Elsevier

Clinical Neurophysiology

Volume 111, Issue 8, 1 August 2000, Pages 1372-1379
Clinical Neurophysiology

The effect of baclofen on the transmission in spinal pathways in spastic multiple sclerosis patients

https://doi.org/10.1016/S1388-2457(00)00352-7Get rights and content

Abstract

Objectives: To measure the effect of baclofen on the transmission in different spinal pathways to soleus motoneurones in spastic multiple sclerosis patients.

Methods: Baclofen was administered orally in 14 and intrathecally in 8 patients. Hmax/Mmax, presynaptic inhibition by biceps femoris tendon tap of femoral nerve stimulation, depression of the soleus H-reflex following previous activation of the Ia afferents from the soleus muscle (i.e. postactivation depression), disynaptic reciprocal Ia inhibition of the soleus H-reflex and the number of backpropagating action potentials in primary afferents, which may be a sign of presynaptic inhibition, were examined.

Results: Baclofen depressed the soleus Hmax/Mmax ratio significantly following oral and intrathecal baclofen. None of the two tests of presynaptic inhibition, or the postactivation depression or the disynaptic reciprocal Ia inhibition of the soleus H-reflex were affected by baclofen administration. Also the action potentials of the primary afferents were unchanged during baclofen administration.

Conclusions: The antispastic effect of baclofen is not caused by an effect on the transmitter release from Ia afferents or on disynaptic reciprocal Ia inhibition. One possible explanation of the depression of the H-reflex by baclofen is suggested to be a direct depression of motoneuronal excitability.

Introduction

Although the pathophysiology of spasticity has been addressed in a number of studies during the past 20–30 years there is still no general agreement about the significance of different spinal control mechanisms for the exaggerated stretch reflex activity and hypertonicity observed in spastic patients (Pierrot-Deseilligny, 1990, Nielsen and Hultborn, 1993). The treatment of spasticity therefore also rests almost solely on an empirical basis.

Ideally an antispastic drug should depress the unwanted exaggerated stretch reflex activity and reduce the muscle tone without affecting the functional ability of the patients during voluntary movements, such as walking. For a long time it has been thought that baclofen fulfilled this criteria, since animal experiments have shown that baclofen rather selectively activates GABAB receptors, which are mainly found presynaptically (Tillakaratne et al., 1995). Baclofen has also been found to depress the transmitter release from Ia afferents in the cat without any postsynaptic effects on the motoneurones (Jimenez et al., 1991). Because of this baclofen has been thought to selectively depress the exaggerated stretch reflex activity mediated by stretch sensitive afferents without affecting the voluntary movements of the subjects.

More recently some doubt about the selectivity of baclofen has been raised. Azouvi et al. (1993) demonstrated that the soleus H-reflex was depressed by intrathecal baclofen without any apparent change in the efficacy of synaptic inputs (based on lack of change in the monosynaptic facilitation of the soleus H-reflex evoked by femoral nerve stimulation) to the motoneurones, suggesting that baclofen mainly acted at a postsynaptic site. If this is correct baclofen is not an ideal antispastic drug and should be avoided in patients in whom preservation of their functional ability is of importance. There is consequently a great need of evaluating the mode of action of baclofen in spastic patients. In the present study we have evaluated the effect of orally and intrathecally administered baclofen on soleus H-reflexes as well as on 3 different mechanisms which regulate stretch reflex excitability. (1) We tested presynaptic inhibition of Ia afferents on soleus motoneurones by measuring either the depression of the soleus H-reflex evoked by a biceps femoris tendon tap (Nielsen and Petersen, 1994) or the monosynaptic heteronymous facilitation of the soleus H-reflex following femoral nerve stimulation (Hultborn et al., 1987). In addition compound sensory action potentials (CSAPs) were investigated (Shefner et al., 1992). Recurrent potentials in the CSAP have been suggested to be related to primary afferent depolarization and to presynaptic inhibition of the primary afferents (Shefner et al., 1992). (2) We tested the depression of the soleus H-reflex following previous activation of tibial nerve afferents (postactivation depression) by slow stretch of the ankle plantar flexors (Nielsen et al., 1993, Nielsen et al., 1995, Hultborn et al., 1996). (3) We tested disynaptic reciprocal Ia inhibition of the soleus H-reflex following stimulation of the antagonistic common peroneal nerve (Crone et al., 1994).

Section snippets

Patients

Twenty-two patients aged 24–57 years (mean±SD 42.8±8.7) with clinically definite multiple sclerosis (MS) (Poser et al., 1983) participated in the study. In all patients the disease had been stable for at least 1 month and all gave informed consent to the examination which was approved by the local ethics committee. All patients were clinically evaluated and spasticity was graded according to the Ashworth Index (Table 1). Eight patients received baclofen intrathecally, whereas 14 patients

H-reflex

Administration of baclofen both orally and intrathecally produced a significant decrease in the size of the soleus H-reflex measured as the Hmax/Mmax ratio. In all but 3 of the 13 patients who participated in the double-blind placebo-controlled study on the effect of oral baclofen, a significantly (P<0.05) smaller Hmax/Mmax ratio was observed during the period when the patients received oral baclofen daily (mean±SEM 44.0±6.2%) as compared to the period when they received either placebo

Discussion

This study has investigated the mode of action of baclofen in spastic MS patients. Baclofen was administered either intrathecally or orally. In the latter case the patients received a daily dose of baclofen for 3 weeks prior to the investigation and the study was designed as a double-blind placebo-controlled study. The study on the effect of intrathecal baclofen was designed as an open-label study. In both cases a clear depression of the soleus H-reflex was observed. Although a similar

Acknowledgements

This study was supported by grants from the Danish Society of Multiple Sclerosis, Warwara Larsens Foundation, Lily Benthine Lunds Foundation, Dagmar Marshalls Foundation, Hestehandler Ole Jakobsens Foundation and Foundation for Research in Neurology. Novartis supplied identical baclofen and placebo tablets.

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