Effects of Baclofen on Central Paroxysmal Positional Downbeat Nystagmus.

Paroxysmal positional nystagmus frequently occurs in lesions involving the cerebellum, and has been ascribed to disinhibition and enhanced canal signals during positioning due to cerebellar dysfunction. This study aims to elucidate the mechanism of central positional nystagmus (CPN) by determining the effects of baclofen on the intensity of paroxysmal positional downbeat nystagmus due to central lesions. Fifteen patients with paroxysmal downbeat CPN were subjected to manual straight head-hanging before administration of baclofen, while taking baclofen 30 mg per day for at least one week, and two weeks after discontinuation of baclofen. The maximum slow phase velocity (SPV) and time constant (TC) of the induced paroxysmal downbeat CPN were analyzed. The positional vertigo was evaluated using an 11-point numerical rating scale (0 to 10) in 9 patients. After treatment with baclofen, the median of the maximum SPV of paroxysmal downbeat CPN decreased from 30.1°/s [interquartile range (IQR) = 19.6-39.0°/s] to 15.2°/s (IQR = 11.2-22.0°/s, Wilcoxon signed rank test, p < 0.001) with the median decrement ratio at 40.2% (IQR = 28.2-50.6%). After discontinuation of baclofen, the maximum SPV re-increased to 24.6°/s (IQR = 13.1-34.4°/s, Wilcoxon signed rank test, p = 0.001) with the median increment ratio at 23.5% (IQR = 5.2-87.9%). In contrast, the TCs of paroxysmal downbeat CPN remained unchanged at approximately 3.0 s throughout the evaluation. The positional vertigo also decreased with the medication (Wilcoxon signed rank test, p = 0.020), and remained unchanged even after discontinuation of medication (Wilcoxon signed rank test, p = 0.737). The results of this study support the prior presumption that paroxysmal CPN is caused by enhanced responses of the semicircular canals during positioning due to cerebellar disinhibition. Baclofen may be tried in symptomatic patients with paroxysmal CPN.

Intrathecal baclofen efficacy for managing motor function and spasticity severity in patients with cerebral palsy: a systematic review and meta-analysis.

BACKGROUND: Spasticity can significantly affect a patient's quality of life, caregiver satisfaction, and the financial burden on the healthcare system. Baclofen is one of only a few options for treating spasticity. The purpose of this study is to investigate the impact of intrathecal baclofen (ITB) therapy on severe40.23 spasticity and motor function in patients with cerebral palsy. METHODS: We conducted a systematic review in PubMed, Scopus, Ovid, and the Cochrane Library in accordance with the PRISMA guidelines. We included studies based on eligibility criteria that included desired participants (cerebral palsy patients with spasticity), interventions (intrathecal baclofen), and outcomes (the Ashworth scales and the Gross Motor Function Measure [GMFM]). The within-group Cohen's d standardized mean differences (SMD) were analyzed using the random effect model. RESULTS: We screened 768 papers and included 19 in the severity of spasticity section and 6 in the motor function section. The pre-intervention average spasticity score (SD) was 3.2 (0.78), and the post-intervention average score (SD) was 1.9 (0.72), showing a 40.25% reduction. The SMD for spasticity reduction was - 1.7000 (95% CI [-2.1546; -1.2454], p-value < 0.0001), involving 343 patients with a weighted average age of 15.78 years and a weighted average baclofen dose of 289 µg/day. The SMD for the MAS and Ashworth Scale subgroups were - 1.7845 (95% CI [-2.8704; -0.6986]) and - 1.4837 (95% CI [-1.8585; -1.1088]), respectively. We found no relationship between the participants' mean age, baclofen dose, measurement time, and the results. The pre-intervention average GMFM (SD) was 40.03 (26.01), and the post-intervention average score (SD) was 43.88 (26.18), showing a 9.62% increase. The SMD for motor function using GMFM was 0.1503 (95% CI [0.0784; 0.2223], p-value = 0.0030), involving 117 patients with a weighted average age of 13.63 and a weighted average baclofen dose of 203 µg/day. In 501 ITB implantations, 203 medical complications were reported, including six new-onset seizures (2.96% of medical complications), seven increased seizure frequency (3.45%), 33 infections (16.26%), eight meningitis (3.94%), and 16 cerebrospinal fluid leaks (7.88%). Delivery system complications, including 75 catheter and pump complications, were also reported. CONCLUSION: Despite the risk of complications, ITB has a significant impact on the reduction of spasticity. A small but statistically significant improvement in motor function was also noted in a group of patients.

Potentially Life-Threatening Interaction between Opioids and Intrathecal Baclofen in Individuals with a Childhood-Onset Neurological Disorder: A Case Series and Review of the Literature.

