Doses Of Baclofen Research Articles

Phone-based safety monitoring of the first year of baclofen treatment for alcohol use disorder: the BACLOPHONE cohort study protocol

ABSTRACTBackground: In France, baclofen is frequently used off-label for alcohol use disorder (AUD). Baclofen has been associated with diverse adverse events (AEs), but the causality of these AEs has never been properly assessed.Methods/Design: BACLOPHONE is a prospective multicenter cohort study conducted in the Hauts-de-France and Normandie French regions. BACLOPHONE consists of the phone-based monitoring of 792 patients during their first year of baclofen treatment for AUD. Two initial phone interviews assess the medical history, current medications, and substance use as well as complete the alcohol use identification test (AUDIT) and severity of alcohol dependence questionnaire (SADQ). Daily alcohol use and baclofen doses are noted throughout the follow-up. For every reported AE, additional phone interviews determine the seriousness of the AE, the causality of baclofen using validated causality algorithms, and the final outcome. The main objective of the study is to determine the rate of patients who stop baclofen due to an AE during the first year of treatment.Discussion: BACLOPHONE will provide important safety data on baclofen as a complement to the forthcoming efficacy data of randomized clinical trials.

A Randomized Dose Escalation Study of Intravenous Baclofen in Healthy Volunteers: Clinical Tolerance and Pharmacokinetics

BackgroundAbrupt discontinuation of baclofen can result in a potentially severe withdrawal syndrome. The current treatment for baclofen withdrawal is inadequate, resulting in a critical need to develop an alternative method to prevent or treat this withdrawal syndrome. ObjectiveTo evaluate the safety profile and pharmacokinetics of oral (PO) and investigational intravenous (IV) baclofen formulations at clinically relevant doses. DesignRandomized, open-label, dose-escalation, crossover study. SettingContract Research Organization (CRO). MethodsThree cohorts of 12 healthy adults received single doses of PO baclofen (10 mg, 15 mg or 20 mg) and 10-minute infusions of IV baclofen (7.5 mg, 11.5 mg, or 15 mg) with a minimum 48-hour wash-out period. The third cohort also received a 60-minute infusion of 15 mg IV baclofen after an additional 48-hour wash-out period. Main Outcome MeasuresSubjects were observed in a CRO for 24 hours after each dose of baclofen, and were assessed for nystagmus, ataxia, and sedation. Blood samples were collected from 0 to 24 hours and analyzed for baclofen concentration using high-performance liquid chromatography−mass spectroscopy. Noncompartmental pharmacokinetic analyses were performed. Dose linearity and proportionality was assessed using 2-way repeated-measures analysis of variance and a power model analysis. ResultsNone of the PO or IV doses resulted in significant sedation compared to baseline. All subjects could perform tandem gait after each baclofen dose. The most common side effect, transient mild nystagmus, was noted in 4 of 36 and in 13 of 36 subjects after PO and IV administration, respectively. This was likely related to increased maximum concentrations (Cmax). After the 20 mg PO and 15 mg IV doses, mean Cmax levels were 255 and 722 ng/mL and half-lives were 5.24 and 5.79 hours for PO and IV baclofen, respectively. The mean oral bioavailability for the 20-mg PO dose was approximately 80%. ConclusionsAll PO and IV doses of baclofen were well tolerated clinically. The 80% bioavailability suggests that a 20% reduction in IV dose will produce comparable total drug exposures to that of the PO dose. When PO therapy is interrupted, bridging with IV baclofen may be feasible. Level of EvidenceII

Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: A multicentre, randomised, double-blind controlled trial

