A systematic review of phenibut withdrawal focusing on complications, therapeutic approaches, and single substance versus polysubstance withdrawal.

INTRODUCTION: Phenibut is an unregulated supplement that acts primarily as a gamma-aminobutyric acid type B receptor agonist. Use of phenibut can lead to dependence and subsequent withdrawal when use is stopped. Phenibut withdrawal can cause severe symptoms such as delirium, hallucinations, and seizures. The purpose of this systematic review is to characterize the natural history of phenibut withdrawal and summarize treatment strategies published in the literature. METHODS: A systematic review was conducted using the preferred reporting items for systematic reviews and meta-analyses checklist. English language peer-reviewed articles or conference abstracts in humans describing phenibut withdrawal after cessation of use were included. Databases (Ovid/MEDLINE, Web of Science, and Science Direct) and references of included articles were searched. Case reports were appraised using the Joanna Briggs Institute critical appraisal checklist for case reports. Patient demographics and key outcomes, including withdrawal characteristics and treatment characteristics, were collected into a predefined data collection sheet by six independent reviewers. RESULTS: Search results yielded 515 articles of which 25 were included. All articles were case reports or published conference abstracts. All of the cases (100 percent) involved male patients and the median age was 30 years, (interquartile range 23.5-34 years, range 4 days-68 years). The median daily phenibut dose prior to experiencing withdrawal was 10 g (interquartile range 4.75-21.5 g, range 1-200 g). The shortest duration of phenibut use (2-3 g daily) prior to withdrawal was one week. Withdrawal symptoms occurred as quickly as two hours after the last phenibut dose. Sixteen patients (64 percent) reported progression of withdrawal severity within the first 24 hours of healthcare contact. Seizures were reported in two patients (8 percent), intubation in six patients (24 percent), and intensive care unit admission in 11 patients (44 percent). Withdrawal patterns and outcomes were similar in those using phenibut alone and those with comorbid polysubstance use. Withdrawal treatment strategies varied widely. Only three cases (12 percent) were managed outpatient and all three utilized a phenibut tapering strategy. All patients undergoing medication-assisted abstinence were admitted inpatient for symptom management and received a drug that acts on gamma-aminobutyric acid receptors. The most commonly used medication was a benzodiazepine, reported in 17 cases (68 percent). Nineteen patients (76 percent) required at least two drug therapies to manage symptoms. Baclofen was used in 15 cases (60 percent), primarily in conjunction with gamma-aminobutyric acid type A agonists (12 of 15 cases) or as monotherapy during a phenibut taper (two of 15 cases). Two patients using baclofen monotherapy outpatient, after initial stabilization with multiple drug classes, reported adverse effects. One patient had a seizure and the other experienced recurrent withdrawal symptoms, returned to using phenibut, and was admitted to a hospital for withdrawal symptom management with benzodiazepines. LIMITATIONS: This review is subject to several limitations. Due to the manual nature of article selection, it is possible relevant articles may not have been included. As the entire data set is comprised of case reports it may suffer from publications bias. Outcomes and meaningful conclusions from specific treatment strategies were rarely available because of the heterogeneous nature of case reports. It is possible those reporting only phenibut use were actually using multiple substances. The doses of phenibut a user believed they were taking may be different from what was present in the unregulated product. CONCLUSIONS: Phenibut withdrawal appears to have a range of severity. It is important to recognize that patients undergoing phenibut abstinence may have progressive symptom worsening during early withdrawal. All published cases of abrupt phenibut abstinence were admitted inpatients for symptom management. Benzodiazepines or barbiturates with adjunctive baclofen appear to be the most commonly used drugs for moderate to severe withdrawal. Outpatient management via slow phenibut tapers with or without adjunctive gamma-aminobutyric acid agonist therapy may be successful. However, there is no standard treatment, and consultation with experts (e.g., toxicologists, addiction specialists) experienced in managing withdrawal syndromes is recommended. Significant study is warranted to develop methods of triaging phenibut withdrawal (e.g., severity scoring, inpatient versus outpatient management) and creating optimal treatment regimens.

[Effects of Governor Vessel electroacupuncture on chloridion homeostasis in the cortex of rats with limb spasm after cerebral ischemia-reperfusion].