BACKGROUND: Spasticity and dystonia are movement impairments that can occur in childhood-onset neurological disorders. Severely affected individuals can be treated with intrathecal baclofen (ITB). Concomitant use of ITB and opioids has been associated with central nervous system (CNS) depression. This study aims to describe the clinical management of this interaction, based on a case series and review of literature. METHODS: Four individuals with childhood-onset CNS disorders (age 8-24) and CNS-depressant overdose symptoms after the concomitant use of ITB and opioids are described. The Drug Interaction Probability Scale (DIPS) was calculated to assess the cause-relationship (doubtful <2, possible 2-4, probable 5-8, and highly probable >8) of the potential drug-drug interaction. A literature review of similar previously reported cases and the possible pharmacological mechanisms of opioid-baclofen interaction is provided. RESULTS: After ITB and opioid co-administration, three out of four patients had decreased consciousness, and three developed respiratory depression. DIPS scores indicated a possible cause-relationship in one patient (DIPS: 4) and a probable cause-relationship in the others (DIPS: 6, 6, and 8). Discontinuation or adjusting ITB or opioid dosages resulted in clinical recovery. All patients recovered completely. In the literature, two articles describing nine unique cases were found. CONCLUSION: Although the opioid-ITB interaction is incompletely understood, concomitant use may enhance the risk of symptoms of CNS-depressant overdose, which are potentially life-threatening. If concomitant use is desirable, we strongly recommend to closely monitor these patients to detect interaction symptoms early. Awareness and monitoring of the potential opioid-ITB interaction is essential to reduce the risk of severe complications.

Combining clinically common drugs with hindlimb stretching in spinal cord injured rodents.

STUDY DESIGN: Preclinical pilot study. OBJECTIVES: To explore peripheral and central nociceptive mechanisms that contribute to muscle stretch-induced locomotor deficits following spinal cord injury. SETTING: Kentucky Spinal Cord Injury Research Center, Louisville, KY, USA. METHODS: Ten female Sprague-Dawley rats received moderate, 25 g/cm T10 contusion injuries and recovered for 4 weeks. Rats were divided into three groups: Morphine/Ibuprofen-treated, Acetaminophen/Baclofen-treated, and saline control. Each group received daily hindlimb muscle stretching during weeks 4, 5, 9, and 10 post-injury and drugs were administered with stretching during weeks 4 and 9 only. Locomotor function was assessed throughout the experiment using the BBB Open Field Locomotor Scale. Hindlimb responses including spasticity, writhing, and clonic-like vibrations during muscle stretching were classified and scored. RESULTS: Consistent with our previous studies, hindlimb muscle stretching caused significant deficits in locomotor recovery following spinal cord injury. Baclofen and Ibuprofen partially mitigated the stretching effect, but none of the drugs significantly prevented the drop in locomotor function during stretching. Interestingly, treatment with Baclofen or Ibuprofen significantly reduced hindlimb responses such as spasticity and writhing during stretching, while Morphine exacerbated clonic-like vibrations in response to stretching maneuvers. CONCLUSIONS: These findings suggest that stretching may inhibit locomotor recovery through combined mechanisms of peripheral inflammation and sensitization of nociceptive afferents. When combined with central sprouting and loss of descending controls after SCI, this results in exaggerated nociceptive input during stretching. The inability of the applied clinical drugs to mitigate the detrimental effects of stretching highlights the complexity of the stretching phenomenon and emphasizes the need for further investigation.

Outcomes, complications, and dosing of intrathecal baclofen in the treatment of multiple sclerosis: a systematic review.

OBJECTIVE: The purpose of this systematic review was to evaluate empirical outcomes of studies in the literature that investigated effectiveness of intrathecal baclofen (ITB) in the treatment of multiple sclerosis (MS)-related spasticity (MSRS) based on various metrics. Since the first description of this route of baclofen delivery for MS patients by Penn and Kroin in 1984, numerous studies have contributed to the medical community's knowledge of this treatment modality. The authors sought to add to the literature a systematic review of studies over the last 2 decades that elucidates the clinical impact of ITB in treating MSRS with the following endpoints: impact on patient-centered outcomes, such as spasticity reduction (primary), complications (secondary), and dosing (secondary). METHODS: The authors queried three databases (PubMed, Scopus, and Cochrane Library) using the following search terms: (intrathecal baclofen) AND (multiple sclerosis). The set inclusion criteria were as follows: 1) original, full-text article; 2) written in the English language; 3) published between and including the years 2000 and 2023; 4) discussion of pre- and post-ITB pump implantation outcomes (e.g., reduction in spasticity and improved comfort) in MSRS patients with long-term ITB treatment; and 5) contained a minimum of 5 MS patients. Data on study type, patient demographics, follow-up periods, primary outcomes, and secondary outcomes were extracted from the included studies. RESULTS: The authors' search yielded 465 studies, of which 17 met inclusion criteria. Overall, they found evidence for the effectiveness of ITB in treating MSRS patients whose condition was refractory to oral medications, with significant reported changes in spasm frequency from pre- to postimplantation. They also found evidence supporting the positive impact of ITB on MSRS patients' quality of life. Moreover, the authors found that most complications were surgical rather than pharmacological. In addition, the average 1-year dose of ITB (reported in 7 of the included studies) was 191.93 µg/day, which is substantially lower than ITB doses reported in the literature for patients with central (non-MS) or spinal origins of spasticity at 1-year follow-up. CONCLUSIONS: The evidence supports ITB as a clinically effective treatment for MSRS, particularly in patients in whom oral antispasmodics and physiotherapy have failed. This systematic review contributes a comprehensive synthesis of clinical benefits, complications, and dosing of ITB reported over the past 2 decades, which furthers an understanding of ITB's clinical utility in practice.