Previous randomised placebo-controlled trials with low-to-medium doses of baclofen (30–60mg) showed inconsistent results, but case studies suggested a dose-response effect and positive outcomes in patients on high doses of baclofen (up to 270mg). Its prescription was temporary permitted for the treatment of alcohol dependence (AD) in France, and baclofen is now widely prescribed. Recently, a small RCT found a strong effect of a mean dose of 180mg baclofen. In the present study the efficacy and safety of high doses of baclofen was examined in a multicentre, double-blind, placebo-controlled trial. 151 patients were randomly assigned to either six weeks titration and ten weeks high-dose baclofen (N=58; up to 150mg), low-dose baclofen (N=31; 30mg), or placebo (N=62). The primary outcome measure was time to first relapse. Nine of the 58 patients (15.5%) in the high-dose group reached 150mg and the mean baclofen dose in this group was 93.6mg (SD=40.3). No differences between the survival distributions for the three groups were found in the time to first relapse during the ten-weeks high-dose phase (χ2=0.41; p=0.813) or the 16-weeks complete medication period (χ2=0.04; p=0.982). There were frequent dose-related adverse events in terms of fatigue, sleepiness, and dry mouth. One medication related serious adverse event occurred in the high-dose baclofen group. Neither low nor high doses of baclofen were effective in the treatment of AD. Adverse events were frequent, although generally mild and transient. Therefore, large-scale prescription of baclofen for the treatment of AD seems premature and should be reconsidered.

Bomba intratecal de baclofeno, ¿una intervención terapéutica útil y segura en pacientes con espasticidad? Presentación de casos

Spasticity may cause immobility, prostration, chronic pain, bedsores, infections, thrombosis and pneumonia; the purposes of its treatment are to control pain, improve mobility and quality of life, and reincorporate the patient to its daily activities by means of oral anti-spastic drugs; however, patients suffering from severe spasticity may require high oral doses of these medications, which may lead to adverse effects. In such cases, intrathecal baclofen has been proposed as a solution. This procedure has not been widely used in Colombia, so that protocols to perform it have not been established. We report the results obtained with the intrathecal administration of baclofen in four severely spastic patients, who had not previously responded to oral anti-spastic drugs, including high doses of baclofen. Pain, spasticity and quality of life significantly improved in three of them. The remaining one presented tolerance to the medication. Intrathecal baclofen pump is a useful and safe procedure for patients with severe spasticity and poor response to oral treatment.

Quantitative pharmacokinetic-pharmacodynamic modelling of baclofen-mediated cardiovascular effects using BP and heart rate in rats.

While the molecular pathways of baclofen toxicity are understood, the relationships between baclofen-mediated perturbation of individual target organs and systems involved in cardiovascular regulation are not clear. Our aim was to use an integrative approach to measure multiple cardiovascular-relevant parameters [CV: mean arterial pressure (MAP), systolic BP, diastolic BP, pulse pressure, heart rate (HR); CNS: EEG; renal: chemistries and biomarkers of injury] in tandem with the pharmacokinetic properties of baclofen to better elucidate the site(s) of baclofen activity. Han-Wistar rats were administered vehicle or ascending doses of baclofen (3, 10 and 30mg·kg(-1) , p.o.) at 4h intervals and baclofen-mediated changes in parameters recorded. A pharmacokinetic-pharmacodynamic model was then built by implementing an existing mathematical model of BP in rats. Final model fits resulted in reasonable parameter estimates and showed that the drug acts on multiple homeostatic processes. In addition, the models testing a single effect on HR, total peripheral resistance or stroke volume alone did not describe the data. A final population model was constructed describing the magnitude and direction of the changes in MAP and HR. The systems pharmacology model developed fits baclofen-mediated changes in MAP and HR well. The findings correlate with known mechanisms of baclofen pharmacology and suggest that similar models using limited parameter sets may be useful to predict the cardiovascular effects of other pharmacologically active substances.

Possible involvement of ATP-sensitive potassium channels in the antidepressant-like effect of baclofen in mouse forced swimming test.

