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Refractory chronic cough causes substantial symptoms and quality-of-life impairment. Similarities between central reflex sensitisation in refractory chronic cough and neuropathic pain suggest that neuromodulators such as gabapentin might be effective for refractory chronic cough. We established the efficacy of gabapentin in patients with refractory chronic cough. This randomised, double-blind, placebo-controlled trial was undertaken at an outpatient clinic in Australia. Adults with refractory chronic cough (>8 weeks' duration) without active respiratory disease or infection were randomly assigned to receive gabapentin (maximum tolerable daily dose of 1800 mg) or matching placebo for 10 weeks. Block randomisation was done with randomisation generator software, stratified by sex. Patients and investigators were masked to assigned treatment. The primary endpoint was change in cough-specific quality of life (Leicester cough questionnaire [LCQ] score) from baseline to 8 weeks of treatment, analysed by intention to treat. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12608000248369. 62 patients were randomly assigned to gabepentin (n=32) or placebo (n=30) and ten patients withdrew before the study end. Gabapentin significantly improved cough-specific quality of life compared with placebo (between-group difference in LCQ score during treatment period 1·80, 95% CI 0·56–3·04; p=0·004; number needed to treat of 3·58). Side-effects occurred in ten patients (31%) given gabapentin (the most common being nausea and fatigue) and three (10%) given placebo. The treatment of refractory chronic cough with gabapentin is both effective and well tolerated. These positive effects suggest that central reflex sensitisation is a relevant mechanism in refractory chronic cough. National Health and Medical Research Council of Australia and Hunter Medical Research Institute, Newcastle, Australia.

This trial assessed the efficacy of and iatrogenic worsening (augmentation) with pregabalin and pramipexole in patients with RLS. Pregabalin improved symptoms, as compared with placebo, and augmentation rates with pregabalin were lower than with pramipexole. Moderate-to-severe restless legs syndrome (RLS), now also known as Willis–Ekbom disease, with its predominantly nocturnal, rest-induced, distressing urge to move the legs, is a significant but poorly recognized and undertreated health problem. 1 Clinically significant RLS, which affects 2 to 3% of the European and American populations, 2 , 3 profoundly disrupts sleep, quality of life, and daytime productivity and often requires treatment for years, if not for life. Levodopa 4 and short-acting dopamine agonists (pramipexole and ropinirole) 5 , 6 relieve RLS symptoms. 7 , 8 In patients treated with dopamine agonists, RLS can worsen over several years. 9 This worsening results in symptoms that are both more . . .

There is increasing interest in the use of cannabis and its major non-intoxicating component cannabidiol (CBD) as a treatment for mental health and neurodevelopmental disorders, such as autism spectrum disorder (ASD). However, before launching large-scale clinical trials, a better understanding of the effects of CBD on brain would be desirable. Preclinical evidence suggests that one aspect of the polypharmacy of CBD is that it modulates brain excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) levels, including in brain regions linked to ASD, such as the basal ganglia (BG) and the dorsomedial prefrontal cortex (DMPFC). However, differences in glutamate and GABA pathways in ASD mean that the response to CBD in people with and without ASD may be not be the same. To test whether CBD ‘shifts’ glutamate and GABA levels; and to examine potential differences in this response in ASD, we used magnetic resonance spectroscopy (MRS) to measure glutamate (Glx = glutamate + glutamine) and GABA+ (GABA + macromolecules) levels in 34 healthy men (17 neurotypicals, 17 ASD). Data acquisition commenced 2 h (peak plasma levels) after a single oral dose of 600 mg CBD or placebo. Test sessions were at least 13 days apart. Across groups, CBD increased subcortical, but decreased cortical, Glx. Across regions, CBD increased GABA+ in controls, but decreased GABA+ in ASD; the group difference in change in GABA + in the DMPFC was significant. Thus, CBD modulates glutamate-GABA systems, but prefrontal-GABA systems respond differently in ASD. Our results do not speak to the efficacy of CBD. Future studies should examine the effects of chronic administration on brain and behaviour, and whether acute brain changes predict longer-term response.

Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of γ-aminobutyric acid type A (GABA A ) receptors to dampen neuronal activity in the brain 1 – 5 . However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABA A receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABA A receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain. Cryo-electron microscopy structures of GABA A receptors bound to intravenous anaesthetics and benzodiazepines reveal both common and distinct transmembrane binding sites, and show that the mechanisms of action of anaesthetics partially overlap with those of benzodiazepines.