Safety and efficacy of continuous intrathecal baclofen via cervical catheter tip: a retrospective case series.

OBJECTIVE: Intrathecal baclofen (ITB) is an effective treatment for hypertonia in children involving the implantation of a pump and catheter system. The highest concentration of ITB is at the catheter tip. The catheter tip location is most commonly within the lumbar or thoracic spine. The cervical tip location has traditionally been avoided because of concerns of hypoventilation and pneumonia; however, these complications in cervical compared with thoracic or lumbar placement have not been reliably proven. Some studies have suggested that cervical ITB location better treats upper-extremity hypertonia. There are limited data describing the safety and efficacy of cervical ITB on hypertonia. The authors present a single-institution retrospective case series highlighting the safety and efficacy of using cervical ITB location for the treatment of hypertonia. METHODS: Retrospective data analysis was performed for children who underwent continuous dosing cervical ITB between April 2022 and October 2023. Nonmodifiable risk factors, clinical variables, operative characteristics, and adverse outcomes were collected. RESULTS: This study included 25 patients (8 female). The mean age at implantation was 12.4 years, and the mean operative duration was 90 minutes. The mean Barry-Albright Dystonia Scale score decreased by 9.5 points (p = 0.01). The mean aggregated modified Ashworth scale score in the upper extremities decreased by 2.14 points (p = 0.04), and that in the lower extremities decreased by 4.98 points (p < 0.01). One patient each (4%) had infection and baclofen toxicity. Two patients (8%) had respiratory depression requiring continuous positive airway pressure. There was no incidence of pneumonia or wound dehiscence. CONCLUSIONS: The cervical catheter tip location for ITB is safe, is effective to control tone, and should be considered for the treatment of hypertonia. Larger studies with longer follow-up are necessary to further determine upper-limit dosing safety along with long-term functional benefits in these patients.

Uncovering the rate and risk factors of intrathecal baclofen pump-associated complications in the adult population.

OBJECTIVE: The aim of this study was 1) to describe the rate of intrathecal baclofen (ITB)-associated complications at a large tertiary center, and 2) to evaluate the impact of patient-related factors on the likelihood of developing such complications. METHODS: A retrospective single-center study was carried out. A total of 301 eligible patients were included in the analysis. Univariate regression models were used to evaluate the impact of age, sex, diagnosis, ambulation status, modified Ashworth scale score, body mass index, diabetes status, and pain level on the likelihood of developing a device-related infection, pump malfunction, catheter malfunction, and other clinically significant complications. RESULTS: Overall, 27% of patients experienced an ITB-related complication. The most common complications included infection (6%, 18/301), pump malfunction (7.3%, 22/301), and catheter malfunction (14%, 42/301). The univariate analyses revealed that the patient's ambulatory status had a significant impact on the likelihood of developing a catheter-related malfunction. Furthermore, a trend toward significance was identified between patients' preoperative body mass index and device-related infection. Finally, the risk of suffering any ITB-related complications was statistically correlated with the number of years that had passed since the initial pump implantation. CONCLUSIONS: The authors' analysis reveals a previously underrecognized association between ambulatory status at the time of ITB pump implantation and the incidence of catheter-related complications, and confirms the impact of time since surgery on the risk of developing any ITB-related complication. The patient's age, sex, diagnosis, diabetes status, or pain level at baseline were not associated with the risk of complications. Collectively, these insights contribute novel information to the existing literature, providing practical value for physicians in guiding patient selection for ITB therapy.

Spinal catheter revision in pediatric intrathecal baclofen pumps: risk factors and postoperative outcomes.