Previous study confirmed that the acute treatment with baclofen by inhibition of the l-arginine-nitric oxide (NO) pathway diminished the immobility behavior in the forced swimming test (FST) of mice. Considering the involvement of NO in adenosine triphosphate (ATP)-sensitive potassium channels (KATP), in the present study we investigated the involvement of KATP channels in antidepressant-like effect of baclofen in the forced swimming test (FST). After assessment of locomotor behavior in the open-field test (OFT), FST was applied for evaluation of the antidepressant-like activity of baclofen in mice. Baclofen at different doses (0.1, 0.3, and 1mg/kg) and fluoxetine (20mg/kg) were administrated by intraperitoneal (ip) route, 30min before the FST or OFT. To clarify the probable involvement of KATP channels, after determination of sub-effective doses of glibenclamide as a KATP channel blocker and cromakalim, as an opener of these channels, they were co-administrated with the sub-effective and effective doses of baclofen, respectively. Baclofen at dose 1mg/kg significantly decreased the immobility behavior of mice similar to fluoxetine (20mg/kg). Co-administration of gelibenclamide sub-effective dose (1mg/kg) with baclofen (0.1mg/kg) showed a synergistic antidepressant-like effect in the FST. Also, sub-effective dose of cromakalim (0.1mg/kg) inhibited the antidepressant-like effect of baclofen (1mg/kg) in the FST. All aforementioned treatments had not any impact on the locomotor movement of mice in OFT. Our study for the first time revealed that antidepressant-like effect of baclofen on mice is KATP-dependent, and baclofen seems that exert this effect by blocking the KATP channels.

Unexpected Baclofen Subdural Infusion in a Patient who Carries an Internal Pump for Intrathecal Infusion: A Case Report

Objective: We report a case of intrathecal baclofen infusion pump implantation complicated by migration of the catheter tip. Subdural migration, of the intrathecal catheter tip, in who has been having an infusion pump for years and is experiencing swinging dosage related effects it is not the first thing one takes into consideration. A case of subdural migration of intrathecal catheters is presented. Methods: Subsequent X-ray and computed tomography evaluations of the catheter system revealed pooling of contrast medium outside of the intrathecal space, in the lumbar subdural region of the vertebral channel and therefore migration of the pump catheter tip. Results: The spinal catheter was subsequently revised, and the patient made a full recovery. From few days after surgery, the patients spasticity improved and up to now (six months later), he has been experiencing no further complications, is requiring an average baclofen dosage of 150 mcg/day. Conclusion: The possible migration of an intrathecal catheter into the subdural space should be included as differential diagnosis in a patient who experiences a lack of drug effect, despite increases in dosage, after years from pump implantation. We recommend the use of the CT scan, after contrast injection, to detect the distal catheter tip and confirm a normal diffusion into the subarachnoid space.

Effects of severe spasticity treatment with intrathecal Baclofen in multiple sclerosis patients: Long term follow-up.

Intrathecal Baclofen is available to treat severe generalized spasticity in Multiple Sclerosis (MS) unresponsive to oral drug delivery. The aims of this study were to investigate the effects and the drug dosage of intrathecal Baclofen in a selected population of MS patients, affected by severe spasticity at long term follow-up. A prospective cohort study of 14 MS patients is presented. Spasticity and pain were periodically assessed and the Baclofen dosage was adjusted. The initial Baclofen dosage was 136.2 ± 109.3 μg, then it was increased at 12 months to 228.6 ± 179.2 μg (p < 0.05). The subsequent dose adjustments did not result in significant changes up to 76 months. Spasticity on the lower limbs decreased significantly from pre-implantation assessment (median: 3.5, IQR: 3.0-4.0) to 12 months evaluation (median: 0.5, IQR: 0.0-2.0) (p < 0.001); no further decrease was observed after 24 months (median: 0.5, IQR: 0.0-1.5); when pain was present, it decreased. Some effects on cerebellar symptoms were observed. Botulinum toxin injections were used with intrathecal Baclofen therapy. A reduced spasticity and pain was observed after the intrathecal Baclofen infusion for at least 76 months. To obtain these results a dosage adjustment was needed only in the first year after the implantation.

