Influence of adrenergic and cholinergic mechanisms in baclofen induced analgesia

1. Baclofen induced analgesia was confirmed by means of the mouse hot plate test. 2. Physostigmine significantly increased the response to baclofen whilst neostigmine was ineffective. Baclofen analgesia was reduced by atropine. 3. The response to baclofen was increased by the administration of tolazoline, propranolol and nadolol. In contrast, the analgesic response to morphine was attenuated by the antiadrenergic drugs phenoxybenzamine, tolazoline and nadolol.     

On the involvement of GABA in the analgesia produced by baclofen,muscimol and morphine

In the mouse hot-plate test (50°C), muscimol produced analgesia which was blocked by bicuculline but not by picrotoxin. Analgesia produced by baclofen was dose-dependent and stereoselective, but was not blocked by bicuculline, picrotoxin or naloxone. Morphine-induced analgesia was not altered by bicuculline. The inhibitors of GABA-transaminase, amino-oxyacetic acid, γ-acetylenic GABA and γ-vinyl GABA, produced analgesia which was much more prolonged than that observed with muscimol, baclofen or morphine. The analgesic action of these agents was not significantly altered by bicuculline. At a higher plate temperature (55°C), GABA-transaminase inhibitors produced minimal analgesia but significantly enhanced the analgesic action of baclofen. γ- Vinyl GABA markedly increased both the peak effect and the duration of analgesia but γ-acetylenic GABA and amino-oxyacetic acid caused smaller increases. In the mouse hot-plate test, bicuculline-sensitive GABA receptors appear to mediate the analgesic action of muscimol. Analgesia produced by baclofen, morphine and inhibitors of GABA-transaminase may involve another class of GABA receptors which are insensitive to bicuculline.     

Synthesis and biochemical evaluation of baclofen analogues locked in the baclofen solid-state conformation.

The synthesis of six close analogues of baclofen [3-(4-chlorophenyl)-4-aminobutyric acid] (BAC), a potent GABAB agonist, are reported. The compounds were designed starting from the structural informations contained in the solid state of BAC, regarded as a possible bioactive conformation, in which the p-chlorophenyl ring is perpendicular to the GABA backbone. A similar conformational situation was created by rigidifying the BAC structure by means of methylene (1), ethylene (2 and 6), or propylene (3) units, or by introducing chlorine atoms (4 and 5) into the ortho positions ("ortho effect"). Only compound 5 showed affinity for the GABAB receptor. Compound 6 [1-(aminomethyl)-5-chloro-2,3-dihydro-1H-indene-1-acetic acid], which was initially considered as representing the optimal mimic of the solid-state conformation of BAC, was surprisingly found inactive. An extensive conformational analysis was performed on compounds 1-6 in order to evaluate their flexibility and the overlap of their conformational population with respect to BAC. For this purpose a distance map was generated from three possible pharmacophoric groups: the amino and the carboxylic functions, and the phenyl ring. Finally, several explanations are proposed to account for the poor affinities of the prepared compounds such as steric hindrance or flexibility demand of the receptor.     

Psycho- and immunomodulation properties of baclofen

Psycho- and immunomodulator activity of GABA(B)-mimetic drug baclofen was studied on Wistar-line rats with the cyclophosphamide-induced immunosuppression and lypopolysaccharide-induced immune stress. It was established that the stimulation of GABA(B) receptors in animals with the immune system hypofunction favors regeneration of the cellular and humoral components of immune response. At the same time, under the conditions of immune hyperreactivity, the modulating effect of baclofen appears only in respect of the cell-mediated immune reaction. Moreover, it was shown that baclofen suppresses psychoemotional disorders that develop under the conditions of cyclophosphamide- and lipopolysaccharide-induced immunopathology. The results obtained in this study confirm that GABA(B) receptors participate in the processes of psycho- and immunomodulation.     

Haemodialysis clearance of baclofen

Background Baclofen is a centrally acting gamma-aminobutyric acid agonist used for spasticity of spinal origin and mainly excreted unchanged by the kidneys. We report haemodialysis clearance and the haemodialysis removal rate constant of baclofen in a comatose patient with baclofen overdose due to acute renal failure. Case report A 60-year-old man with spastic tetraplegia on chronic baclofen therapy was admitted due to pneumonia and acute renal failure. The patient became comatose and, as a result of the baclofen dosage being left unchanged despite a deterioration leading to renal failure due to hypotension, the concentration of baclofen was determined to be in the toxic range (0.70 mg/L). During a 4-hour-long bicarbonate haemodialysis the patient woke up and became completely orientated and cooperative. Baclofen therapy was subsequently stopped, and the patient remained conscious. The pharmacokinetics calculations revealed a baclofen haemodialysis removal rate constant of 0.152 h^-1 and a haemodialysis clearance of 2.14 mL/s. Conclusions Patients on a stable baclofen regime can develop baclofen toxicity due to acute renal failure. Haemodialysis removes baclofen as effectively as normal kidneys, and it would appear that haemodialysis is a reasonable treatment modality in patients with accidental baclofen overdose due to acute renal failure.     

Baclofen withdrawal following removal of an intrathecal baclofen pump despite oral baclofen replacement

Intrathecal baclofen is used as a muscle relaxant and antispasmodic in cases of spasticity resulting from central nervous system trauma. The baclofen withdrawal syndrome may include hyperthermia, tachycardia, hypertension, seizures, altered mental status, and psychomotor agitation. We report a case in which the removal of a baclofen pump lead tothe development of severe withdrawal symptoms despite oral baclofen replacement therapy. In order to avoid the development of withdrawal, adequate doses of GABA agonist agents should be administered immediately prior to, and following, baclofen pump removal.     