OBJECTIVE: Intrathecal baclofen (ITB) pumps are commonly used in pediatric patients with cerebral palsy (CP) and medically refractory spasticity. However, catheter malfunction and associated risk factors are not well understood. The aim of this study was to examine potential risk factors for spinal catheter malfunction and characterize postoperative follow-up to understand the clinical consequences. METHODS: Patients who received ITB pump replacement or revision at Boston Children's Hospital between 2010 and 2023 were retrospectively reviewed. The spinal catheter revision cohort (SCRC) included patients whose spinal catheter was occluded requiring lumbar catheter revision. The second cohort included abdominal pump replacements only (APRC). Between-group comparisons and multivariable regression identified factors associated with catheter revision and postoperative outcomes. RESULTS: Forty-one (33.6%) patients underwent spinal catheter revision and were compared with 81 patients (66.4%) who underwent abdominal pump replacement only. Younger age at surgery and an elevated preoperative lower-extremity modified Ashworth scale grade were associated with spinal catheter revision (p < 0.05). Catheter model type, tip location, and history of spinal fusion were not associated with obstruction. Postoperatively, SCRC patients experienced a higher rate of infection (17.1%) relative to APRC patients (0%) within 30 days from their ITB pump replacement procedure (p < 0.05) and greater likelihood of subsequent ITB system removal compared with the APRC (24.4% vs 7.4%, p < 0.05). Although not differing preoperatively, SCRC patients had lower postoperative ITB doses when compared with the APRC group (median dose 143 vs 350 µg/day, p < 0.05) at hospital discharge and remained statistically different at the 6-month and 1-year follow-ups (p < 0.05). There were no postoperative differences in baclofen overdose, withdrawal, or median number of hospital readmissions within 30 days. Overall, 31.7% of spinal catheter revisions were unanticipated by the clinical team at time of surgery. CONCLUSIONS: Younger age at surgery and increased preoperative lower-extremity tone may be risk factors for catheter obstruction, resulting in a higher rate of postoperative infection and subsequent ITB pump removal compared with pump replacement alone. Spinal catheter occlusion can complicate revision or replacement procedures, especially when unanticipated. Routine clinical assessment may be inadequate for diagnosing insidious catheter malfunction. Catheter occlusion deserves further study, and routine assessment of catheter patency may be warranted to prevent suboptimal tone therapy.

Intraventricular baclofen for intractable spasticity and secondary dystonia: a frame-based stereotactic approach and case series.

OBJECTIVE: Intraventricular baclofen has been reported as an alternative to intrathecal baclofen for managing refractory spasticity and dystonia in some circumstances. In this report, we described a frame-based stereotactic approach for precisely positioning of the infusion catheter into the third ventricle. MATERIAL AND METHODS: High resolution contrast-enhanced anatomical MR sequences was acquired prior to surgery for pre-planning. Catheter trajectory was planned to pass from the lateral ventricle to the third ventricle through the Foramen of Monro. The surgical procedure was adapted from the frame-based deep brain stimulation surgery. The Touch-Loc kit (SceneRay, China) was used to temporarily secure the catheter in place during the surgery. From July 2022 to December 2022, three patients suffering from intractable spasticity and/or secondary dystonia received IVB successfully using the described technique. RESULTS: No severe adverse events, including death, intracranial hemorrhage, infection, catheter migration or fracture, were documented at the last follow-up (range: 12‒24 months). Transient side effects included mild nausea following the initiation of infusion or the increase in infusion rate. All three patients responded to the IVB. CONCLUSIONS: The described frame-based stereotactic technique for IVB catheter implant is feasible and could be quickly mastered by neurosurgeons in related fields. Larger prospective cohorts with longer follow-up periods are necessary to further evaluate the long-term safety and efficacy of this procedure.

Postoperative outcomes and stimulation responses for sectioned nerve roots during selective dorsal rhizotomy in cerebral palsy.

BACKGROUND: Cerebral palsy (CP) is the most cause of motor dysfunction in children. Selective dorsal rhizotomy (SDR) plays a major role in long term spasticity control. However, limited data exists on the effect of SDR on postoperative spasticity treatment requirements and supraspinal effects, and the stimulation responses of dorsal nerve roots in those with CP. METHODS: The current study included the outcome for 35 individuals undergoing SDR for motor functional outcome, spasticity, baclofen dose changes, botulinum toxin injection frequency, and spasticity related orthopedic procedures. We also report on the stimulation responses in 112 individuals who underwent SDR at our institution. RESULTS: There was a significant difference in gross motor function measures (GMFM)-66 scores at last follow up that remained present when considering only ambulatory children but not with non-ambulatory children. Ashworth scores were significantly decreased for both upper and lower extremities after SDR at all follow up points. There was a significant decrease in Baclofen dose and botulinum toxin injections requirements after SDR, but no significant difference in the need for orthopedic intervention. A total of 5502 dorsal nerve roots were tested showing a decrease in stimulation intensity and increase in grade on the right side and for descending lumbosacral levels. CONCLUSIONS: SDR improves gross motor scores during short term follow up but has additional benefits in decreasing baclofen dosing and botulinum toxin injections requirements after surgery. They stimulation responses of sectioned dorsal nerve roots adds to the limited available data and our understanding of the pathological changes that occur in CP.

