Baclofen

Baclofen is a gamma-amino-butyric acid (GABA) derivative used as a skeletal muscle relaxant. Target: GABA Receptor Baclofen, a lipophilic analog of gamma-aminobutyric acid, is clinically used to control spasticity. Baclofen pretreatment (3 mg/kg) not only prolonged the time taken for animals to reach a core body temperature of 40 degrees C (P < 0.001), but also reduced the percentage of rats attaining a core body temperature of 40 degrees C [1]. Baclofen overdose may result in coma, apnea, autonomic disturbances, cardiac conduction abnormalities, and seizures. Levels obtained shortly after overdose correlate with length of mechanical ventilation [2].

References:
[1]. Bexis, S., et al., Baclofen prevents MDMA-induced rise in core body temperature in rats. Drug Alcohol Depend, 2004. 74(1): p. 89-96. [2]. Perry, H.E., et al., Baclofen overdose: drug experimentation in a group of adolescents. Pediatrics, 1998. 101(6): p. 1045-8.

A GAMMA-AMINOBUTYRIC ACID derivative that is a specific agonist of GABA-B RECEPTORS. It is used in the treatment of MUSCLE SPASTICITY, especially that due to SPINAL CORD INJURIES. Its therapeutic effects result from actions at spinal and supraspinal sites, generally the reduction of excitatory transmission.

A Randomized, Placebo-Controlled Trial of Ibuprofen Plus Metaxalone, Tizanidine, or Baclofen for Acute Low Back Pain.[Pubmed:30955985]

Ann Emerg Med. 2019 Apr 5. pii: S0196-0644(19)30139-8.

STUDY OBJECTIVE: Patients with low back pain are often treated with nonsteroidal anti-inflammatory drugs and skeletal muscle relaxants. We compare functional outcomes and pain among patients with acute low back pain who were randomized to a 1-week course of ibuprofen plus placebo versus ibuprofen plus 1 of 3 skeletal muscle relaxants: Baclofen, metaxalone, and tizanidine. METHODS: This was a randomized, double-blind, parallel-group, 4-arm study conducted in 2 urban emergency departments (EDs). Patients with nonradicular low back pain for less than or equal to 2 weeks were eligible if they had a score greater than 5 on the Roland-Morris Disability Questionnaire, a 24-item inventory of functional impairment caused by low back pain. All participants received 21 tablets of ibuprofen 600 mg, to be taken 3 times a day as needed. Additionally, they were randomized to Baclofen 10 mg, metaxalone 400 mg, tizanidine 2 mg, or placebo. Participants were instructed to take 1 or 2 of these capsules 3 times a day as needed. All participants received a 10-minute educational session. The primary outcome was improvement on the Roland-Morris Disability Questionnaire between ED discharge and 1week later. Secondary outcomes included pain intensity 1 week after ED discharge (severe, moderate, mild, or none). RESULTS: Three hundred twenty patients were randomized. One week later, the mean Roland-Morris Disability Questionnaire score of patients randomized to placebo improved by 11.1 points (95% confidence interval [CI] 9.0 to 13.3), Baclofen by 10.6 points (95% CI 8.6 to 12.7), metaxalone by 10.1 points (95% CI 8.0 to 12.3), and tizanidine by 11.2 points (95% CI 9.2 to 13.2). At 1-week follow-up, 30% of placebo patients (95% CI 21% to 41%) reported moderate to severe low back pain versus 33% of Baclofen patients (95% CI 24% to 44%), 37% of metaxalone patients (95% CI 27% to 48%), and 33% of tizanidine patients (95% CI 23% to 44%). CONCLUSION: Adding Baclofen, metaxalone, or tizanidine to ibuprofen does not appear to improve functioning or pain any more than placebo plus ibuprofen by 1 week after an ED visit for acute low back pain.

Successful Management of Gamma-hydroxybutyrate (GHB) Withdrawal Using Baclofen as a Standalone Therapy: A Case Report.[Pubmed:30907765]

J Addict Med. 2019 Mar 19.

BACKGROUND: Gamma-hydroxybutyrate (GHB)-a GABA-B agonist-can lead to a use disorder, and a withdrawal syndrome similar to that of alcohol. At present, evidence is lacking for how to best manage GHB withdrawal, and often clinicians rely on alcohol withdrawal management approaches, using medications like benzodiazepines (BZD). However, BZD doses needed to control GHB withdrawal symptoms are typically much higher than those required for alcohol, posing significant safety risks. Novel approaches include the use of Baclofen as an adjunct to BZD, allowing reductions in BZD requirements. While the use of Baclofen as monotherapy may result in even greater risk reductions, research to support this approach is limited. CASE: We present a case of a 26-year-old female with severe GHB use disorder and history of severe withdrawal symptoms, whose withdrawal was successfully, managed using Baclofen alone. CONCLUSION: In keeping with other case reports, Baclofen appears to have potential to be used in the management of GHB withdrawal. Here, we presented a case of severe GHB withdrawal which was managed solely by Baclofen. Clinical research is needed to evaluate Baclofen's potential as a standalone treatment for GHB withdrawal.

Intrathecal Baclofen Infusion for the Treatment of Movement Disorders.[Pubmed:30898271]

Neurosurg Clin N Am. 2019 Apr;30(2):203-209.