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of Governor Vessel on chloridion (Cl-) homeostasis and the expression of γ-aminobutyric acid (GABA) and Na+-K+-Cl- cotransporter 1 (NKCC1) in the cerebral cortex of cerebral ischemia-reperfusion injury (CIRI) model rats, so as to explore its mechanism underl-ying alleviating limb spasm after stroke. METHODS: Forty-five male SD rats were randomly divided into normal, sham-operation, model, EA and baclofen groups, with 9 rats in each group. The CIRI model was established by occlusion of the middle cerebral artery and reperfusion. EA(100 Hz) was applied to "Dazhui" (GV14), "Jizhong"(GV6) and "Houhui" for 30 min. Rats of the baclofen group received gavage of baclofen solution (0.4 mg/kg, 1 mL/100 g), once daily for 7 consecutive days. Neurological deficit score was assessed according to Zea Longa's method. The muscular tone of quadriceps femoris of the limb was evaluated by modified Ashworth scale and electrophysiological recor-ding methods, separately. TTC staining was used to detect cerebral infarction volume, and the brain water content of rats in each group was determined by wet and dry weight method. The contents of Cl- and GABA in the cerebral cortex were detected by colorimetric method, and the expression levels of NKCC1 mRNA and protein in the cerebral cortex were detected by quantitative real-time PCR and Western blot, separately. RESULTS: No significant differences were found between the normal and sham-operation groups in all the indexes. Compared with the normal and sham-operation groups, the neurological deficit score, modified Ashworth muscle tone score, brain water content, cerebral infarct volu-me percent, Cl- content and expression levels of NKCC1 mRNA and protein were all evidently increased (P<0.01), and muscle tone of electrophyiological electromyogram (EMG) signal and GABA content were strikingly decreased (P<0.01) in the model group. Compared with the model group, both EA and baclofen groups had an obvious increase in EMG signal displayed muscle tone, and GABA content (P<0.05, P<0.01), and a marked decrease in the neurological deficit score, modified Ashworth score, brain water content, cerebral infarct percent, Cl- content and expression levels of NKCC1 mRNA and protein (P<0.05, P<0.01). CONCLUSION: EA stimulation of acupoints of the Governor Vessel can improve the degree of limb spasm and reduce the degree of cerebral edema and infarction in rats with stroke, which may be related to its functions in protecting Cl- homeostasis, up-regulating GABA concentration, and down-regulating the expression of NKCC1 protein and mRNA in the cerebral cortex.

Safety of baclofen versus tizanidine for older adults with musculoskeletal pain.

BACKGROUND: Baclofen and tizanidine are both muscle relaxants that carry the risk for neuropsychiatric events in older adults but there is a lack of data directly comparing their safety. This study aimed to investigate the relative risk between these two medications in causing injury and delirium in older adults. METHODS: This was a retrospective cohort study that was completed in an integrated healthcare system in the United States and included patients aged 65 years or older who started baclofen or tizanidine for the treatment of musculoskeletal pain from January 2016 through December 2018. Outcomes included new incidence of injury (concussion, contusion, dislocation, fall, fracture, or other injuries) and delirium. The cohort was followed from the initiation of therapy until the first occurrence of any of the following events: end of the index drug exposure, end of health plan membership, death, or the study end date of December 31st, 2019. Descriptive statistics were used to compare baseline patient characteristics between baclofen and tizanidine treatment groups. Cox proportional hazards model was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals. RESULTS: The final study cohort included 12,101 and 6,027 older adults in the baclofen and tizanidine group respectively (mean age 72.2 ± 6.2 years old, 59% female). Older adults newly started on baclofen had a greater risk of injury (HR = 1.54, 95% CI = 1.21-1.96, P = < 0.001) and delirium (HR = 3.33, 95% CI = 2.11-5.26, p = <0.001) compared to those started on tizanidine. CONCLUSION: The results of this study suggest that baclofen is associated with higher incidences of injury and delirium compared to tizanidine when used for the treatment of musculoskeletal pain. Future studies should investigate if these risks are dose-related and include a comparison group not exposed to either drug.

Pectin-Coated Baclofen-Layered Zinc Hydroxide Nanohybrid as a Bio-Based Nanocomposite Carrier for Oral Delivery.