The Role of Tissue Expansion Before Baclofen Pump Insertion in the Pediatric Population.

BACKGROUND: Tissue expansion is a well-established technique for soft tissue reconstruction in the pediatric population. We present a case series of this technique to create a safe pocket for baclofen pump insertion to minimize risk of complications including pump migration, extrusion, wound dehiscence and infection. METHODS: A case series of 3 pediatric patients undergoing tissue expansion prior to baclofen pump insertion at a single center in Melbourne. The expansion procedure was performed by senior surgeon N Low in all cases, and patients followed up 6 months after expander-pump exchange. The study was conducted over a 4-year period 2019 to 2023. RESULTS: We suffered 2 minor complications with the tissue expansion process including cellulitis and pump deflation. Neither complication precluded further tissue expansion nor led to premature removal of the expander. All patients proceeded to safely complete expander-pump exchange. One patient suffered a small (6 mL) abdominal seroma associated with pump insertion, which required no intervention. All patients have had a successful outcome 6 months after pump insertion. CONCLUSIONS: We describe a reliable and reproducible approach in creating a safe abdominal wall pocket to better accommodate baclofen pump insertion. Our series has overcome the imbalance between device size and abdominal wall pocket, now offering an alternative approach to achieve the safe delivery of intrathecal baclofen in the pediatric population.

Posterior Occipitocervical Fixation and Intrathecal Baclofen Therapy for the Treatment of Basilar Invagination with Klippel-Feil Syndrome: A Case Report.

Klippel-Feil syndrome (KFS) is characterized by the congenital fusion of the cervical vertebrae and is sometimes accompanied by anomalies in the craniocervical junction. In basilar invagination (BI), which is a dislocation of the dens in an upper direction, compression of the brainstem and cervical cord results in neurological defects and surgery is required. A 16-year-old boy diagnosed with KFS and severe BI presented with spastic tetraplegia, opisthotonus and dyspnea. CT scans showed basilar impression, occipitalization of C1 and fusion of C2/C3. MRI showed ventral compression of the medullocervical junction. Posterior occipitocervical reduction and fusion along with decompression were performed. Paralysis gradually improved postoperatively over 3 weeks. However, severe spasticity and opisthotonus persisted and intrathecal baclofen (ITB) therapy was initiated. Following this, opisthotonus disappeared and spasticity of the extremities improved. Rehabilitation therapy continued by controlling the dose of ITB. Five years after the surgery, self-propelled wheelchair driving was achieved and activities of daily life improved. The treatment strategy for patients with BI and congenital anomalies remains controversial. Posterior reduction and internal fixation using instrumentation were effective techniques in this case. Spasticity control achieved through a combination of surgery and ITB treatment enabled the amelioration of therapeutic efficacy of rehabilitation and the improvement of ADL.

[Intrathecal baclofen therapy: a 30-year experience]. / Intratekal'naya baklofenovaya terapiya: 30 let primeneniya.

BACKGROUND: The first pump for intrathecal administration of baclofen was implanted in 1984. Over thirty years, intrathecal prolonged infusion of muscle relaxants has occupied a worthy niche among all methods for correction of non-focal drug-resistant disabling muscle spasticity. However, this method has not become routine despite high awareness of specialists in Russia and abroad, as well as undeniable advantages for restoring the daily activity, improving the walking pattern and providing care and quality of life in people with limited mobility. This is due to scrupulous analysis of adverse events and accurate attitude towards its use.The purpose of this review was to systematize data on indications, selection criteria, pump implantation technique, subsequent patient management and treatment outcomes over a 30-year history. METHOD: A review of national and foreign literature was performed. RESULTS AND CONCLUSION: Prolonged intrathecal baclofen therapy is perspective for long-term treatment of severe spasticity interfering with quality of life and self-care if oral muscle relaxants are contraindicated or ineffective. This procedure is effective for impaired articulation, chewing and spastic pain syndrome. One can reduce the incidence of side effects via correct dosage of the drug, and tolerance to therapy can be reduced by timely elimination of problems with catheter.

Role of Projections between Piriform Cortex and Orbitofrontal Cortex in Relapse to Fentanyl Seeking after Palatable Food Choice-Induced Voluntary Abstinence.

