Positive allosteric modulators of the GABAB receptor: a new class of ligands with therapeutic potential for alcohol use disorder.

BACKGROUND: Positive allosteric modulators (PAMs) of the GABAB receptor constitute a new class of GABAB-receptor ligands. GABAB PAMs reproduce several pharmacological effects of the orthosteric GABAB receptor agonist, baclofen, although displaying a better safety profile. AIMS: This paper reviews the reducing or, frequently, even suppressing effects of all GABAB PAMs tested to date on multiple alcohol-related behaviours in laboratory rodents exposed to validated experimental models of human alcohol use disorder. RESULTS: Acute or repeated treatment with CGP7930, GS39783, BHF177, rac-BHFF, ADX71441, CMPPE, COR659, ASP8062, KK-92A, and ORM-27669 reduced excessive alcohol drinking, relapse- and binge-like drinking, operant alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced conditioned place preference in rats and mice. CONCLUSIONS: These effects closely mirrored those of baclofen; notably, they were associated to remarkably lower levels of tolerance and toxicity. The recent transition of ASP8062 to clinical testing will soon prove whether these highly consistent preclinical data translate to AUD patients.

Utilizing combination intrathecal baclofen and analgesic medication to manage spasticity and pain in patients with pediatric-onset disability: Case series.

PURPOSE: The use of intrathecal medications for the management of spasticity and various pain syndromes in the adult population has been previously reported. However, no evidence-based guidelines currently exist in the pediatric population. This case series presents patients (n = 8) with pediatric-onset disability who underwent placement of intrathecal baclofen pumps initially for management of severe spasticity. Despite titration of dose and use of oral analgesia, their uncontrolled pain persisted. Each patient was transitioned to a combination of baclofen and analgesic intrathecal therapy. The outcome in pain improvement and quality of life, as reported by patients and/or caregivers, were retrospectively reviewed. METHODS: Retrospective review of the background and decision-making process regarding transition to combination intrathecal therapy identified patient selection characteristics. Each patient and/or their caregivers completed a survey regarding improvements in pain, spasticity, function, and quality of life following initiation of combination intrathecal medications. RESULTS: Survey results revealed improvements in functional and pain assessments after initiation of combination baclofen and analgesic intrathecal medication. Patients and caregivers reported decreases in pain and oral spasticity medications. CONCLUSION: Use of pumps with antispasmodic and analgesic medication for combination intrathecal medication delivery should be considered in the management of patients with childhood-onset disabilities who have both severe spasticity and pain.

Repurposing drugs for treatment of alcohol use disorder.

Repurposing drugs for the treatment of alcohol dependence involves the use of drugs that were initially developed for other conditions, but have shown promise in reducing alcohol use or preventing relapse. This approach can offer a more cost-effective and time-efficient alternative to developing new drugs from scratch. Currently approved medications for alcohol use disorder (AUD) include acamprosate, disulfiram, naltrexone, nalmefene, baclofen, and sodium oxybate. Acamprosate was developed specifically for AUD, while disulfiram's alcohol-deterrent effects were discovered incidentally. Naltrexone and nalmefene were originally approved for opioids but found secondary applications in AUD. Baclofen and sodium oxybate were repurposed from neurological conditions. Other drugs show promise. Topiramate and zonisamide, anticonvulsants, demonstrate efficacy in reducing alcohol consumption. Another anticonvulsant, gabapentin has been disappointing overall, except in cases involving alcohol withdrawal symptoms. Varenicline, a nicotinic receptor agonist, benefits individuals with less severe AUD or concurrent nicotine use. Ondansetron, a 5-HT3 antagonist, has potential for early-onset AUD, especially when combined with naltrexone. Antipsychotic drugs like aripiprazole and quetiapine have limited efficacy. Further investigation is needed for potential repurposing of α1 adrenergic receptor antagonists prazosin and doxazosin, glucocorticoid receptor antagonist mifepristone, the phosphodiesterase inhibitor Ibudilast, the cysteine prodrug N-acetylcysteine, and the OX1R and OX2R blocker Suvorexant. This review supports repurposing drugs as an effective strategy for expanding treatment options for AUD.