pH-sensitive pectin beads were proposed as a protective capsule for layered zinc hydroxide-drug (LZH-Drug) nanohybrids in the gastrointestinal tract in this paper. Baclofen was intercalated between LZH layers using the co-precipitation method as a model drug. By combining LZH-baclofen with pectin, the resulting nanohybrid (LZH-baclofen) was used to make bio-nanocomposite hydrogel beads. FTIR, XRD, and SEM analyses were used to characterize the produced products. Baclofen anions are vertical to the LZH layers in the shape of a monolayer, according to the interlayer space of 19.6Å. The presence of nanocomposites is demonstrated by FTIR, which exhibits a peak at 3489 cm-1 for the OH group, 1564 and 1384 cm-1 for the-COO- vibration mode, indicating that baclofen is intercalated between the layered structures. After intercalation, baclofen's thermal stability is greatly improved. The nanohybrid is more compact, with agglomerates and flat surfaces of the intercalated substance, shown by SEM. In vitro release behaviors of baclofen from LZH and bio-nanocomposites in buffer solution were examined under pH values (pH = 1.2, 6.8, 7.4) chosen from a model of the passing materials through the gastrointestinal tract. For pectin encapsulated LZH-baclofen nanohybrid, drug release studies indicated superior protection against stomach pH and regulated release under intestinal tract conditions. Furthermore, nanohybrid and nanocomposite treatment of a normal fibroblast cell line resulted in cell survival up to 12.5 g/mL for a 24-h period, with inhibition reducing dose-dependently at higher concentrations. A novel intercalation molecule with a sustained release mode and improved toxicity against normal fibroblast cell lines has been produced as a result of the strong host-guest contacts between the LZH lattice and the baclofen anion. Further study into the utilization of brucite-like host materials in drug delivery systems should be based on these findings.

Predictors of muscle hypertrophy responsiveness to electrically evoked resistance training after spinal cord injury.

The purpose of the study was to identify potential predictors of muscle hypertrophy responsiveness following neuromuscular electrical stimulation resistance training (NMES-RT) in persons with chronic spinal cord injury (SCI). Data for twenty individuals with motor complete SCI who completed twice weekly NMES-RT lasting 12-16 weeks as part of their participation in one of two separate clinical trials were pooled and retrospectively analyzed. Magnetic resonance imaging (MRI) was used to measure muscle cross-sectional area (CSA) of the whole thigh and knee extensor muscle before and after NMES-RT. Muscle biopsies and fasting biomarkers were also measured. Following the completion of the respective NMES-RT trials, participants were classified into either high-responders (n = 8; muscle CSA > 20%) or low-responders (n = 12; muscle CSA < 20%) based on whole thigh muscle CSA hypertrophy. Whole thigh muscle and knee extensors CSAs were significantly greater (P < 0.0001) in high-responders (29 ± 7% and 47 ± 15%, respectively) compared to low-responders (12 ± 3% and 19 ± 6%, respectively). There were no differences in total caloric intake or macronutrient intake between groups. Extensor spasticity was lower in the high-responders compared to the low-responders as was the dosage of baclofen. Prior to the intervention, the high-responders had greater body mass compared to the low-responders with SCI (87.8 ± 13.7 vs. 70.4 ± 15.8 kg; P = 0.012), body mass index (BMI: 27.6 ± 2.7 vs. 22.9 ± 6.0 kg/m2; P = 0.04), as well as greater percentage in whole body and regional fat mass (P < 0.05). Furthermore, high-responders had a 69% greater increase (P = 0.086) in total Akt protein expression than low-responders. High-responders also exhibited reduced circulating IGF-1 with a concomitant increase in IGFBP-3. Exploratory analyses revealed upregulation of mRNAs for muscle hypertrophy markers [IRS-1, Akt, mTOR] and downregulation of protein degradation markers [myostatin, MurF-1, and PDK4] in the high-responders compared to low-responders. The findings indicate that body composition, spasticity, baclofen usage, and multiple signaling pathways (anabolic and catabolic) are involved in the differential muscle hypertrophy response to NMES-RT in persons with chronic SCI.

Reduced motor cortex GABABR function following chronic alcohol exposure.

The GABAB receptor (GABABR) agonist baclofen has been used to treat alcohol and several other substance use disorders (AUD/SUD), yet its underlying neural mechanism remains unclear. The present study aimed to investigate cortical GABABR dynamics following chronic alcohol exposure. Ex vivo brain slice recordings from mice chronically exposed to alcohol revealed a reduction in GABABR-mediated currents, as well as a decrease of GABAB1/2R and G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) activities in the motor cortex. Moreover, our data indicated that these alterations could be attributed to dephosphorylation at the site of serine 783 (ser-783) in GABAB2 subunit, which regulates the surface expression of GABABR. Furthermore, a human study using paired-pulse-transcranial magnetic stimulation (TMS) analysis further demonstrated a reduced cortical inhibition mediated by GABABR in patients with AUD. Our findings provide the first evidence that chronic alcohol exposure is associated with significantly impaired cortical GABABR function. The ability to promote GABABR signaling may account for the therapeutic efficacy of baclofen in AUD.