We recently developed a rat model of relapse to drug seeking after food choice-induced voluntary abstinence. Here, we used this model to study the role of the orbitofrontal cortex (OFC) and its afferent projections in relapse to fentanyl seeking. We trained male and female rats to self-administer palatable food pellets for 6 d (6 h/d) and intravenous fentanyl (2.5 µg/kg/infusion) for 12 d (6 h/d). We assessed relapse to fentanyl seeking after 13-14 voluntary abstinence days, achieved through a discrete choice procedure between fentanyl infusions and palatable food (20 trials/d). In both sexes, relapse after food choice-induced abstinence was associated with increased expression of the activity marker Fos in the OFC. Pharmacological inactivation of the OFC with muscimol plus baclofen (50 + 50 ng/side) decreased relapse to fentanyl seeking. We then determined projection-specific activation of OFC afferents during the relapse test by using Fos plus the retrograde tracer cholera toxin B (injected into the OFC). Relapse to fentanyl seeking was associated with increased Fos expression in the piriform cortex (Pir) neurons projecting to the OFC, but not in projections from the basolateral amygdala and thalamus. Pharmacological inactivation of the Pir with muscimol plus baclofen decreased relapse to fentanyl seeking after voluntary abstinence. Next, we used an anatomical disconnection procedure to determine whether projections between the Pir and OFC are critical for relapse to fentanyl seeking. Unilateral muscimol plus baclofen injections into the Pir in one hemisphere plus unilateral muscimol plus baclofen injections into the OFC in the contralateral, but not ipsilateral, hemisphere decreased relapse. Our results identify Pir-OFC projections as a new motivation-related pathway critical to relapse to opioid seeking after voluntary abstinence.SIGNIFICANCE STATEMENT There are few preclinical studies of fentanyl relapse, and these studies have used experimenter-imposed extinction or forced abstinence procedures. In humans, however, abstinence is often voluntary, with drug available in the drug environment but forgone in favor of nondrug alternative reinforcers. We recently developed a rat model of drug relapse after palatable food choice-induced voluntary abstinence. Here, we used classical pharmacology, immunohistochemistry, and retrograde tracing to demonstrate a critical role of the piriform and orbitofrontal cortices in relapse to opioid seeking after voluntary abstinence.

Ivermectin Increases Random-Pattern Skin Flap Survival in Rats: The Novel Role of GABAergic System.

BACKGROUND: Ivermectin (IVM) was first used as an antiparasitic agent; however, the role of this drug evolved into a broad spectrum. Many mechanisms have been proposed, including interaction with the GABAergic system. Considering the presence of GABA receptor in the skin tissue and its role in ischemia-reperfusion I/R injury, we aimed to evaluate the effect of IVM through GABA receptors on random-pattern skin flap survival. METHODS: Sixty Wistar male rats were used. Multiple doses of IVM (0.01, 0.05, 0.2, and 0.5 mg/kg) were injected intraperitoneally before the surgery. Baclofen (selective GABAB agonist) and bicuculline (selective GABAA antagonist) were administered in combination with IVM to assess the role of the GABAergic system. Histopathological evaluations, immunohistochemical staining, quantitative assessment of IL-1ß and TNFα, and the expression of GABAA α1 subunit and GABAB R1 receptors were evaluated in the skin tissue. RESULTS: IVM 0.05 mg/kg could significantly increase flap survival compared with the control group (P < 0.001). Subeffective dose of baclofen (0.1 mg/kg) had synergistic effect with the subeffective dose of IVM (0.01 mg/kg) (P < 0.001), whereas bicuculline 1 mg/kg reversed the effect of IVM (0.05 mg/kg) (P < 0.001). IVM 0.05 mg/kg could also decrease the IL-1ß and TNFα levels and increase the expression of GABAA α1 subunit and GABAB R1 receptors in the flap tissue compared with the control group. CONCLUSIONS: IVM could improve skin flap survival, probably mediated by the GABAergic pathway. Both GABAA and GABAB receptors are involved in this process. This finding may repurpose the use of old drug, "Ivermectin."

Treatment of spasticity in children and adolescents with cerebral palsy in Northern Europe: a CP-North registry study.