Intrathecal Baclofen infusion is an accepted treatment for spasticity. Evidence also exists for the treatment of secondary generalized dystonia with intrathecal Baclofen infusion. Benefits include decreased tone, improved positioning, and decreased decubitus ulcers. Despite these benefits, there are significant complications that can occur with this therapy, including drug withdrawal, catheter infection, drug overdose, failure, and pump failure. In some cases, practitioners encourage a trial dose of intrathecal Baclofen by injection or catheter infusion before pump implantation. To improve patient selection and outcomes many centers offering intrathecal Baclofen therapy use a multidisciplinary team composed of physicians, surgeons, and physical therapists.

Inherited Ataxia and Intrathecal Baclofen for the Treatment of Spasticity and Painful Spasms.[Pubmed:30870851]

Stereotact Funct Neurosurg. 2019 Mar 14:1.

BACKGROUND: Intrathecal Baclofen (ITB) treatment is considered a powerful tool in the management of severe spasticity in neurological conditions such as multiple sclerosis, cerebral palsy, and traumatic spinal cord and brain injury. OBJECTIVES: The objective of this study was to assess the effectiveness of the ITB in patients with inherited ataxia suffering from severe painful spasms and/or spasticity. METHOD: A total of 5 patients with spinocerebellar ataxia 3 or 7 or Friedreich's ataxia were included in this observational multicenter study. The patients were interviewed and completed outcome measures assessing pain (The Brief Pain Inventory), fatigue (Fatigue Severity Scale), and life satisfaction (LiSAT-9) before and 1 year after the treatment. Spasticity (Modified Ashworth Scale) and spasm frequency (SPFS) were measured objectively for each patient. RESULTS: The mean treatment time was 1.9 years. Evaluation of established standard forms revealed symptomatic relief from spasticity, spasms, pain, and fatigue in addition to improved body posture, sleep, and life satisfaction after ITB treatment. CONCLUSIONS: We report the potential beneficial effects of ITB treatment in patients with inherited ataxia who also suffer from spasticity/spasms. ITB treatment indication in neurological disorders allows for extension to the treatment of spasticity/ spasms in patients with hereditary ataxia.

GABAB receptor pharmacology.[Pubmed:8388192]

Annu Rev Pharmacol Toxicol. 1993;33:109-47.

In conclusion, GABAB receptors appear to be of major importance in synaptic processing within the brain and are present at both post- and presynaptic sites. Their activation can hyperpolarize neurones and diminish neurotransmitter release from presynaptic terminals. We already know that drugs, i.e. Baclofen, that mimic this activation are therapeutically useful, although the full significance of their use both inside and outside the brain has yet to be realized. Drugs that interfere with GABAB receptor activation should also prove to be important therapeutic agents. A number of suggestions have been proposed but it will be many years before the potential effects can be consolidated or refuted in humans. Only now are brain-penetrating GABAB antagonists being discovered, due largely to the expertise of the research group at CIBA-Geigy, Basel. The emergence of such compounds makes future studies an exciting prospect. In particular, the discovery that GABAB antagonism can suppress absence seizures in rats has provided an important therapeutic target. It is now just over ten years since we first designated the term GABAB. Since then a wealth of information has been obtained, but perhaps the best is still to come.

3-Thienyl- and 3-furylaminobutyric acids. Synthesis and binding GABAB receptor studies.[Pubmed:1652022]

J Med Chem. 1991 Aug;34(8):2557-60.

Baclofen (beta-(p-chlorophenyl)-GABA) is a selective agonist for the bicuculline-insensitive GABAB receptor. The search for new compounds that bind to the GABAB receptor is very important to clarify structural requirements. We report herein the synthesis and the binding studies of variously substituted 3-thienyl- and 3-furylaminobutyric acids. 4-Amino-3-(5-methyl-2-thienyl)butyric acid (5d) and 4-amino-3-(5-chloro-2-thienyl)butyric acid (5h) are potent and specific ligands for GABAB receptor. The IC50 values for the displacement of (R)-(-)-[3H]Baclofen are 1.34 and 0.61 microM for 5d and 5h, respectively, as compared to 0.33 microM for Baclofen.

3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABA B sites in rat brain.[Pubmed:6259535]

Nature. 1981 Mar 12;290(5802):149-52.

The presence of a novel receptor for the neurotransmitter gamma-aminobutyric acid (GABA) on peripheral autonomic nerve terminals and in mammalian brain slices has been described recently. This receptor differs from the classical GABA site as it is unaffected by recognized GABA antagonists such as bicuculline and is not sensitive to the majority of accepted GABA-mimetics such as 3-aminopropanesulphonic acid (3-APS) or isoguvacine. We propose to designate the classical site as the GABA A and the novel site as the GABA B receptor. The beta-p-chlorophenyl derivative of GABA, Baclofen, is stereospecifically active at the GABA B site whereas it is devoid of activity at the classical GABA A3 site. We now report that high-affinity saturable binding of 3H-Baclofen and 3H-GABA to the GABA B site can be detected in fragments of crude synaptic membranes prepared from rat brain. The results support the concept of a novel GABA receptor within the mammalian brain and show that GABA and Baclofen can compete for the same recognition site.