Optimal management of severe symptomatic gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is a common disorder, and empirical proton pump inhibitor (PPI) treatment is often the first step of management; however, up to 40% of patients remain symptomatic despite PPI treatment. Refractory reflux refers to continued symptoms despite an adequate trial of PPI, and management remains challenging. The differential diagnosis is important; other oesophageal (e.g. eosinophilic oesophagitis) and gastroduodenal disorders (e.g. functional dyspepsia) should be ruled out, as this changes management. A combination of clinical assessment, endoscopic evaluation and in selected cases oesophageal function testing can help characterize patients with refractory reflux symptoms into oesophageal phenotypes so appropriate therapy can be more optimally targeted. Medical options then may include adding a H2 receptor antagonist, alginates, baclofen or antidepressant therapy, and there is emerging evidence for bile acid sequestrants and diaphragmatic breathing. The demonstration of a temporal association of symptoms with reflux events on pH-impedance testing (reflux hypersensitivity) serves to focus the management on modulating oesophageal perception and reducing the reflux burden, or identifies those with no obvious pathophysiologic abnormalities (functional heartburn). Anti-reflux surgery based on randomized controlled trial evidence has a role in reflux hypersensitivity or continued pathological acid reflux despite PPI in carefully considered, fully worked up cases that have failed medical therapy; approximately two of three cases will respond but there is a small risk of complications. In patients with persistent volume reflux despite medical therapy, given the lack of alternatives, anti-reflux surgery is a consideration. Promising newer approaches include endoscopic techniques. This review aims to summarize current diagnostic approaches and critically evaluates the evidence for the efficacy of available treatments.

A Critical Review of the Role of the Cannabinoid Compounds Δ9-Tetrahydrocannabinol (Δ9-THC) and Cannabidiol (CBD) and their Combination in Multiple Sclerosis Treatment.

Many people with MS (pwMS) use unregulated cannabis or cannabis products to treat the symptoms associated with the disease. In line with this, Sativex, a synthetic combination of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) has been approved to treat symptoms of spasticity. In animals, CBD is effective in reducing the amounts of T-cell infiltrates in the spinal cord, suggesting CBD has anti-inflammatory properties. By doing this, CBD has shown to delay symptom onset in animal models of multiple sclerosis and slow disease progression. Importantly, combinations of CBD and Δ9-THC appear more effective in treating animal models of multiple sclerosis. While CBD reduces the amounts of cell infiltrates in the spinal cord, Δ9-THC reduces scores of spasticity. In human studies, the results are less encouraging and conflict with the findings in animals. Drugs which deliver a combination of Δ9-THC and CBD in a 1:1 ratio appear to be only moderately effective in reducing spasticity scores, but appear to be almost as effective as current front-line treatments and cause less severe side effects than other treatments, such as baclofen (a GABA-B receptor agonist) and tizanidine (an α2 adrenergic receptor agonist). The findings of the studies reviewed suggest that cannabinoids may help treat neuropathic pain in pwMS as an add-on therapy to already established pain treatments. It is important to note that treatment with cannabinoid compounds may cause significant cognitive dysfunction. Long term double-blind placebo studies are greatly needed to further our understanding of the role of cannabinoids in multiple sclerosis treatment.

F-phenibut (ß-(4-Fluorophenyl)-GABA), a potent GABAB receptor agonist, activates an outward-rectifying K+ current and suppresses the generation of action potentials in mouse cerebellar Purkinje cells.

The GABA analog phenibut (ß-Phenyl-GABA) is a GABAB receptor agonist that has been licensed for various uses in Russia. Phenibut is also available as a dietary supplement from online vendors worldwide, and previous studies have indicated that phenibut overdose results in intoxication, withdrawal symptoms, and addiction. F-phenibut (ß-(4-Fluorophenyl)-GABA), a derivative of phenibut, has not been approved for clinical use. However, it is also available as a nootropic supplement from online suppliers. F-phenibut binds to GABAB with a higher affinity than phenibut; therefore, F-phenibut may lead to more serious intoxication than phenibut. However, the mechanisms by which F-phenibut acts on GABAB receptors and influences neuronal function remain unknown. In the present study, we compared the potency of F-phenibut, phenibut, and the GABAB agonist (±)-baclofen (baclofen) using in vitro patch-clamp recordings obtained from mouse cerebellar Purkinje cells slice preparations Our findings indicate that F-phenibut acted as a potent GABAB agonist. EC50 of outward current density evoked by the three GABAB agonists decreased in the following order: phenibut (1362 µM) > F-phenibut (23.3 µM) > baclofen (6.0 µM). The outward current induced by GABAB agonists was an outward-rectifying K+ current, in contrast to the previous finding that GABAB agonists activates an inward-rectifying K+ current. The K+ current recorded in the present study was insensitive to extracellular Ba2+, intra- or extracellular Cs+, and intra- or extracellular tetraethylammonium-Cl. Moreover, F-phenibut suppressed action potential generation in Purkinje cells. Thus, abuse of F-phenibut may lead to severe damage by inhibiting the excitability of GABAB-expressing neurons.