BACKGROUND: Spasticity is present in more than 80% of the population with cerebral palsy (CP). The aim of this study was to describe and compare the use of three spasticity reducing methods; Botulinum toxin-A therapy (BTX-A), Selective dorsal rhizotomy (SDR) and Intrathecal baclofen therapy (ITB) among children and adolescents with CP in six northern European countries. METHODS: This registry-based study included population-based data in children and adolescents with CP born 2002 to 2017 and recorded in the follow-up programs for CP in Sweden, Norway, Denmark, Iceland and Scotland, and a defined cohort in Finland. RESULTS: A total of 8,817 individuals were included. The proportion of individuals treated with SDR and ITB was significantly different between the countries. SDR treatment ranged from 0% ( Finland and Iceland) to 3.4% (Scotland) and ITB treatment from 2.2% (Sweden) to 3.7% (Denmark and Scotland). BTX-A treatment in the lower extremities reported 2017-2018 ranged from 8.6% in Denmark to 20% in Norway (p < 0.01). Mean age for undergoing SDR ranged from 4.5 years in Norway to 7.3 years in Denmark (p < 0.01). Mean age at ITB surgery ranged from 6.3 years in Norway to 10.1 years in Finland (p < 0.01). Mean age for BTX-A treatment ranged from 7.1 years in Denmark to 10.3 years in Iceland (p < 0.01). Treatment with SDR was most common in Gross Motor Function Classification System (GMFCS) level III, ITB in level V, and BTX-A in level I. The most common muscle treated with BTX-A was the calf muscle, with the highest proportion in GMFCS level I. BTX-A treatment of hamstring and hip muscles was most common in GMFCS levels IV-V in all countries. CONCLUSION: There were statistically significant differences between countries regarding the proportion of children and adolescents with CP treated with the three spasticity reducing methods, mean age for treatment and treatment related to GMFCS level. This is likely due to differences in the availability of these treatment methods and/or differences in preferences of treatment methods among professionals and possibly patients across countries.

Pharmacological and neurosurgical interventions for individuals with cerebral palsy and dystonia: a systematic review update and meta-analysis.

AIM: To update a systematic review of evidence published up to December 2015 for pharmacological/neurosurgical interventions among individuals with cerebral palsy (CP) and dystonia. METHOD: Searches were updated (January 2016 to May 2020) for oral baclofen, trihexyphenidyl, benzodiazepines, clonidine, gabapentin, levodopa, botulinum neurotoxin (BoNT), intrathecal baclofen (ITB), and deep brain stimulation (DBS), and from database inception for medical cannabis. Eligible studies included at least five individuals with CP and dystonia and reported on dystonia, goal achievement, motor function, pain/comfort, ease of caregiving, quality of life (QoL), or adverse events. Evidence certainty was evaluated using GRADE. RESULTS: Nineteen new studies met inclusion criteria (two trihexyphenidyl, one clonidine, two BoNT, nine ITB, six DBS), giving a total of 46 studies (four randomized, 42 non-randomized) comprising 915 participants when combined with those from the original systematic review. Very low certainty evidence supported improved dystonia (clonidine, ITB, DBS) and goal achievement (clonidine, BoNT, ITB, DBS). Low to very low certainty evidence supported improved motor function (DBS), pain/comfort (clonidine, BoNT, ITB, DBS), ease of caregiving (clonidine, BoNT, ITB), and QoL (ITB, DBS). Trihexyphenidyl, clonidine, BoNT, ITB, and DBS may increase adverse events. No studies were identified for benzodiazepines, gabapentin, oral baclofen, and medical cannabis. INTERPRETATION: Evidence evaluating the use of pharmacological and neurosurgical management options for individuals with CP and dystonia is limited to between low and very low certainty. What this paper adds Meta-analysis suggests that intrathecal baclofen (ITB) and deep brain stimulation (DBS) may improve dystonia and pain. Meta-analysis suggests that DBS may improve motor function. Clonidine, botulinum neurotoxin, ITB, and DBS may improve achievement of individualized goals. ITB and DBS may improve quality of life. No direct evidence is available for oral baclofen, benzodiazepines, gabapentin, or medical cannabis.

Is R(+)-Baclofen the best option for the future of Baclofen in alcohol dependence pharmacotherapy? Insights from the preclinical side.

For several decades, studies conducted to evaluate the efficacy of RS(±)-Baclofen in the treatment of alcohol dependence yielded contrasting results. Human and animal studies recently questioned the use of the racemic drug in patients since a potential important role of the different enantiomers has been revealed with an efficacy thought to reside with the active R(+)-enantiomer. Here we conducted experiments in the postdependent rat model of alcohol dependence to compare the efficacy of R(+)-Baclofen or S(-)-Baclofen to that of RS(±)-Baclofen on ethanol intake, seeking, and relapse. R(+)-Baclofen was more effective than RS(±)-Baclofen in reducing ethanol intake and seeking during acute withdrawal and during relapse after abstinence. We also used an original population approach in order to identify drug responders. We found a significant proportion of responders to S(-)-Baclofen and RS(±)-Baclofen, displaying an increase in ethanol intake, and this increasing effect on alcohol intake was not seen in the R(+)-Baclofen group. At an intermediate dose of R(+)-Baclofen, devoid of any motor side effects, we identified a very large proportion of responders (75%) with a large decrease in ethanol intake (90% decrease). Finally, the response to RS(±)-Baclofen on ethanol intake was correlated to plasma level of Baclofen. R(+)-Baclofen and RS(±)-Baclofen were effective in reducing sucrose intake. Our study has important clinical implication since it suggests that the wide variability in the therapeutic responses of patients to RS(±)-Baclofen may come from the sensitivity to the R(+)-Baclofen but also to the one of the S(-)-Baclofen that can promote an increase in ethanol intake.