Symptomatic Treatment of Myelopathy.

OBJECTIVE: This article discusses the effects of myelopathy on multiple organ systems and reviews the treatment and management of some of these effects. LATEST DEVELOPMENTS: Recent advances in functional electrical stimulation, epidural spinal cord stimulation, robotics, and surgical techniques such as nerve transfer show promise in improving function in patients with myelopathy. Ongoing research in stem cell therapy and neurotherapeutic drugs may provide further therapeutic avenues in the future. ESSENTIAL POINTS: Treatment for symptoms of spinal cord injury should be targeted toward patient goals. If nerve transfer for upper extremity function is considered, the patient should be evaluated at around 6 months from injury to assess for lower motor neuron involvement and possible time limitations of surgery. A patient with injury at or above the T6 level is at risk for autonomic dysreflexia, a life-threatening condition that presents with elevated blood pressure and can lead to emergent hypertensive crisis. Baclofen withdrawal due to baclofen pump failure or programming errors may also be life-threatening. Proper management of symptoms may help avoid complications such as autonomic dysreflexia, renal failure, heterotopic ossification, and fractures.

A case report of integrating Chinese and Western medicine: A new era in the treatment of stiff person syndrome.

RATIONALE: At present, there are limitations to the treatment of stiff person syndrome (SPS). Current treatments are still ineffective or financially burdensome for some patients, so it is imperative to explore more appropriate treatments for patients. This is a case report of a SPS with a more significant effect of combined Chinese and Western medicine, which may provide new treatment ideas for other patients. PATIENT CONCERNS: This patient presented with episodes of stiffness and pain in the lower back and lower extremities. His electromyography shows continued activation of normal motor units in the paraspinal and abdominal muscles. However, relevant laboratory tests including glutamic acid decarboxylase antibody and Amphiphysin antibody were negative. After a period of treatment including clonazepam, baclofen, prednisone and intravenous immunoglobulin, this patient experiences a shortened maintenance period of medication, accompanied by symptoms such as emotional anxiety and cognitive decline, which severely affects his life. DIAGNOSES: This patient was diagnosed with SPS. INTERVENTIONS: In May 2022 the patient decided to combine Chinese medicine for simultaneous treatment. OUTCOMES: During the period of simultaneous treatment with Chinese and Western medicine, the patient experienced remission of clinical symptoms, reduction of concomitant symptoms and improved quality of life. CONCLUSION: A combination of Western and Chinese medicine was effective in relieving this patient pain and stiffness and reducing the patient anxiety. Combined Chinese and Western medicine treatment may be able to bring better results to more patients with stiff person syndrome.

Efficacy and safety of alcohol reduction pharmacotherapy according to treatment duration in patients with alcohol dependence or alcohol use disorder: A systematic review and network meta-analysis.

BACKGROUND AND AIMS: Relapse is common in alcohol dependence (AD) and alcohol use disorder (AUD), so alcohol reduction therapy should be measured over as long a period as possible; however, existing reviews do not consider the duration of treatment and therefore alcohol reduction therapy may not have been appropriately evaluated. This review evaluated the efficacy and safety of alcohol reduction pharmacotherapy in patients with AD or AUD according to the duration of treatment. METHODS: We conducted a systematic review and network meta-analysis of randomized controlled trials (RCTs) that assessed 15 pharmacological agents. MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials, the ClinicalTrials.gov and the International Clinical Trials Registry Platform were searched for eligible trials through to May 2021. Outcomes were heavy drinking days (HDD), total alcohol consumption (TAC), any adverse event and days without drinking. RESULTS: Fifty-five RCTs (n = 8891) were included. Nalmefene was superior to placebo for reducing HDD (standard mean difference [SMD] -0.28, 95% confidence interval [CI] -0.37, -0.18) and TAC (SMD -0.25, 95% CI -0.35, -0.16) in the long-term, but not in the short-term. Topiramate was superior to placebo for reducing HDD (SMD -0.35, 95% CI -0.59, -0.12) and days without drinking (SMD 0.46, 95% CI 0.11, 0.82), and baclofen was superior for reducing TAC (SMD -0.70, 95% CI -1.29, -0.11), in the short-term. The frequency of adverse events was higher with nalmefene and topiramate than with placebo. CONCLUSION: Nalmefene, topiramate and baclofen may be effective as alcohol reduction pharmacotherapy; however, only nalmefene has demonstrated long-term efficacy, and nalmefene and topiramate have a significantly higher frequency of adverse events compared with placebo.