Structure optimization of positive allosteric modulators of GABAB receptors led to the unexpected discovery of antagonists/potential negative allosteric modulators.

Positive allosteric modulators (PAMs) of GABAB receptor represent an interesting alternative to receptor agonists such as baclofen, as they act on the receptor in a more physiological way and thus are devoid of the side effects typically exerted by the agonists. Based on our interest in the identification of new GABAB receptor PAMs, we followed a merging approach to design new chemotypes starting from selected active compounds, such as GS39783, rac-BHFF, and BHF177, and we ended up with the synthesis of four different classes of compounds. The new compounds were tested alone or in the presence of 10 µM GABA using [35S]GTPγS binding assay to assess their functionality at the receptor. Unexpectedly, a number of them significantly inhibited GABA-stimulated GTPγS binding thus revealing a functional switch with respect to the prototype molecules. Further studies on selected compounds will clarify if they act as negative modulators of the receptor or, instead, as antagonists at the orthosteric binding site.

GABA consumption during early pregnancy impairs endometrial receptivity and embryo development in mice.

γ-Aminobutyrate (GABA) is commonly used as a food supplement and a health care product by young females, due to its positive roles in relieving stress, alleviating anxiety, and improving sleep. However, its recommended daily dose in different products varies widely. Besides, it is unknown whether, and how, GABA consumption during early pregnancy influences pregnancy establishment. In this study, we found that when pregnant mice were treated with a high (12.5 mg/g) dose of GABA (orally) during preimplantation, there was a reduction in the number of implantation sites on day 5 of pregnancy. Also, among these unimplanted embryos, most exhibited morphological degeneration and developmental retardation, and only a few of them developed into blastocysts but could not implant into the uterus. Moreover, the expression of uterine receptivity-related factors-LIF, E-cadherin, and HOXA10-were all downregulated, while the number of uterine glands was reduced in the high GABA dose group. Finally, in vitro results demonstrated that GABA (ranging from 10 to 50 µg/µL) markedly inhibited preimplantation embryo development in a dose-response manner. However, this inhibitory effect was not observed when the embryos were pretreated with 40 µΜ 2-hydroxysaclofen, a GABAB antagonist, indicating that GABA exerts its inhibitory effects via its B-type receptor. Our results suggest that exposure to certain GABA concentrations, during early pregnancy, can impair preimplantation embryo development via its B-type receptor, and endometrial receptivity, which greatly disturbs early embryo implantation in mice. These findings could raise concerns about GABA consumption during the early stages of pregnancy.

Italian consensus on treatment of spasticity in multiple sclerosis.

BACKGROUND: Spasticity is a frequent multifactorial manifestation of multiple sclerosis (MS), affecting mostly the chronic courses of the disease. Its impact on patient functioning and quality of life is profound. Treatment of spasticity includes oral and intrathecal anti-spastic drugs, muscle injections with relaxant agents, physical therapy, electrical and magnetic stimulation and peripheral nerve stimulation, alone or in various combinations. METHODS: This Italian consensus on the treatment of spasticity in MS was produced by a large group of Italian MS experts in collaboration with neurophysiologists, experts in the production of guidelines and patients' representatives operating under the umbrella of the Italian Neurological Society, the Associazione Italiana Sclerosi Multipla and the European Charcot Foundation. This guideline was developed in accordance with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A total of 11 questions were formulated following the PICO framework (patients, intervention, comparator, outcome). Controlled studies only were included in the analysis. RESULTS: Despite some consistent limitations due to the poor methodological quality of most studies, there was a consensus on a strong recommendation for the use of intrathecal baclofen, oromucosal spray of nabiximols and intramuscular injection of botulinum toxin. The level of recommendation was weak for oral baclofen, tizanidine, gabapentin, benzodiazepines and transcranial magnetic stimulation. CONCLUSIONS: There is a clear need for new larger multicentre well-designed clinical trials with a duration that allows the persistence of the effects and the long-term safety of the interventions to be evaluated.

GABAB receptor activation attenuates inflammatory orofacial pain by modulating interleukin-1ß in satellite glial cells: Role of NF-κB and MAPK signaling pathways.