Systemic and intrathecal baclofen produce bladder antinociception in rats.

BACKGROUND: Baclofen, a clinically available GABAB receptor agonist, produces non-opioid analgesia in multiple models of pain but has not been tested for effects on bladder nociception. METHODS: A series of experiments examined the effects of systemic and spinally administered baclofen on bladder nociception in female anesthetized rats. Models of bladder nociception included those which employed neonatal and adult bladder inflammation to produce bladder hypersensitivity. RESULTS: Cumulative intraperitoneal dosing (1-8 mg/kg IP) and cumulative intrathecal dosing (10-160 ng IT) of baclofen led to dose-dependent inhibition of visceromotor responses (VMRs) to urinary bladder distension (UBD) in all tested models. There were no differences in the magnitude of the analgesic effects of baclofen as a function of inflammation versus no inflammation treatments. Hemodynamic (pressor) responses to UBD were similarly inhibited by IT baclofen as well as UBD-evoked excitatory responses of spinal dorsal horn neurons. The GABAB receptor antagonist, CGP 35,348, antagonized the antinociceptive effects of IT baclofen on VMRs in all tested models but did not affect the magnitude of the VMRs by itself suggesting no tonic GABAB activity was present in this preparation. Tolerance to a seven day continuous IT infusion of baclofen was not observed. CONCLUSIONS: These data provide support for a clinical trial of baclofen as a non-opioid treatment of human bladder pain.

Effect of High-Dose Baclofen on Agitation-Related Events Among Patients With Unhealthy Alcohol Use Receiving Mechanical Ventilation: A Randomized Clinical Trial.

Importance: Unhealthy alcohol use can lead to agitation in the intensive care unit (ICU). Objective: To assess whether high-dose baclofen reduces agitation-related events compared with placebo in patients with unhealthy alcohol use receiving mechanical ventilation. Design, Settings, and Participants: This phase 3, double-blind, placebo-controlled, randomized clinical trial conducted in 18 ICUs in France recruited adults receiving mechanical ventilation who met criteria for unhealthy alcohol use. Patients were enrolled from June 2016 to February 2018; the last follow-up was in May 2019. Interventions: Baclofen (n = 159), adjusted from 50 to 150 mg per day based on estimated glomerular filtration rate, or placebo (n = 155) during mechanical ventilation up to a maximum of 15 days before gradual dose reduction over 3 to 6 days. Main Outcomes and Measures: The primary end point was the percentage of patients with at least 1 agitation-related event over the treatment period. Secondary outcomes included duration of mechanical ventilation, length of ICU stay, and 28-day mortality. Results: Among 314 patients who were randomized (mean age, 57 years; 60 [17.2%] women), 313 (99.7%) completed the trial. There was a statistically significant decrease in the percentage of patients who experienced at least 1 agitation-related event in the baclofen group vs the placebo group (31 [19.7%] vs 46 [29.7%]; difference, -9.93% [95% CI, -19.45% to -0.42%]; adjusted odds ratio, 0.59 [95% CI, 0.35-0.99]). Of 18 prespecified secondary end points, 14 were not significantly different. Compared with the placebo group, the baclofen group had a significantly longer median length of mechanical ventilation (9 vs 8 days; difference, 2.00 [95% CI, 0.00-3.00]; hazard ratio [HR] for extubation, 0.76 [95% CI, 0.60-0.97]) and stay in the ICU (14 vs 11 days; difference, 2.00 [95% CI, 0.00-4.00]; HR for discharge, 0.70 [95% CI, 0.54-0.90]). At 28 days, there was no significant difference in mortality in the baclofen vs placebo group (25.3% vs 21.6%; adjusted odds ratio, 1.24 [95% CI, 0.72-2.13]). Delayed awakening (no eye opening at 72 hours after cessation of sedatives and analgesics) occurred in 14 patients (8.9%) in the baclofen group vs 3 (1.9%) in the placebo group. Conclusions and Relevance: Among patients with unhealthy alcohol use receiving mechanical ventilation, treatment with high-dose baclofen, compared with placebo, resulted in a statistically significant reduction in agitation-related events. However, considering the modest effect and the totality of findings for the secondary end points and adverse events, further research is needed to determine the possible role of baclofen in this setting and to potentially optimize dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT02723383.