The positive allosteric GABAB receptor modulator rac-BHFF enhances baclofen-mediated analgesia in neuropathic mice

Neuropathic pain is associated with impaired inhibitory control of spinal dorsal horn neurons, which are involved in processing pain signals. The metabotropic GABAB receptor is an important component of the inhibitory system and is highly expressed in primary nociceptors and intrinsic dorsal horn neurons to control their excitability. Activation of GABAB receptors with the orthosteric agonist baclofen effectively reliefs neuropathic pain but is associated with severe side effects that prevent its widespread application. The recently developed positive allosteric GABAB receptor modulators lack most of these side effects and are therefore promising drugs for the treatment of pain. Here we tested the high affinity positive allosteric modulator rac-BHFF for its ability to relief neuropathic pain induced by chronic constriction of the sciatic nerve in mice. rac-BHFF significantly increased the paw withdrawal threshold to mechanical stimulation in healthy mice, indicating an endogenous GABABergic tone regulating the sensitivity to mechanical stimuli. Surprisingly, rac-BHFF displayed no analgesic activity in neuropathic mice although GABAB receptor expression was not affected in the dorsal horn as shown by quantitative receptor autoradiography. However, activation of spinal GABAB receptors by intrathecal injection of baclofen reduced hyperalgesia and its analgesic effect was considerably potentiated by co-application of rac-BHFF. These results indicate that under conditions of neuropathic pain the GABAergic tone is too low to provide a basis for allosteric modulation of GABAB receptors. However, allosteric modulators would be well suited as an add-on to reduce the dose of baclofen required to achieve analgesia.

Safety reports on the off-label use of baclofen for alcohol-dependence: recommendations to improve causality assessment

ABSTRACTIntroduction: The off-label use of high-dose baclofen (HDB) for alcohol-dependence has recently spread. However, HDB has been associated with numerous reports of adverse events (AEs). Pharmacovigilance reporting is supposed to differentiate AEs from adverse drug reactions (ADRs), for which the causality of the drug is determined using validated methods.Areas covered: Since 2010, we found 20 publications on baclofen-related AEs in alcohol dependence, in Medline-referenced journals or national pharmacovigilance reports. We focused on whether these reports used causality algorithms, and provided essential elements for determining baclofen causality and excluding the involvement of alcohol and other psychoactive substances or psychotropic drugs. In half of the cases, no causality algorithm was used. Detailed information on baclofen dosing was found in 17 out of 20 (85%) articles, whereas alcohol doses were given only in 10 (50%) publications. Other psychoactive substances and psychotropic drugs were broached in 14 (70%) publications.Expert opinion: future publications reporting suspected HDB-induced ADRs should use validated causality algorithms and provide sufficient amount of contextual information for excluding other potential causes. For HDB, the psychiatric history, and the longitudinal description of alcohol consumptions and associated doses of psychoactive substances or psychotropic medications should be detailed for every reported case.

Recovery from ketamine-induced amnesia by blockade of GABA-A receptor in the medial prefrontal cortex of mice

Ketamine and other noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists are known to induce deficits in learning and cognitive performance sensitive to prefrontal cortex (PFC) functions. The interaction of a glutamatergic and GABAergic systems is essential for many cognitive behaviors. In order to understand the effect of γ-aminobutyric acid (GABA)/glutamate interactions on learning and memory, we investigated the effects of intra medial prefrontal cortex (mPFC) injections of GABAergic agents on ketamine-induced amnesia using a one-trial passive avoidance task in mice. Pre-training systemic administration of ketamine (5, 10 and 15mg/kg, i.p.) dose-dependently decreased the memory acquisition of a one-trial passive avoidance task. Pre-training intra-mPFC injection of muscimol, GABAA receptor agonist (0.05, 0.1 and 0.2μg/mouse) and baclofen GABAB receptor agonist (0.05, 0.1, 0.5 and 1μg/mouse), impaired memory acquisition. However, co-pretreatment of different doses of muscimol and baclofen with a lower dose of ketamine (5mg/kg), which did not induce amnesia by itself, caused inhibition of memory formation. Our data showed that sole pre-training administration of bicuculline, GABA-A receptor antagonist and phaclofen GABA-B receptor antagonist into the mPFC, did not affect memory acquisition. In addition, the amnesia induced by pre-training ketamine (15mg/kg) was significantly decreased by the pretreatment of bicuculline (0.005, 0.1 and 0.5μg/mouse). It can be concluded that GABAergic system of the mPFC is involved in the ketamine-induced impairment of memory acquisition.