Gamma-amino butyric acid (GABA) has in experimental studies been found to promote beta-cell proliferation, enhance insulin secretion and reduce inflammation, positioning it as a candidate drug for type 1 diabetes (T1D) therapy. This phase I/II randomized controlled trial assessed the safety and efficacy of long-term treatment with Remygen ® (Diamyd Medical), a controlled-release oral GABA formulation, as a potential beta-cell regenerative therapy in adults with long-standing T1D. Thirty-five male subjects with T1D (≥ 5 years) were randomized into three arms receiving the study drug(s) once daily for 6 months: GABA 200 mg (Arm 1), GABA 600 mg (Arm 2) and GABA 600 mg + alprazolam 0.5 mg for 3 months followed by GABA 600 mg alone for 3 months (Arm 3). Safety measures, hormonal counter-regulation during hypoglycemic clamps, fasting- and stimulated C-peptide levels, were assessed at multiple timepoints. Safety concerns included elevated aspartate aminotransferase (AST) in nine subjects, leading to the withdrawal of two subjects. Most elevations were, however, transient with no dose-differences. No effects were observed on fasting- or stimulated C-peptide levels, CGM metrics or HbA1c. Hypoglycemic hormonal counter-regulation was unaltered. To conclude, we found no clinical evidence of a beta-cell regenerative effect of GABA, but side effects were commonly observed.

A major problem in pain medicine is the lack of knowledge about which treatment suits a specific patient. We tested the ability of quantitative sensory testing to predict the analgesic effect of pregabalin and placebo in patients with chronic pancreatitis. Sixty-four patients with painful chronic pancreatitis received pregabalin (150-300 mg BID) or matching placebo for three consecutive weeks. Analgesic effect was documented in a pain diary based on a visual analogue scale. Responders were defined as patients with a reduction in clinical pain score of 30% or more after three weeks of study treatment compared to baseline recordings. Prior to study medication, pain thresholds to electric skin and pressure stimulation were measured in dermatomes T10 (pancreatic area) and C5 (control area). To eliminate inter-subject differences in absolute pain thresholds an index of sensitivity between stimulation areas was determined (ratio of pain detection thresholds in pancreatic versus control area, ePDT ratio). Pain modulation was recorded by a conditioned pain modulation paradigm. A support vector machine was used to screen sensory parameters for their predictive power of pregabalin efficacy. The pregabalin responders group was hypersensitive to electric tetanic stimulation of the pancreatic area (ePDT ratio 1.2 (0.9-1.3)) compared to non-responders group (ePDT ratio: 1.6 (1.5-2.0)) (P = 0.001). The electrical pain detection ratio was predictive for pregabalin effect with a classification accuracy of 83.9% (P = 0.007). The corresponding sensitivity was 87.5% and specificity was 80.0%. No other parameters were predictive of pregabalin or placebo efficacy. The present study provides first evidence that quantitative sensory testing predicts the analgesic effect of pregabalin in patients with painful chronic pancreatitis. The method can be used to tailor pain medication based on patient's individual sensory profile and thus comprises a significant step towards personalized pain medicine.

Gamma aminobutyric acid (GABA) is the principal inhibitory neurotransmitter playing a key role in anxiety and depression disorders in mammals. Recent studies revealed that members of the gut microbiota are able to produce GABA modulating the gut–brain axis response. Among members of the human gut microbiota, bifidobacteria are well known to establish many metabolic and physiologic interactions with the host. In this study, we performed genome analyses of more than 1,000 bifidobacterial strains publicly available revealing that Bifidobacterium adolescentis taxon might represent a model GABA producer in human gastrointestinal tract. Moreover, the in silico screening of human/animal metagenomic datasets showed an intriguing association/correlation between B. adolescentis load and mental disorders such as depression and anxiety. Interestingly, in vitro screening of 82 B. adolescentis strains allowed identifying two high GABA producers, i.e. B. adolescentis PRL2019 and B. adolescentis HD17T2H, which were employed in an in vivo trial in rats. Feeding Groningen rats with a supplementation of B. adolescentis strains, confirmed the ability of these microorganisms to stimulate the in vivo production of GABA highlighting their potential implication in gut–brain axis interactions.

Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (γ-aminobutyric acid) and its synaptic target, the type A GABA receptor (GABA receptor). Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABA receptor is also a prolific target for therapeutic, illicit and recreational drugs, including benzodiazepines, barbiturates, anaesthetics and ethanol. Here we present high-resolution cryo-electron microscopy structures of the human α1β2γ2 GABA receptor, the predominant isoform in the adult brain, in complex with GABA and the benzodiazepine site antagonist flumazenil, the first-line clinical treatment for benzodiazepine overdose. The receptor architecture reveals unique heteromeric interactions for this important class of inhibitory neurotransmitter receptor. This work provides a template for understanding receptor modulation by GABA and benzodiazepines, and will assist rational approaches to therapeutic targeting of this receptor for neurological disorders and mental illness.

Background Postherpetic neuralgia (PHN) is the most common chronic complication of herpes zoster (HZ), and current treatment regimens often fail to effectively control the pain. Aim The purpose of this study is to compare the efficacy and tolerability of duloxetine combined with pregabalin and amitriptyline combined with pregabalin in the treatment of PHN, as well as their impact on sleep and quality of life in patients with PHN. Methods This is a double‐blind, randomized, crossover trial involving PHN patients. About 220 participants were randomly assigned (1:1) to either the duloxetine combined with pregabalin or the amitriptyline combined with pregabalin. The patient takes duloxetine or amitriptyline orally before bedtime for 6 weeks each time. Perform a 2‐week single‐blind placebo washout between the two treatments, and a 2‐week single‐blind placebo washout at the end of the treatment period. In the last week of the treatment cycle, evaluate the 7‐day average daily pain, Pittsburgh Sleep Quality Index, 17‐item Hamilton Depression Rating Scale, 36‐Item Short Form Health Survey, and record the occurrence of major adverse events. A median reduction of 50%, 25%–50%, and 25% in pain score is considered good, moderate, and mild improvement, respectively. Results Both treatment methods can significantly improve the baseline pain value (p < 0.001 for both). The combination of duloxetine and pregabalin resulted in good, moderate, and mild pain relief of 52%, 24%, and 7%, respectively. The combination of amitriptyline and pregabalin resulted in good, moderate, and mild pain relief of 48%, 21%, and 9%, respectively. There was no significant difference in the measurement of various results between the two groups. In the reported adverse events, patients in the amitriptyline group had significantly more dry mouth compared to the duloxetine group (26% vs. 11%; p = 0.008). Conclusions Duloxetine and amitriptyline have similar analgesic effects, and the difference is not statistically significant. The combination of pregabalin has good tolerability and better pain relief in PHN patients, thus providing clinically relevant benefits. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2100054831 This is a double‐blind, randomized, crossover trial involving PHN patients. The purpose of this study is to compare the efficacy and tolerability of duloxetine combined with pregabalin and amitriptyline combined with pregabalin in the treatment of PHN, as well as their impact on sleep and quality of life in patients with PHN.

Intense abdominal pain is the dominant feature of chronic pancreatitis. During the disease changes in central pain processing, e.g. central sensitization manifest as spreading hyperalgesia, can result from ongoing nociceptive input. The aim of the present study is to evaluate the effect of pregabalin on pain processing in chronic pancreatitis as assessed by quantitative sensory testing (QST). This randomized, double-blind, placebo-controlled trial evaluated effects of pregabalin on pain processing. QST was used to quantify pain processing by measuring thresholds to painful electrical and pressure stimulation in six body dermatomes. Descending endogenous pain modulation was quantified using the conditioned pain modulation (CPM) paradigm to elicit a DNIC (diffuse noxious inhibitory controls) response. The main effect parameter was the change in the sum of all body pain threshold values after three weeks of study treatment versus baseline values between both treatment groups. 64 patients were analyzed. No differences in change in sum of pain thresholds were present for pregabalin vs. placebo after three weeks of treatment. For individual dermatomes, change vs. baseline pain thresholds was significantly greater in pregabalin vs. placebo patients for electric pain detection threshold in C5 (P = 0.005), electric pain tolerance threshold in C5 (P = 0.04) and L1 (P = 0.05), and pressure pain tolerance threshold in T4 (P = 0.004). No differences were observed between pregabalin and placebo regarding conditioned pain modulation. Our study provides first evidence that pregabalin has moderate inhibitory effects on central sensitization manifest as spreading hyperalgesia in chronic pancreatitis patients. These findings suggest that QST can be of clinical use for monitoring pain treatments in the context of chronic pain. ClinicalTrials.gov NCT00755573.