Effect of baclofen on tardive dyskinesia

Eighteen chronic psychiatric patients with neuroleptic-induced tardive dyskinesia of 1/2–9 years duration participated in a double-blind crossover study on the effect and side effects of baclofen and placebo in the treatment of tardive dyskinesia. Each treatment phase lasted 3 weeks. Evaluation of the results included an assessment of video-tape recording. Baclofen (20–120 mg daily) reduced the hyperkinesias (median score from 5 to 3, P<0.05) and increased the parkinsonism (median score from 5 to 7, P<0.01). The effect on the oral movement pattern of tardive dyskinesia was characterized by a reduced frequency, an unchanged or slightly reduced amplitude, and an increased duration of each separate mouth opening and tongue protrusion, a response pattern very similar to the response pattern of -methyl-p-tyrosine, an inhibitor of the catecholamine synthesis. Sedation, muscular weakness, and confusion were observed in 50% of the patients. These side effects, appearing mainly in elderly patients, sometimes set in before the anti-hyperkinetic effect, thus limiting the practical usefulness of baclofen in the treatment of tardive dyskinesia.     

High-dose baclofen for treatment-resistant alcohol dependence

Alcohol dependence is associated with a wide array of physical and psychiatric complications and is a major cause of morbidity and mortality worldwide. Recent randomized trials of baclofen, with a total daily dose 30 mg administered in 3 divided doses, have supported its efficacy in reducing craving and promoting abstinence from alcohol. Individual case studies support a possible increased effect at higher doses for treatment-resistant patients. Here, we report on 4 alcohol-dependent patients resistant to standard treatments who responded to higher doses of baclofen ranging from 75 to 125 mg daily. Further research into the use of high-dose baclofen for treatment-resistant alcohol dependence is warranted.     

Adverse effects secondary to baclofen withdrawal

Drug therapy is now the preferred method of treatment for spasticity, and several effective agents have been developed. The safety and efficacy of these drugs has been established in short-term studies. Overall, due to its low incidence of sedation and serious side effects, baclofen appears to be the drug of choice in the treatment of spinal cord-related spasticity. It is, however, not without its side effects due to both its administration and abrupt withdrawal. This case illustrates some significant problems associated with the abrupt withdrawal of long-term baclofen therapy in a patient with multiple sclerosis.     

Pronounced hypothermic synergy between systemic baclofen and NOS inhibitor

Baclofen was administered to rats systemically (intraperitoneal, i.p.) by itself or with L-NAME. Baclofen (1-7.5 mg/kg, i.p.) evoked dose-dependent hypothermia. L-NAME (50 mg/kg, i.p.) was ineffective. For combined administration, L-NAME increased the relative potency of baclofen (F=10.77, p<0.05), indicating multiplicative interaction and synergism. The present data reveal a surprising and significant interaction between nitric oxide synthase (NOS) and baclofen-induced hypothermia.     

The spectrum of analgesic activity of baclofen and tolibut

Spectrum of the analgetic activity of GABA derivatives baclofen (2.5-10.0 mg/kg) and tolibut (12.5-100.0 mg/kg) was studied in experiments on albino mice and rats. Baclofen and especially tolibut showed a dose-dependent inhibition of perceptive, emotional and autonomic manifestations of nociceptive reactions at the tail's thermal and electrical stimulation and enhancement of the analgetic effect of promedol. The regressive analysis made it possible to show dependence of the analgetic effect on the level of pain sensitivity and emotional reactivity of the animals. Tolibut deepens and prolongs sombrevin anesthesia, baclofen fails to alter it.     

Quipazine antagonizing baclofen activity. Influence of baclofen and gamma-hydroxybutyric acid on serotonin metabolism in rat brain (author's transl)

Baclofen increases the concentration of serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) in the rat c. striatum without causing concomitant increase in 5-HT biosynthesis. The effect of baclofen on 5-HIAA, but not that on 5-HT, was antagonized dose-dependently by quipazine. It is assumed that quipazine acts by stimulating 5-HT autoreceptors.     

Antinociceptive effects of baclofen and muscimol upon intraventricular administration

The effects of intraventricularly administered baclofen and muscimol were investigated on tail-flick responding and on vocalization and motor responses to nociceptive pinch. Baclofen (1 μg) and muscimol (0.1 μg) strongly reduced responding to pinch, particularly vocalization, without altering tail-flick responding. When given systemically, however, baclofen markedly attenuated tail-flick as well as pinch responding. Muscimol produced only weak antinociception by systemic administration, suggesting that it may have poor access to brain. At antinociceptive doses, i. vent. muscimol produced less apparent muscle relaxation than did baclofen. These results suggest that baclofen's antinociceptive action may be mediated in part by a supraspinal, GABAergic substrate, in addition to a spinal component which may not directly involve GABA.     

Reversible akinetic mutism possibly induced by baclofen

A 76-year-old man developed akinetic mutism after 3 days of receiving low-dosage baclofen. Electroencephalography showed a diffusely slow background with intermittent generalized sharp wave discharges. The condition resolved after discontinuing baclofen. To our knowledge, this is the first reported case of baclofen-induced akinetic mutism in a patient with normal renal function. The pathophysiology of this condition is unknown, but it may result from selective binding of the drug to the gamma-aminobutyric acid-B receptors located in the frontal lobes or thalamic nuclei, interrupting the thalamocortical limbic pathways.