Orofacial inflammation could activate satellite glial cells (SGCs) in the trigeminal ganglion (TG) to produce interleukin 1ß (IL-1ß) which plays crucial roles in the development of inflammatory pain. Recent studies have shown that gamma-amino butyric acid-B (GABAB) receptor could modulate the expression of inflammatory cytokines in microglia and astrocytes in the spinal cord. The objective of this study was to investigate whether GABAB receptors in TG SGCs attenuate inflammatory facial pain via mediating IL-1ß following inflammation and its mechanisms. Complete Freund's adjuvant (CFA) was injected into the whisker pad of rats to induce inflammation in vivo. Lipopolysaccharide (LPS) was added to culture medium to activate SGCs in vitro. Behavioral measures showed that microinjection of baclofen (a selective GABAB receptor agonist) into the TG ameliorated the mechanical allodynia of CFA-treated rats. Interestingly, baclofen pretreatment inhibited SGC activation and IL-1ß production, however, preserved the decreased expression of GABAB receptors in SGCs activated by CFA in vivo and LPS in vitro. In addition, baclofen suppressed the increased expression of p-NF- κ B p65, p-I κ Bα, and p-p38 MAPK, while reversed the decreased production of I κ Bα, and further enhanced the increased expression of p-ERK(1/2) in LPS-treated SGCs in vitro. Finally, those effects of baclofen were abolished by saclofen (a specific GABAB receptor antagonist) co-administration. Altogether, these results demonstrated for the first time that activation of GABAB receptor might inhibit IL-1ß production by suppressing NF- κ B and p38 MAPK signaling pathway activation and restore GABAB receptor expression in SGCs to attenuate inflammatory facial pain.

Delirium tremens in an AUD patient after an intrathecal baclofen pump induced total alcohol abstinence.

OBJECTIVE: Delirium Tremens (DT) is the most severe complication of alcohol withdrawal syndrome (AWS), and has a mortality rate of 1-5%. Baclofen is recommended for spasticity treatment, but it has recently been used for alcohol withdrawal symptoms reduction and alcohol abstinence. CASE REPORT: A cervical spinal cord injury patient was treated for two years with oral baclofen 80 mg/day for spasticity. He is alcohol-dependent and a cannabis user and required an intrathecal baclofen (ITB) pump implant. A week after the implant, he stopped drinking, as "he didn't felt the urge anymore". The AWS appeared five days after the last alcohol intake and DT at 7 days. Diazepam 20 mg was used up to three times per day, but didn't seem to improve or reduce the anxiety, agitation, visual or auditory hallucinations. Two years later the patient remains alcohol abstinent and still on intrathecal baclofen. CONCLUSIONS: Alcohol-dependent patients can abruptly stop their alcohol intake, while in continuous infusion of intrathecal baclofen. Baclofen can be useful in the acute treatment of AWS as it seems to reduce diazepam requirements and in long-term alcohol abstinence. In the presence of AWS, while on chronic baclofen, no dose reduction should be attempted, as it can worsen the AWS or trigger baclofen withdrawal.

A review of the effects of baclofen and of THC:CBD oromucosal spray on spasticity-related walking impairment in multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a complex disease with a heterogeneous and unpredictable clinical course. Mobility impairment after progressive paralyses and muscle tone spasticity is common. Areas covered: The prevalence, assessment, and pharmacological management of gait impairment and spasticity in MS and their effects on health-related quality of life (HRQoL) are discussed. The roles of oral and intrathecal baclofen and of delta-9-tetrahydrocannabinol/cannabidiol (THC:CBD) oromucosal spray in treating MS spasticity-related gait impairment are reviewed. Expert commentary: Mobility impairment and spasticity are experienced by approximately 90% and 80% of MS patients, respectively, during the disease course. Prevalence and severity of gait impairment and spasticity increase as disease progresses. The symptoms are related and both impact negatively on HRQoL. Oral baclofen and tizanidine are generally used for first-line treatment of MS spasticity but are ineffective in approximately 40% of cases. Second-line therapy includes add-on THC:CBD spray for patients with resistant MS spasticity. Results of studies evaluating baclofen for treating MS spasticity gait impairment are equivocal. In studies of patients with resistant MS spasticity, THC:CBD spray consistently improved the timed 10-meter walk test and significantly improved multiple spatial-temporal and kinematic gait parameters. THC:CBD oromucosal spray warrants further investigation as a treatment for MS spasticity-related gait impairment.

Pharmacological therapies for management of opium withdrawal.

