposed to opioids, as well as neonatal exposure to gabapentin via breastmilk. Moreover, nonprescribed gabapentin use has become an increasing problem, with opioid use disorder being the greatest risk factor for such misuse. This article summarizes the current literature regarding gabapentin use during pregnancy and related prenatal and neonatal exposure outcomes with special consideration for interactions between gabapentin and opioid use. Taken together, the current literature suggests that gabapentin use should be considered with caution during pregnancy and during the post-partum period. Well-controlled, prospective research studies are needed to determine the extent of the risks and benefits of prescribed and nonprescribed gabapentin exposure to pregnant people and their neonates.

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.

Gabapentin-Induced Overflow Urinary Incontinence: A Case Report and Review of the Literature.

Gabapentin (GBP) is a structural analog of gamma-aminobutyric acid (GABA) that is commonly used in palliative care for symptom management indications including neuropathic pain syndromes, hiccups, cough, and anxiety. An uncommon adverse effect of GBP is urinary incontinence (UI). We report the case of a 61-year-old male with metastatic non-small cell lung cancer who developed probable overflow UI while receiving 1200 mg/day of GBP for chemotherapy-induced peripheral neuropathy. The patient self-tapered GBP to 600 mg/day which resolved the overflow UI, but resulted in poorly controlled bilateral foot pain. The palliative care physician rotated the patient to pregabalin 150 mg/day and his bilateral foot pain improved after his regimen was titrated to 200 mg/day. The patient did not experience overflow UI while taking pregabalin despite the similar pharmacology and comparable doses to GBP. We believe this is the first case report to describe subsequent achievement of pain control by substituting pregabalin without recurrence of UI. Healthcare professionals should consider GBP as a potential cause when evaluating patients presenting with new onset overflow UI.

The risk of fragility fractures following initiation of gabapentin and pregabalin-A Danish, nationwide, high-dimensional propensity score-matched cohort study.

Gabapentin and pregabalin have been associated with an increased risk of fragility fractures. Due to differences in pharmacokinetics, we aimed to assess the fracture-risk difference between the two medicines. We performed a Danish nationwide new user, high-dimensional propensity score-matched cohort study to assess the 90-day risk of fragility fractures among adults, from January 1996 to December 2018. We applied a high-dimensional propensity score to match new users of gabapentin with new users of pregabalin in a 1:1 intention-to-treat approach. Hazard ratios (HRs), incidence rates (IRs) and incidence rate difference (IRD) were obtained. We identified 388 236 eligible patients of which 294 223 and 98 869 initiated gabapentin and pregabalin, respectively. We included 48 272 matched pairs for further analysis. The mean age was 56 (IQR 44-69) years, and the average follow-up was approximately 11 500 person-years (PY). The IRs of fragility fractures were 23.7 (95%CI 21.0-26.7) and 23.2 (95%CI 20.5-26.2) per 1000 PY for gabapentin and pregabalin-exposed patients, respectively. This yielded an HR of 1.02 (95%CI 0.86-1.21) when using gabapentin as the intervention drug and pregabalin as the reference drug. The IRD was estimated to 0.5 PY (95%CI -3.5-4.5). In conclusion, short-term risk of fragility fractures among gabapentin initiators was not different compared to those initiating pregabalin.

Neonatal outcomes after gamma-aminobutyric acid analog use during pregnancy: a meta-analysis of cohort studies.

BACKGROUND: Gamma-aminobutyric acid (GABA) analogs are being used by an increasing number of reproductive-age women. However, there is concern regarding the teratogenic potential of GABA analogs. METHODS: We performed this systematic review and meta-analysis to assess the relationship between GABA analog exposure and risk of adverse neonatal outcomes. RESULTS: Eight cohort studies were included in the meta-analysis. Exposure to a GABA analog during pregnancy was not associated with an increased risk of congenital malformation (odds ratio [OR] 1.19, 95% confidence interval [CI] 0.96-1.46, P = 0.106) or a small for gestational age (SGA) infant (OR 1.99, 95% CI 0.78-5.1, P = 0.152) compared to no exposure. However, exposure to a GABA analog was associated with an increased risk of preterm birth (PB) (OR 1.56, 95% CI 1.04-2.35, P = 0.033), spontaneous abortion (SA) (OR 1.64, 95% CI 1.14-2.38, P = 0.008), or termination of pregnancy (TOP) (OR 3.02, 95% CI 2-4.56, P < 0.001). CONCLUSION: Exposure to GABA analogs during pregnancy does not appear to be associated with congenital malformation, although there was some evidence of a higher risk of several other negative neonatal outcomes. Given the few studies included, larger prospective studies controlling for important confounders are needed to verify our findings.

Cardiovascular risk of gabapentin and pregabalin in patients with diabetic neuropathy.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Pruritus in dialysis patients. Review and new perspectives.

Uremic pruritus (UP) is one of the most uncomfortable symptoms for patients in dialysis. UP has a great impact on dialysis patients' quality of life and has a great prevalence between those (28-70%). Physiopathology of UP is unknown and usually is unnoticed for most nephrologists (in more than 65% of centers is underdiagnosed). This lack of awareness drives to the unsuccessful treatment of this symptom. Moreover, the fact that most studies have been carried out on small populations and the difficulty assessing UP complicates a correct therapeutical approach. For this reason, we have designed treatment algorithms based on the efficacy of the drugs but also its safeness to avoid adverse effects.

Patient empowerment brochures to increase gabapentinoid deprescribing: protocol for the prospective, controlled before-and-after GABA-WHY trial.

BACKGROUND: Off-label use of gabapentinoids is common among patients admitted to hospital medical wards, who are at risk of adverse drug events. In this study, we will assess if educational brochures can increase rates of gabapentinoid deprescription among medical inpatients, compared with usual care. METHODS: We describe the protocol for a prospective before-and-after trial that will take place on 5 medical wards of 2 tertiary care hospitals in Montréal, Canada. The study intervention will include distribution of educational brochures to users of gabapentinoids during hospital admission, as well as short educational sessions for medical staff on safe gabapentinoid prescribing practices. We will include patients with a gabapentinoid prescription before admission who are aged 60 years or older. Exclusion criteria are known seizure disorder, severe cognitive impairment, expected prognosis less than 3 months and inability to read English or French. The primary outcome is the rate of gabapentinoid deprescription at 8 weeks postdischarge. We aim to recruit 160 participants, with a 1:1 distribution between intervention and control groups. INTERPRETATION: If successful, the use of educational brochures and staff education represents a scalable intervention to reduce gabapentinoid overuse by encouraging deprescription conversations between patients and their health care providers. Results of the study will be disseminated through publication in peer-reviewed journals and presentations at conferences. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT04855578.