Substance use disorders: Baclofen as a promising drug

IntroductionBaclofen, a drug currently used in the treatment of spasticity, has been reported to be useful in reducing the intensity of withdrawal symptoms of substance use disorders of alcohol or other psychotropic drugs.ObjectivesWith our clinical case we aim to demonstrate that baclofen reduces severe withdrawal symptoms and also helps to achieve and maintain abstinence in severe cases, in agreement with the current literature.Aims/methodsWe present a clinical case of a 68 year-old patient with alcohol use disorder since his childhood, with familiar antecedents, multiples relapses and associated organic pathology such as alcoholic polyneuropathy and Wernicke syndrome. We used to high doses of baclofen to reduce the craving and withdrawal symptoms. Additionally, we searched in PubMed for more case reports and for a systematic review of the efficacy and tolerability of baclofen.ResultsWe were able to demonstrate that high doses of baclofen can be useful in resistant cases of substance use disorders like alcoholism. For our case study, we obtained positive results with a large remission, in comparison with the previous detoxications, with doses up to 150 mg/day.ConclusionsWe conclude that baclofen is an interesting alternative for resistant cases, with a good outcome and tolerability, in complicated patients, with important organic repercussions.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Baclofen blocks yohimbine-induced increases in ethanol-reinforced responding in rats

Chronic or repeated stress increases alcohol consumption. The GABA-B agonist baclofen decreases alcohol consumption and may be most effective for individuals with comorbid anxiety/stress disorders. The present study sought to determine if baclofen blocks stress-induced increases in ethanol self-administration as modeled by repeated yohimbine injections in rats. Rats were trained to respond for 15% w/v ethanol in operant chambers using a method that applies neither water deprivation nor saccharin/sucrose fading. Following training, the rats received 6 injections of 1.25mg/kg yohimbine were given immediately prior to the operant sessions during a 2-week time period. Subsequently, some rats were pair-matched to receive either 1.25mg/kg yohimbine or saline in the presence of 0.3, 1, and 3mg/kg baclofen prior to sessions. Acquisition of ethanol self-administration was poor. Pretreatment with yohimbine consistently increased responding across repeated injections. Yohimbine's effect on ethanol intake unexpectedly diverged from the effect on responding as the rats failed to consume all reinforcers earned. Smaller doses of baclofen paired with saline injections had no effect on ethanol responding; only 3mg/kg baclofen reduced ethanol self-administration. The smallest baclofen dose of 0.3mg/kg failed to block the yohimbine-induced increase in self-administration. The large baclofen dose of 3mg/kg continued to suppress ethanol self-administration when given with yohimbine. Baclofen 1mg/kg blocked the effect of yohimbine even though it had no effect when given in the absence of yohimbine. Exposure to high ethanol concentrations may induce self-administration only in certain conditions. The dissociation between responding and intake suggests that repeated yohimbine injections may initiate other behavioral or physiological mechanisms that confound its effects as a pharmacological stressor. Furthermore, an optimal baclofen dose range may specifically protect against stress-induced alcohol self-administration, highlighting a specific contribution of GABA-B receptors and a potential therapeutic efficacy of GABA-B agonists at a non-sedating dose.