Surgical treatment options for spasticity in children and adolescents with hereditary spastic paraplegia.

PURPOSE: To provide an overview of outcome and complications of selective dorsal rhizotomy (SDR) and intrathecal baclofen pump implantation (ITB) for spasticity treatment in children with hereditary spastic paraplegia (HSP). METHODS: Retrospective study including children with HSP and SDR or ITB. Gross motor function measure (GMFM-66) scores and level of spasticity were assessed. RESULTS: Ten patients were included (most had mutations in ATL1 (n = 4) or SPAST (n = 3) genes). Four walked without and two with walking aids, four were non-walking children. Six patients underwent SDR, three patients ITB, and one both. Mean age at surgery was 8.9 ± 4.5 years with a mean follow-up of 3.4 ± 2.2 years. Five of the SDR patients were walking. Postoperatively spasticity in the legs was reduced in all patients. The change in GMFM-66 score was + 8.0 (0-19.7 min-max). The three ITB patients treated (SPAST (n = 2) and PNPLA6 (n = 1) gene mutation) were children with a progressive disease course. No complications of surgery occurred. CONCLUSIONS: SDR is a feasible treatment option in carefully selected children with HSP, especially in walking patients. The majority of patients benefit with respect to gross motor function, complication risk is low. ITB was used in children with severe and progressive disease.

Intraventricular baclofen for palliative management of acquired generalized dystonia in pediatric patients: a case series and literature review.

Dystonia represents a significant source of disability in children. Generalized dystonia, which involves multiple body regions, leads to impaired mobility and motor function, resulting in substantial challenges in daily activities. Surgical treatments are used when medical treatments fail. Intrathecal baclofen (ITB) or deep brain stimulations (DBS) are the most employed surgical therapies. When these options are not feasible or ineffective, some authors have explored the use of intraventricular baclofen (IVB). In this report, we present four cases of pediatric patients with generalized dystonia who underwent treatment with IVB, resulting in notable improvements. To further explore the potential of this treatment modality, we conducted a comprehensive literature review. The findings from our study provide a comprehensive overview that can guide palliative management in similar cases.

[Surgical procedures for treatment of spasticity]. / Chirurgische Verfahren zur Therapie von Spastik.

BACKGROUND: The causes of spasticity are various and include cerebral palsy, spinal cord injury, stroke, multiple sclerosis or other congenital or acquired lesions of the central nervous system (CNS). While there is often a partial functional component, spasticity also results in varying degrees of impairment of the quality of life. OBJECTIVE: A review of surgical treatment options for spasticity. MATERIAL AND METHODS: A systematic PubMed review of the literature on epidemiology and treatment options with a focus on neurosurgical interventions for spasticity and developments in the last 20 years as well as inclusion of still valid older landmark papers was carried out. Illustration of indications, technique, follow-up, and possible pitfalls of the different methods for the surgical treatment of spasticity. RESULTS: Depending on the affected region, the number of muscle groups, and the extent of spasticity, focal (selective peripheral neurotomy, nerve transfer), regional (selective dorsal rhizotomy), or generalized (baclofen pump) procedures can be performed. The indications are usually established by an interdisciplinary team. Conservative (physiotherapy, oral medications) and focally invasive (botulinum toxin injections) methods should be performed in advance. In cases of insufficient response to treatment or only short-term relief, surgical methods can be evaluated. These are usually preceded by test phases with, for example, trial injections. CONCLUSION: Surgical methods are a useful adjunct in cases of insufficient response to conservative treatment in children and adults with spasticity.

