Development of baclofen tolerance in a rat model of chronic spasticity and rigidity (original) (raw)
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2021
Spinal cord injury (SCI) leads to severe motor and sensory functional impairments that affect personal and social behaviors. With no effective treatment, deficits in motor function are the most visible consequence of SCI. However, other complications produce a significant impact on SCI patient’s welfare. Spasticity is a neurological impairment that affects the control of muscle tone as a consequence of an insult in the central nervous system (e.g., SCI). Baclofen, a GABA agonist, is the most effective drug for spasticity treatment. This drug activates GABAB receptors decreasing the neurotransmitters release and neuronal hyperpolarization, which results in spasticity relief. Interestingly, emerging data reveals that Baclofen can also play a role on neuroprotection and regeneration after SCI. Our goal is to highlight the role of Baclofen as a potential treatment to promote recovery from SCI. We used a compression SCI mouse model with the administration of Baclofen at different time-po...
A Longitudinal Study of the Neurologic Safety of Acute Baclofen Use After Spinal Cord Injury
Neurotherapeutics
The objective of our study was to determine whether treatment with baclofen is neurologically safe with respect to exposure during recovery from spinal cord injury. We performed a secondary longitudinal analysis of a cohort of adult patients with traumatic acute spinal cord injury. Cumulative baclofen dose was computed over the first 4 weeks following injury from concomitant medication information from a completed clinical trial. The main outcome measure was neurologic status, which was assessed over 52 weeks with Bmarked recovery^defined as the conversion to higher sensory and motor function. To complete the drug safety profile, drug toxicity was assessed with assays from standard blood work. Multivariable Cox regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). Of the cohort (n = 651), 18% (n = 115) received baclofen within 4 weeks post injury. Baclofen use was associated with higher rates of marked neurologic recovery, even after adjustment for injury severity (HR = 2.1, 95% CI 1.5-3.0 for high dose vs none). Baclofen exposure was not associated with liver or renal side effects. The use of other medications indicated for spasticity was not associated with neurological outcomes. Overall, this longitudinal analysis provides level 3 evidence on the neurologic safety of baclofen and potential beneficial effects on recovery in the early days after acute traumatic spinal cord injury. The usefulness of concomitant medication files from completed clinical trials is highlighted. We also highlight the importance of incorporating logical patient questions and neurological outcomes into research addressing drug safety.
A pharmacokinetic-pharmacodynamic model for intrathecal baclofen in patients with severe spasticity
British Journal of Clinical Pharmacology, 2015
Intrathecal baclofen (ITB) has proven to be an effective and safe treatment for severe spasticity. However, although ITB is used extensively, clinical decisions are based on very scarce pharmacokinetic-pharmacodynamic (PKPD) data. The aim of this study was to measure baclofen CSF concentrations and clinical effects after administration of various ITB boluses in patients with spasticity and to create a PKPD model for ITB. METHODS Twelve patients with severe spasticity received four different bolus doses of ITB (0, 25, 50, 75 μg and an optional dose of 100 μg), administered via a catheter with the tip at thoracic level (Th) 10. After each bolus, 10 CSF samples were taken at fixed time intervals, using a catheter with the tip located at Th12. Clinical effect was assessed by measuring spasticity with the Modified Ashworth Scale (MAS). These data were used to develop a PKPD model. RESULTS All patients achieved an adequate spasmolytic effect with ITB doses varying from 50 to 100 μg. No serious side effects were observed. CSF baclofen concentrations, as well as the clinical effects, correlated significantly with ITB doses. The PK model predicted a steep spinal concentration gradient of ITB along the spinal axis. The clinical effect could be predicted using a delayed-effect model. CONCLUSIONS ITB is an effective and safe therapy with, however, a steep concentration gradient along the spinal axis. This means that the administered baclofen is staying mainly around the catheter tip, which stresses the importance to position the ITB catheter tip closely to the targeted spinal level.
Pharmacology Biochemistry and Behavior, 1999
ADVOKAT, C., M. DUKE AND R. ZERINGUE. Dissociation of ( Ϫ )baclofen-induced effects on the tail withdrawal and hindlimb flexor reflexes of chronic spinal rats . PHARMACOL BIOCHEM BEHAV 63 (4) 527-534, 1999.-We previously reported that the antinociceptive effect of the GABA B receptor agonist, ( Ϫ )baclofen, in chronic spinal rats depended on the route of administration. That is, subcutaneous (SC) injections significantly increased the latency of the thermally elicited tail withdrawal (tail flick, TF) reflex, whereas spinal (intrathecal, IT) injections did not. The present studies attempted to determine the reason for this differential response. The possible contribution of a peripheral component to the systemic effect was evaluated, but was not supported by negative results of intradermal ( Ϫ )baclofen injections (50 and 500 g) into the tail skin of chronic spinal rats. A spinal site of action was indicated when pretreatment with 30 g, IT of the GABA B receptor antagonist, phaclofen, significantly reduced the antinociceptive effect of SC ( Ϫ )baclofen in both chronic spinal (5 mg/kg) and intact rats (2 mg/kg). Moreover, direct IT injections of ( Ϫ )baclofen in chronic spinal rats produced a modest, but statistically significant increase in TF latency at doses of 0.06, 0.12, 0.3, and 0.6 g, but not 1.2 g. In the same spinal preparation, the flexor response was significantly reduced by IT injection of 0.6 and 1.2 g, but not lower doses of 0.3 and 0.12 g. These results provide the first quantitative, electrophysiological evidence of an antispastic effect of IT ( Ϫ )baclofen in an in vivo, unanesthetized animal model. Second, the data show a separation between an antinociceptive effect of low spinal doses and an antispastic/muscle relaxant effect at higher doses, which may account for the results of our prior report. Finally, the data are also consistent with behavioral reports of antiallodynic/analgesic effects of low-dose baclofen, and may be relevant to the electrophysiological evidence of a preferential presynaptic action of low-dose ( Ϫ )baclofen at the primary afferent synapse.
