*2.3.4 Tizanidine*

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

represent the principal drugs more frequently used.

*2.3.1 Diazepam*

controlled studies.

*2.3.2 Gabapentin*

*2.3.3 Oral baclofen*

approaches, it is important to differentiate these therapeutic objectives. In order to achieve these therapeutic goals, most of the drugs currently used in spasticity influence the activity of the CNS neurotransmitters. Inhibitory neurotransmitters (GABA or glycine), as well as excitatory neurotransmitters (glutamate or the monoamines), are the main target. Diazepam, baclofen, tizanidine, and dantrolene

Diazepam, probably the first and oldest drug used in treating spasticity [34, 35],

Gabapentin is approved as an antiepileptic drug. It is indicated also for posther-

petic neuralgia treatment and as add-on therapy in partial seizures. GABA-B receptors are its target. Moreover, it is quietly safe. In a prospective, double-blind, placebo-controlled, crossover study, conducted on multiple sclerosis patients, a statistically significant reduction of spasticity was shown in gabapentin-treated patients compared to placebo [40]. The most efficient and safe dose range is still an open question. A dose range between 2700 and 3600 mg/day, as therapy for spasticity due to upper motor neuron syndrome, was found as efficient and safe. However,

doses of 400 mg orally three times a day, in another double-blind, placebo-

controlled crossover study, were shown to be effective in the treatment of spasticity and muscle painful cramps in patients with MS [41]. Nevertheless, considering the magnitude of the effect and the good tolerability of the drug, the evidence is on a weak recommendation for using gabapentin to reduce spasticity in MS [42].

Baclofen is another common drug diffusely used in spasticity. This drug is a GABA-B receptor agonist. Its physiological effect is a suppression of excitatory neurotransmitter release and, as a consequence, a potentiation of presynaptic inhibition. The main clinical effects are related mainly to the reduction in flexorextensor spasms and mono- and polysynaptic reflexes. Obviously, related to its mechanism of action, this drug may induce dose-dependent side effects, quite

is a GABA-A receptor agonist. Its binding, to GABA-A receptors diffused in the brainstem and spinal cord, acts in increasing presynaptic inhibition. Consequently, reduction in the resistance to stretch is the principal clinical effect, showing an objectively increasing range of motion. Other clinical effects are also a reduction of deep tendon stretch reflexes and painful spasms [36]. Nevertheless, significant side effects are to be considered. The depressant effect of the drug on the CNS is the principal side effect, causing an influence on cognitive-level, consciousness status, leading to sedation, drowsiness, and attention or memory impairment. The same physiological mechanism explains weakness and motor discoordination caused by diazepam. Tolerance or dependency phenomena are often observed [37, 38]. Spasticity caused by spinal cord lesion, above all incomplete ones like in patients with multiple sclerosis (MS), is the principal indication to use diazepam, since the drug binding is mainly in the brainstem. Less literature are available for the use of diazepam in spasticity caused by cerebral accident, such as traumatic brain injuries, cerebral palsy, and stroke. In literature, a double-blind protocol is available showing the antispastic efficacy of diazepam, only in spinal cord lesions [39]. However, a possible strength and gait deterioration was also shown consistently in placebo-

**120**

Tizanidine, an imidazole derivative approved for the treatment of patients with spasticity [45], acts as an alpha-2 agonist, both in the spinal and supraspinal level. Presynaptic activity reduction of the excitatory interneurons represents the main physiological effect of this treatment. The coeruleo-spinal pathway, because of its involvement in the control of spinal cord activities, was shown as the main target in order to induce clinical effect during tizanidine treatment [46]. Consequently, reduction in tonic and stretch polysynaptic reflexes can be observed. Because of co-contraction reduction, which is observed, a possible effect on reciprocal inhibition is questionable. Possible side effects include sedation, dizziness, and dry mouth. Nevertheless, with respect to diazepam or baclofen, weakness is not reported as a great problem [47]. From the literature, the indications for its use are mainly in spasticity due to spinal cord lesions [48]. It has been particularly used in multiple sclerosis patients [49]. In spasticity caused by cerebral lesions, its efficacy is less well documented in literature. However, there are a certain number of reports regarding its antispastic efficacy, also in controlled studies vs. placebo. In the treatment of spasticity due to cerebral lesions, there are some evidences of its greater efficacy than diazepam [47]. However, there is very little information about the possible functional changes resulting from this treatment, i.e. quality of life and self-care. In fact, although it has been shown to have an antispastic effect, we do not know whether this will translate into long-term functional benefit for the patients. In clinical practice, tizanidine is usually well-tolerated. Drowsiness and dry mouth are the most common although are rare side effects. A range of 24–36 mg is normally the therapeutic dose (20% mean reduction in muscle tone), usually divided in three daily doses [50]. Like oral baclofen and diazepam, there is a consensus for a weak recommendation for the use of tizanidine [42].