The presence of Candida parapsilosis with intrathecal baclofen pump in a person with high cervical spinal cord injury; infection or colonization? A Case Report.

INTRODUCTION: Intrathecal baclofen (ITB) therapy is an effective method of treating spasticity in persons with spasticity due to spinal cord injury (SCI), but complications are not rare and can include spinal fluid leaks, infection, and catheter/pump malfunction. CASE PRESENTATION: This study presents information related to an adult male patient with traumatic SCI and a history of two prior ITB pump pocket infections that required removal due to pump infection. The patient then developed skin erosion over the third pump, and the fluid around the pump grew methicillin-sensitive Staphylococcus aureus, diphtheroids, and Candida parapsilosis. The patient was initially treated with antibiotics and anti-fungal medication without removal of the ITB pump. The ITB pump was eventually removed 27 months later, and the fourth pump was implanted 10 months later. DISCUSSION: ITB pumps can be an effective treatment modality for spasticity in people with SCI; however, complications, including infection, can occur and require pump removal. This case illustrates a case of possible Candida colonization of the ITB pump, which was eventually removed.

Long-term results on the suppression of secondary brain injury by early administered low-dose baclofen in a traumatic brain injury mouse model.

Secondary injury from traumatic brain injury (TBI) perpetuates cerebral damages through varied ways. Attenuating neuroinflammation, which is a key feature of TBI, is important for long-term prognosis of its patients. Baclofen, a muscle relaxant, has shown promise in reducing excessive inflammation in other neurologic disorders. However, its effectiveness in TBI remains ambiguous. Thus, our study aimed to investigate whether early administration of baclofen could elicit potential therapeutic effects by diminishing exaggerated neuroinflammation in TBI mice. In this study, 80 C57BL/6 mice were used, of which 69 mice received controlled cortical impact. The mice were divided into six groups (11-16 mice each). Baclofen, administered at dose of 0.05, 0.2 and 1 mg/kg, was injected intraperitoneally a day after TBI for 3 consecutive weeks. 3 weeks after completing the treatments, the mice were assessed histologically. The results showed that mice treated with baclofen exhibited a significantly lower volume of lesion tissue than TBI mice with normal saline. Baclofen also reduced activated glial cells with neurotoxic immune molecules and inhibited apoptotic cells. Significant recovery was observed and sustained for 6 weeks at the 0.2 mg/kg dose in the modified neurological severity score. Furthermore, memory impairment was recovered with low-doses of baclofen in the Y-maze. Our findings demonstrate that early administration of low dose baclofen can regulate neuroinflammation, prevent cell death, and improve TBI motor and cognitive abnormalities.

Neuromodulation and quality of life for patient with spasticity after spinal cord injury.

RATIONALE: Spasticity develops in 80% of spinal cord injury cases and negatively affects the patents' quality of life. The most common method of surgical treatment for severe spasticity is a long-term intrathecal baclofen therapy (ITB). Long-term spinal cord stimulation is another possible treatment technique. This paper aims to evaluate the changes in quality of life for patients with spasticity who have been treated with neuromodulation (SCS or ITB) in 12 months after the surgery, as well to compare the changes in quality of life for patients who have been treated with spinal cord stimulation and those who received long-term intrathecal baclofen therapy. MATERIALS AND METHODS: The influence of spasticity, experienced by the patients with a spinal cord injury, on their quality of life was analyzed before the surgery and 12 months after it. The severity of the spinal cord damage was determined with the scale of the American Spinal Injury Association (ASIA); spasticity was evaluated with the modified Ashworth scale, Penn Spasm Frequency Scale; pain levels were determined with visual analogue scale (VAS), anxiety and depression levels - with HADS. Functional activity of the patients was evaluated with the help of the Functional Independence Measure (FIM). RESULTS: The treatment results for 33 patients (25 men and 8 women), aged from 18 to 62, are presented. After the trial stimulation, the patients were randomly assigned to either SCS or ITB group (18 and 15 people respectively). The decrease of spasticity in both experimental groups caused lower levels of pain, less functional dependency on other people, lower stress and depression rates and, as a consequence, better quality of life and social adaptation. The obtained results for SCS and ITB groups are statistically similar.