Chronic intrathecal baclofen administration for control of severe spasticity
Journal of Neurosurgery, 1990
✓ Baclofen, the most effective drug for treating spasticity, is a specific agonist of gamma-aminobutyric acid-B receptors, and is very abundant in the superficial layers of the spinal cord. Given orally, baclofen does not easily penetrate the blood-brain barrier, and is distributed equally to the brain and spinal cord. Direct intrathecal administration was given in order to change the distribution of the drug by preferentially perfusing the spinal cord. Eighteen patients presenting a severe spastic syndrome were treated with chronic intrathecal infusion of baclofen in the lumbar cerebrospinal fluid. After clinical preselection, 38 patients were implanted with a lumbar access port allowing long-term trials in order to determine the efficacy of baclofen therapy and the effective 12-hour dose. The 18 patients selected for chronic administration were implanted with a programmable pump. The pathology in these cases was: multiple sclerosis (6 cases), posttrauma spastic syndrome (eight cas...
Intraspinal baclofen in the treatment of severe spasticity and spasms
Acta Neurochirurgica, 1991
Ten patients with severe spasticity were evaluated according to a standardized protocol in order to be treated by intraspinal baclofen. Entry criteria in the protocol were the following: 1) Stable central nervous system lesion, 2) Severe spasticity and/or fiexo-extensor spasms not controllable by oral treatment, 3) Normal CSF circulation and 4) Informed consent. All patients received a test dose of twenty-five micrograms of baclofen injected intrathecally. At intervals of at least one day, doses were increased in 10-25 microgram steps until total abolition of spontaneous spasms was achieved in complete spinal cord lesions. In patients with residual motor function, doses were titrated until the optimal dose was found that reduced spasms and enabled performance of maximum daily life activities according to the patient's neurological level.
The Journal of Spinal Cord Medicine, 2013
Objective: To review the available evidence on the effectiveness of intrathecal baclofen in the treatment of spasticity in individuals with spinal cord injuries (SCIs) at least 6 months post-injury or diagnosis. Data sources: A literature search of multiple databases (Pub Med, CINAHL, EMBASE) was conducted to identify articles published in the English language. Study selection: Studies were included for review if: (1) more than 50% of the sample size had suffered a traumatic or non-traumatic SCI; (2) there were more than three subjects; (3) subjects received continuous intrathecal baclofen via an implantable pump aimed at improving spasticity; and (4) all subjects were ≥6 months post-SCI, at the time of the intervention. Data extraction: Data extracted from the studies included patient and treatment characteristics, study design, method of assessment, and outcomes of the intervention. Data synthesis: Methodological quality was assessed using the PEDro for randomized-controlled trials (RCTs) and the Downs and Black (D&B) tool for non-RCTs. A level of evidence was assigned to each intervention using a modified Sackett scale. Conclusion: The literature search resulted in 677 articles. No RCTs and eight non-RCTs (D&B scores 13-24) met criteria for inclusion, providing a pooled sample size of 162 individuals. There was substantial level 4 evidence that intrathecal baclofen is effective in reducing spasticity. Mean Ashworth scores reduced from 3.1-4.5 at baseline to 1.0-2.0 (P < 0.005) at follow-up (range 2-41 months). Average dosing increased from 57-187 μg/ day at baseline to 218.7-535.9 μg/day at follow-up. Several complications from the use of intrathecal baclofen or pump and catheter malfunction were reported.
Journal of Neurosurgery, 1997
✓ Twelve consecutive patients with severe spasticity and hypertonia following acquired brain injury were treated with continuous intrathecal infusion of baclofen via an implanted, programmable infusion pump—catheter system for a minimum of 3 months. In every case intrathecal baclofen therapy resulted in a statistically significant reduction in upper- and lower-extremity tone, spasm frequency, and reflexes, contributing to improved functional abilities. There were no untoward side effects or complications associated with treatment. This preliminary assessment indicates that intrathecal administration of baclofen is effective in treating the disabling spasticity caused by acquired brain injury in selected patients.
Selective Effects of Baclofen on Use-Dependent Modulation of GABAB Inhibition after Tetraplegia
inhibition was decreased during voluntary contraction compared with rest but there was no effect of SCI or baclofen use. Together, these results demonstrate that baclofen selectively maintains use-dependent modulation of largely subcortical but not cortical GABA B neuronal pathways after human SCI. Thus, cortical GABA B circuits may be less sensitive to baclofen than spinal GABA B circuits. This may contribute to the limited effects of baclofen on voluntary motor output in subjects with motor disorders affected by spasticity.