Baclofen differentially mediates fructose-conditioned flavor preference and quinine-conditioned flavor avoidance in rats

Rats display both fructose-conditioned flavor preference (CFP) and quinine conditioned flavor avoidance (CFA). Dopamine (D1 and D2), muscarinic and nicotinic, but not NMDA or opioid receptor antagonists reduced fructose-CFP expression. Dopamine D1, dopamine D2, muscarinic or NMDA, but not opioid or nicotinic receptor antagonists reduced fructose-CFP acquisition. Dopamine D1, NMDA, nicotinic or opioid, but not dopamine D2 or muscarinic receptor antagonists enhanced quinine-CFA acquisition. Baclofen (BAC), a GABAB receptor agonist, alternately enhances or reduces feeding under specific conditions. The present study examined whether systemic BAC administration mediated fructose-CFP expression and acquisition or quinine-CFA acquisition. Fructose-CFP expression studies trained rats with one flavor (CS+) in 8% fructose and 0.2% saccharin and a second (CS−) flavor in 0.2% saccharin, followed by vehicle (VEH) and BAC (0.5–5mg/kg) preceding 2-bottle (CS+, CS−) 0.2% saccharin choice tests. Fructose-CFP acquisition studies administered VEH or BAC (3 or 5mg/kg) prior to CS+ and CS− training sessions followed by six 2-bottle (CS+, CS−) 0.2% saccharin choice tests. Quinine-CFA acquisition studies administered VEH or BAC (3 or 5mg/kg) prior to CS− (8% fructose+0.2% saccharin) and CS+ (fructose+saccharin+0.030% quinine) training sessions followed by six 2-bottle (CS−, CS+) fructose+saccharin choice tests. BAC (3mg/kg) minimally (66%) reduced fructose-CFP expression. BAC failed to alter fructose-CFP acquisition. Quinine-CFA acquisition was enhanced by the 5mg/kg BAC dose (15–25%) relative to VEH (34–48%). These data implicate GABAB receptor signaling in acquisition of quinine avoidance with minimal or no effects upon fructose preferences.

Clinical experience of baclofen in alcohol dependence: A chart review.

Introduction:Craving is recognized as a formidable barrier in the management of patients with alcohol dependence. Among pharmacological agents that have been used in experimental studies for reduction in craving, baclofen appears to have a significant advantage over other agents.Methodology:The study is retrospective chart review of patients (n = 113) who have been treated with baclofen for alcohol dependence in a tertiary hospital of North India. Baseline assessments included sociodemography, motivation, quantity-frequency of alcohol use, and other alcohol-related clinical parameters. Weekly assessments, for a period of 4 weeks, were extracted from records which included dose of baclofen, craving intensity, and alcohol consumption.Results:The study sample was predominantly male, mean age of 41.49 (±9.75) years, most having a family history of substance use (70.97%), and many reporting binge use pattern in last year (49.46%). Baseline assessment revealed 48.7% of the sample was in precontemplation phase for alcohol use and 70% reported severe and persistent craving. This persistent craving was reported by only 15% of the sample by the end of 4 weeks treatment with baclofen (20–40 mg/day). Thirty-four percent of patients reported continued problematic use of alcohol by the end of 4 weeks.Conclusion:Our clinical experience suggests that baclofen reduces craving and alcohol consumption including in those with poor motivation. The drug causes few side effects and does not add to the intoxication effect of alcohol. Considering that baclofen is safe in those with liver cirrhosis and reduces withdrawal symptoms due to alcohol, a controlled trial comparing it with standard treatment is required.