Spasticity treatment in Norwegian hospitals. / Behandling av spastisitet ved norske sykehus.

BACKGROUND: Spasticity is a frequent complication of diseases of and injuries to the central nervous system. Early treatment prevents further loss of function and spasticity-related complications. Basic spasticity treatment begins in the primary healthcare service and includes physiotherapy, occupational therapy and oral spasmolytics, while treatment with botulinum toxin and baclofen pump is carried out by the specialist healthcare services. The objective of the study was to obtain an overview of the availability and organisation of these specialised forms of spasticity treatment in Norway. MATERIAL AND METHOD: We conducted a survey in which a digital questionnaire was sent to hospitals that offer spasticity treatment. RESULTS: A total of 30 of 47 hospital departments/outpatient clinics (hereafter referred to as 'hospital units') distributed across all Norwegian health regions responded to the questionnaire. Spasticity treatment with botulinum toxin and baclofen pump was available in all of the health regions. Median time from first referral was 10 weeks (interquartile range 7 weeks). A total of 14 of 30 hospital units expressed a need for more treatment days to cover the local demand. Of the 30 hospital units, 23 had interdisciplinary teams with doctors, physiotherapists, occupational therapists and/or nurses. For treatment with botulinum toxin, ultrasound was used as guidance in 22 of 26 hospital units, EMG was used in 15 units and electrical muscle stimulation was used in 11 units. INTERPRETATION: The study suggests that there may be a need for improvements to specialised spasticity treatment in Norway to ensure good patient care pathways, interdisciplinary assessments, and safe and efficient performance of the practical interventions.

γ-aminobutyric acid B2 receptor: A potential therapeutic target for cholangiocarcinoma in patients with diabetes mellitus.

BACKGROUND: The association between diabetes mellitus (DM) and the increased risk and progression of cholangiocarcinoma (CCA) has been reported with unclear underlying mechanisms. Previous studies showed that γ-aminobutyric acid (GABA) B2 receptor (GABBR2) was upregulated in CCA cells cultured in high glucose (HG) conditions. Roles of GABA receptors in CCA progression have also been studied, but their association with DM and hyperglycemia in CCA remains unclarified. AIM: To investigate the effects of hyperglycemia on GABBR2 expression and the potential use of GABBR2 as a CCA therapeutic target. METHODS: CCA cells, KKU-055 and KKU-213A, were cultured in Dulbecco Modified Eagle's Medium supplemented with 5.6 mmol/L (normal glucose, NG) or 25 mmol/L (HG) glucose and assigned as NG and HG cells, respectively. GABBR2 expression in NG and HG cells was investigated using real-time quantitative polymerase chain reaction and western blot. Expression and localization of GABBR2 in CCA cells were determined using immunocytofluorescence. GABBR2 expression in tumor tissues from CCA patients with and without DM was studied using immunohistochemistry, and the correlations of GABBR2 with the clinicopathological characteristics of patients were analyzed using univariate analysis. Effects of baclofen, a GABA-B receptor agonist, on CCA cell proliferation and clonogenicity were tested using the MTT and clonogenic assays. Phospho-kinases arrays were used to screen the affected signaling pathways after baclofen treatment, and the candidate signaling molecules were validated using the public transcriptomic data and western blot. RESULTS: GABBR2 expression in CCA cells was induced by HG in a dose- and time-dependent manner. CCA tissues from patients with DM and hyperglycemia also showed a significantly higher GABBR2 expression compared with tumor tissues from those with euglycemia (P < 0.01). High GABBR2 expression was significantly associated with a poorer non-papillary histological subtype but with smaller sizes of CCA tumors (P < 0.05). HG cells of both tested CCA cell lines were more sensitive to baclofen treatment. Baclofen significantly suppressed the proliferation and clonogenicity of CCA cells in both NG and HG conditions (P < 0.05). Phospho-kinase arrays suggested glycogen synthase kinase 3 (GSK3), ß-catenin, and the signal transducer and activator of transcription 3 (STAT3) as candidate signaling molecules under the regulation of GABBR2, which were verified in NG and HG cells of the individual CCA cell lines. Cyclin D1 and c-Myc, the common downstream targets of GSK3/ß-catenin and STAT3 involving cell proliferation, were accordingly downregulated after baclofen treatment. CONCLUSION: GABBR2 is upregulated by HG and holds a promising role as a therapeutic target for CCA regardless of the glucose condition.