BACKGROUND: Pharmacologic therapies for management of heroin withdrawal have been studied and reviewed widely. Opium dependence is generally associated with less severe dependence and milder withdrawal symptoms than heroin. The evidence on withdrawal management of heroin might therefore not be exactly applicable for opium. OBJECTIVES: To assess the effectiveness and safety of various pharmacologic therapies for the management of the acute phase of opium withdrawal. SEARCH METHODS: We searched the following sources up to September 2017: CENTRAL, MEDLINE, Embase, CINAHL, PsycINFO, regional and national databases (IMEMR, Iranmedex, and IranPsych), main electronic sources of ongoing trials, and reference lists of all relevant papers. In addition, we contacted known investigators to obtain missing data or incomplete trials. SELECTION CRITERIA: Controlled clinical trials and randomised controlled trials on pharmacological therapies, compared with no intervention, placebo, other pharmacologic treatments, different doses of the same drug, and psychosocial intervention, to manage acute withdrawal from opium in a maximum duration of 30 days. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 13 trials involving 1096 participants. No pooled analysis was possible. Studies were carried out in three countries, Iran, India, and Thailand, in outpatient and inpatient settings. The quality of the evidence was generally very low.When the mean of withdrawal symptoms was provided for several days, we mainly focused on day 3. The reason for this was that the highest severity of opium withdrawal is in the second to fourth day.Comparing different pharmacological treatments with each other, clonidine was twice as good as methadone for completion of treatment (risk ratio (RR) 2.01, 95% confidence interval (CI) 1.69 to 2.38; 361 participants, 1 study, low-quality evidence). All the other results showed no differences between the considered drugs: baclofen versus clonidine (RR 1.06, 95% CI 0.63 to 1.80; 66 participants, 1 study, very low-quality evidence); clonidine versus clonidine plus amantadine (RR 1.03, 95% CI 0.86 to 1.24; 69 participants, 1 study); clonidine versus buprenorphine in an inpatient setting (RR 1.04, 95% CI 0.90 to 1.20; 1 study, 35 participants, very low-quality evidence); methadone versus tramadol (RR 0.95, 95% CI 0.65 to 1.37; 1 study, 72 participants, very low-quality evidence); methadone versus methadone plus gabapentin (RR 1.17, 95% CI 0.96 to 1.43; 1 study, 40 participants, low-quality evidence), and tincture of opium versus methadone (1 study, 74 participants, low-quality evidence).Comparing different pharmacological treatments with each other, adding amantadine to clonidine decreased withdrawal scores rated at day 3 (mean difference (MD) -3.56, 95% CI -5.97 to -1.15; 1 study, 60 participants, very low-quality evidence). Comparing clonidine with buprenorphine in an inpatient setting, we found no difference in withdrawal symptoms rated by a physician (MD -1.40, 95% CI -2.93 to 0.13; 1 study, 34 participants, very low-quality evidence), and results in favour of buprenorpine when rated by participants (MD -11.80, 95% CI -15.56 to -8.04). Buprenorphine was superior to clonidine in controlling severe withdrawal symptoms in an outpatient setting (RR 0.35, 95% CI 0.19 to 0.64; 1 study, 76 participants). We found no difference in the comparison of methadone versus tramadol (MD 0.04, 95% CI -2.68 to 2.76; 1 study, 72 participants) and in the comparison of methadone versus methadone plus gabapentin (MD -2.20, 95% CI -6.72 to 2.32; 1 study, 40 participants).Comparing clonidine versus buprenorphine in an outpatient setting, more adverse effects were reported in the clonidine group (1 study, 76 participants). Higher numbers of participants in the clonidine group experienced hypotension at days 5 to 8, headache at days 1 to 8, sedation at days 5 to 8, dizziness and dry mouth at days 1 to 10, and nausea at days 1 to 9. Sweating was reported in a significantly higher number of participants in the buprenorphine group at days 1 to 10. We found no difference between groups for all the other comparisons considering this outcome.Comparing different dosages of the same pharmacological detoxification treatment, a high dose of clonidine (1 to 1.2 mg/day) did not differ from a low dose of clonidine (0.5 to 0.6 mg/day) in completion of treatment in an inpatient setting (RR 1.00, 95% CI 0.84 to 1.19; 1 study, 68 participants), however a higher number of participants with hypotension was reported in the high-dose group (RR 3.25, 95% CI 1.77 to 5.98). Gradual reduction of methadone was associated with more adverse effects than abrupt withdrawal of methadone (RR 2.25, 95% CI 1.02 to 4.94; 1 study, 20 participants, very low-quality evidence). AUTHORS' CONCLUSIONS: Results did not support using any specific pharmacological approach for the management of opium withdrawal due to generally very low-quality evidence and small or no differences between treatments. However, it seems that opium withdrawal symptoms are significant, especially at days 2 to 4 after discontinuation of opium. All of the assessed medications might be useful in alleviating symptoms. Those who receive clonidine might experience hypotension.