Intra-Operative Computed Tomography Confirmation of Intrathecal Drug Delivery System Catheter

A 56 year old female presented with severe continued spasticity after revision of an implanted intrathecal drug delivery system for baclofen administration. The patient suffered a left temporal intracerebral hemorrhage with subsequent right spastic hemiplegia, upper extremity worse than lower. She underwent an initial intrathecal drug delivery system implant with catheter placement at T10. The medication did not affect spasticity of the right upper extremity. Therefore, the catheter position was revised to T4. Following the procedure, the patient was transferred to a skilled nursing facility for medical management and intrathecal baclofen dose titration. Despite titration of baclofen, the spasticity still persisted. Imaging studies, including radiograph, computed tomography and Magnetic Resonance Imaging demonstrated that the catheter tip was adherent to the dorsal membranes, consistent with placement in the subdural space, but possibly not the subarachnoid space. During the second revision of the catheter, intraoperative-computed tomography imaging of the patient’s spine was used to confirm placement prior to closure. This technique clearly demonstrated that the intrathecal catheter entered through the laminectomy at T7 and terminated at T4 in the intrathecal space as anticipated. Future use of this technique may demonstrate the improper placement of an intrathecal drug delivery system catheter. This would allow immediate revision of the catheter and prevent unnecessary returns to the operating suite.

Usefulness of Coupling Transcutaneous Electrical Nerve Stimulation with Routine Physical Therapy in Spinal Spasticity with Intolerant Drug Sideeffects: A Case Report

Spasticity is a common complaint in patients with spinal cord injury. Clinically, spasticity is characterized by increased muscle tone, exaggerated tendon reflex, frequent muscle spasm and clonus. We report a case of worsening spasticity in a patient with incomplete cervical spinal cord injury (ASIA B) as a consequence to urinary tract infection. The initial baclofen dose of 5 mg/dose three times per day was increased to 15 mg/dose three times/day with dosage increment at 3-day intervals by 15 mg (5 mg/dose). Marked weakness and vertigo was reported. He continued to suffer from severe spasms and trunk tightness that limited his daily activities and induced intolerable pain. The Modified Ashworth Score was increased from 1+ initially to 3, and the Pen Spasm frequency Score deteriorated from initial 1 to 3. After eradication of urinary tract infection with ciprofloxacin, spasticity did not improve, and so was administered with high-frequency transcutaneous electrical nerve stimulation at the parameters of frequency 100 Hz, pulse-width 0.2 millisecond, intensity 15 mA for the duration of 60 minutes for 3 weeks, coupling with routine physical therapy. After 3 week of TENS therapy, final Modified Ashworth Score reduced to 1+ , and Final Penn Spasm frequency Score was decreased to 2 with much improved quality of life. We also discuss the role of coupling transcutaneous electrical nerve stimulation with physical therapy in spinal spasticity.

The involvement of NMDA receptor/NO/cGMP pathway in the antidepressant like effects of baclofen in mouse force swimming test

In the current study, the involvement of N-methyl-d-aspartate receptor (NMDAR) and nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) system in the antidepressant-like effects of baclofen was evaluated by using animal model in forced swimming test. Followed by an open field test for the evaluation of locomotor activity, the immobility time for mice in force swimming test was recorded. Only the last four min was analyzed. Administration of Baclofen (0.5 and 1mg/kg, i.p.) reduced the immobility interval in the FST. Prior administration of l-arginine (750mg/kg, i.p.,) a nitric oxide synthase substrate or sildenafil (5mg/kg, i.p.) a phosphodiesterase 5 into mice suppressed the antidepressant-like activity of baclofen (1mg/kg, i.p.).Co-treatment of 7-nitroindazole (50mg/kg, i.p.,) an inhibitor of neuronal nitric oxide synthase, L-NAME (10mg/kg, i.p.,) a non-specific inhibitor of nitric oxide synthase or MK-801 (0.05mg/kg, i.p.) an NMDA receptor antagonist with subeffective dose of baclofen (0.1mg/kg, i.p.), reduced the immobility time in the FST as compared to the drugs when used alone. Co-administrated of lower doses of MK-801 (0.01mg/kg) or l-NAME (1mg/kg) failed to effect immobility time however, simultaneous administration of these two agents in same dose with subeffective dose of baclofen (0.1mg/kg, i.p.), minimized the immobility time in the FST. Thus, our results support the role of NMDA receptors and l-arginine-NO-GMP pathway in the antidepressant-like action of baclofen.