Unique form of catheter malconnection following intrathecal baclofen surgery for spinal cord injury: a case report.

This case report concerns a patient suffering from traumatic spinal cord injury with severe spasticity treated with intrathecal baclofen therapy. After revision surgery for a confirmed catheter obstruction, progressive spasticity reappeared. Diagnostics demonstrated signs of catheter fracture or disconnection adjacent to the pump. During revision surgery, the silicone layer surrounding the sutureless pump connector was shown to be curled up, revealing the cause of dysfunction. As far as we know, this form of malconnection has not been reported before. Therefore, surgeons must be aware of this complication and additional inspection of the silicone connector prior to definite connection is advised.

Spasticity and movement disorders in cerebral palsy.

PURPOSE: To review the neurosurgical treatments of children with movement disorders associated with cerebral palsy (CP) during the previous decades, up to the present day. METHODS: An extensive literature review was undertaken to identify important publications about this subject. My experience treating children with these disorders over the past three decades was included in the individual sections. RESULTS: Peripheral neurotomies have been developed for children with focal spasticity. For those with spastic paraparesis, selective lumbar rhizotomies were developed, and for those with spastic quadriparesis, intrathecal baclofen infusions were developed. Both effectively alleviate spasticity in the affected extremities. Generalized dystonia associated with CP has been treated with deep brain stimulation with mild improvement, but treatment with intrathecal baclofen and intraventricular baclofen improve those movements markedly. No effective treatment has been reported for children with athetoid CP. For those with choreiform CP, deep brain stimulation may be effective but intrathecal baclofen does not appear to be. CONCLUSION: Treatment of children with movement disorders associated with CP increased slowly in the 1970s and 1980s but accelerated rapidly in the 1990s with the introduction of lumbar dorsal rhizotomies and intrathecal baclofen. In the last 30 years, tens of thousands of children with spasticity and movement disorders associated with CP have been treated by pediatric neurosurgeons, and their care has become an integral component of current pediatric neurosurgical practice.

Brief pump externalization without ITB wean to treat a probable pocket infection.

BACKGROUND AND IMPORTANCE: Intrathecal baclofen (ITB) pumps are an effective management tool for spasticity and dystonia. In the pediatric population, ITB complications including infection are common, and strategies to minimize their impact are important. Current standard of care for pump infection involves a wean of the ITB therapy followed by explantation of the hardware, which can be a three to 6-month process. CLINICAL PRESENTATION: We present a 20-year-old female who developed an pump pocket infection after revision. The pump was removed from the body but left connected. The pocket was debrided, thoroughly washed, and packed with multiple microbicidal agents. Nine days later, a new pump and proximal catheter was re-implanted without complications or interruption of medication administered intrathecally. One year later, the patient is doing well without any infectious problems. CONCLUSION: To our knowledge, this is the first report of an externalized pump and expedited reimplantation without a break in ITB therapy. Further studies are required in order to best characterize this technique as a potential alternative for infected baclofen pump pockets.