A mixed treatment comparison on efficacy and safety of treatments for spasticity caused by multiple sclerosis: a systematic review and network meta-analysis.

OBJECTIVES: This study is aimed at providing a quantitative evaluation on different therapies of spasticity caused by multiple sclerosis. DATA SOURCES: PubMed and Embase database. REVIEW METHODS: We searched for randomized controlled trials that met the requirements. Percentages of improved patients' spasticity scale, mild adverse effect and severe adverse effect were extracted as outcomes. The forest plots accompanied with surface under the cumulative ranking curves were used to reveal the efficacy and safety of these therapies. RESULTS: In all, 23 randomized controlled trials with a total of 2720 patients were included in our study. Cannabinoids and botulinum toxin had shown a significantly better efficacy than placebo in the percentage of improved patients. Botulinum toxin also showed such significant difference compared with tizanidine and baclofen. No significant difference was found in spasticity scale. Cannabinoids, tizanidine and diazepam had significantly more mild adverse effect reports than placebo. Surface under the cumulative ranking curves suggested that cannabinoids, botulinum toxin and transcutaneous electric nerve stimulation were preferable therapies. CONCLUSIONS: We recommended botulinum toxin as the optimal intervention for multiple sclerosis-related spasticity. Cannabinoids and transcutaneous electric nerve stimulation could also be considered as multiple sclerosis-related spasticity treatments but their safety remained to be verified.

Inhibitory Modulation of Orbitofrontal Cortex on Medial Prefrontal Cortex-Amygdala Information Flow.

The amygdala receives cortical inputs from the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) that are believed to affect emotional control and cue-outcome contingencies, respectively. Although mPFC impact on the amygdala has been studied, how the OFC modulates mPFC-amygdala information flow, specifically the infralimbic (IL) division of mPFC, is largely unknown. In this study, combined in vivo extracellular single-unit recordings and pharmacological manipulations were used in anesthetized rats to examine how OFC modulates amygdala neurons responsive to mPFC activation. Compared with basal condition, pharmacological (N-Methyl-D-aspartate) or electrical activation of the OFC exerted an inhibitory modulation of the mPFC-amygdala pathway, which was reversed with intra-amygdala blockade of GABAergic receptors with combined GABAA and GABAB antagonists (bicuculline and saclofen). Moreover, potentiation of the OFC-related pathways resulted in a loss of OFC control over the mPFC-amygdala pathway. These results show that the OFC potently inhibits mPFC drive of the amygdala in a GABA-dependent manner; but with extended OFC pathway activation this modulation is lost. Our results provide a circuit-level basis for this interaction at the level of the amygdala, which would be critical in understanding the normal and pathophysiological control of emotion and contingency associations regulating behavior.

Acupuncture reduces relapse to cocaine-seeking behavior via activation of GABA neurons in the ventral tegmental area.

There is growing public interest in alternative approaches to addiction treatment and scientific interest in elucidating the neurobiological underpinnings of acupuncture. Our previous studies showed that acupuncture at a specific Shenmen (HT7) points reduced dopamine (DA) release in the nucleus accumbens (NAc) induced by drugs of abuse. The present study was carried out to evaluate the effects of HT7 acupuncture on γ-aminobutyric acid (GABA) neuronal activity in the ventral tegmental area (VTA) and the reinstatement of cocaine-seeking behavior. Using microdialysis and in vivo single-unit electrophysiology, we evaluated the effects of HT7 acupuncture on VTA GABA and NAc DA release and VTA GABA neuronal activity in rats. Using a within-session reinstatement paradigm in rats self-administering cocaine, we evaluated the effects of HT7 stimulation on cocaine-primed reinstatement. Acupuncture at HT7 significantly reduced cocaine suppression of GABA release and GABA neuron firing rates in the VTA. HT7 acupuncture attenuated cocaine-primed reinstatement, which was blocked by VTA infusions of the selective GABAB receptor antagonist 2-hydroxysaclofen. HT7 stimulation significantly decreased acute cocaine-induced DA release in the NAc, which was also blocked by 2-hydroxysaclofen. HT7 acupuncture also attenuated cocaine-induced sensitization of extracellular DA levels in the NAc. Moreover, HT7 acupuncture reduced both locomotor activity and neuronal activation in the NAc induced by acute cocaine in a needle-penetration depth-dependent fashion. These results suggest that acupuncture may suppress cocaine-induced DA release in the NAc and cocaine-seeking behavior through activation of VTA GABA neurons. Acupuncture may be an effective therapy to reduce cocaine relapse by enhancing GABAergic inhibition in the VTA.