Validated Method for the Quantification of Baclofen in Human Plasma Using Solid-Phase Extraction and Liquid Chromatography-Tandem Mass Spectrometry.

A highly sensitive and fully validated method was developed for the quantification of baclofen in human plasma. After adjusting the pH of the plasma samples using a phosphate buffer solution (pH 4), baclofen was purified using mixed mode (C8/cation exchange) solid-phase extraction (SPE) cartridges. Endogenous water-soluble compounds and lipids were removed from the cartridges before the samples were eluted and concentrated. The samples were analyzed using triple-quadrupole liquid chromatography-tandem mass spectrometry (LC-MS-MS) with triggered dynamic multiple reaction monitoring mode for simultaneous quantification and confirmation. The assay was linear from 25 to 1,000 ng/mL (r(2) > 0.999; n = 6). Intraday (n = 6) and interday (n = 15) imprecisions (% relative standard deviation) were <5%, and the average recovery was 30%. The limit of detection of the method was 5 ng/mL, and the limit of quantification was 25 ng/mL. Plasma samples from healthy male volunteers (n = 9, median age: 22) given two single oral doses of baclofen (10 and 60 mg) on nonconsecutive days were analyzed to demonstrate method applicability.

Intrathecal Versus Oral Baclofen: A Matched Cohort Study of Spasticity, Pain, Sleep, Fatigue, and Quality of Life

BackgroundBaclofen commonly is used to manage spasticity caused by central nervous system lesions or dysfunction. Although both intrathecal and oral delivery routes are possible, no study has directly compared clinical outcomes associated with these 2 routes of treatment. ObjectiveTo compare spasticity levels, pain, sleep, fatigue, and quality of life between individuals receiving treatment with intrathecal versus oral baclofen. DesignCross-sectional matched cohort survey study. SettingUrban academic rehabilitation outpatient clinics. ParticipantsAdult patients with spasticity, treated with intrathecal or oral baclofen for at least 1 year, matched 1:1 for age, gender, and diagnosis. MethodsStandardized surveys were administered during clinic appointments or by telephone. Main Outcome MeasuresSurveys included the Penn Spasm Frequency Scale, Brief Pain Inventory, Epworth Sleepiness Scale, Fatigue Severity Scale, Life Satisfaction Questionnaire, and Diener Satisfaction with Life Scale. ResultsA total of 62 matched subjects were enrolled. The mean (standard deviation [SD]) age was 46 (11) years with a mean duration of intrathecal baclofen or oral baclofen treatment of 11 (6) and 13 (11) years, respectively. There were 40 (64%) male and 22 (36%) female subjects. Primary diagnoses included spinal cord injury (n = 38), cerebral palsy (n = 10), stroke (n = 10), and multiple sclerosis (n = 4). The mean (SD) dose of intrathecal and oral baclofen at the time of survey were 577 (1429) μg/day and 86 (50) mg/day, respectively. Patients receiving intrathecal compared with oral baclofen experienced significantly fewer (1.44 [0.92] versus 2.37 [1.12]) and less severe (1.44 [0.92] versus 2.16 [0.83]) spasms, respectively as measured by the Penn Spasm Frequency Scale (P < .01; P < .01). There were no significant differences in pain, sleep, fatigue, and quality of life between groups. Subanalysis of patients with SCI mirrored results of the entire study sample, with significant decreases in spasm frequency and severity associated with intrathecal compared to oral baclofen (P < .01; P < .01), but no other between group differences. The mean (SD) percent change in dose of oral (21% [33%]) compared with intrathecal (3% [28%]) baclofen was significantly larger two years prior to the date of survey (P = .02). ConclusionsLong-term treatment with intrathecal compared with oral baclofen is associated with reduced spasm frequency and severity as well as greater dose stability. These benefits must be weighed against the risks of internal pump and catheter placement in patients considering intrathecal baclofen therapy.