*2.3.6 Cannabinoids*

It is known, from many evidences, that the psychoactive ingredient in cannabis, delta-9-tetrahydrocannabinol (delta-9-THC), is able to treat muscle spasticity and pain. Two types of cannabinoid receptors can be described: CB1 and CB2. CB1s are located both in the central and peripheral neurons. CB1 and CB2 receptors are equally activated by delta-9-THC, a cannabinoid receptor agonist [53, 54]. On the contrary, cannabidiol, a natural cannabinoid, is inactive on the CB1 receptor. Some studies reported that cannabis extracts, containing approximately equal concentrations of delta-9-THC and cannabidiol administered through sublingual way, can significantly reduce spasticity. During the last years, several studies investigated and argued on the efficacy and safety of oral cannabinoid administration in MS patients as an add-on treatment for spasticity. A multicentre, double-blind, placebo-controlled trial showed that in MS spasticity treatment, cannabinoid may help to treat MS-related spasticity and pain [53]. However, according to the results from clinical trials, it is not allowed to use cannabinoids in MS as a general use. In a recent study, 630 MS patients affected by muscle spasticity were randomised to be treated with oral delta-9-THC, cannabis extract, or placebo for up to 12 months. The results showed a controversial effect; in fact, there was a small treatment effect on muscle spasticity and disability as functional independence measure, but patients' sensation was that these drugs were helpful in treating their disease [54]. Adverse side effects are generally mild, in particular dry mouth, somnolence, dizziness, nausea, and rarely intoxication. However, there is a need of longer-term studies to evaluate other, well-known, adverse side effects of cannabinoid such as risks of lung cancer and other respiratory dysfunctions. A recent multicentre observational study confirmed the efficacy and safety of delta-9-THC in clinical practice, as an effective and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs [55]. In a recent consensus, a significant recommendation for the use of cannabinoids in spasticity emerged, particularly for oromucosal spray nabiximols, as treatment of spasticity in MS; the strength of the recommendation is strong [42].

### **2.4 Botulinum toxin**

BTX type A is considered as the first-line treatment of multifocal muscle overactivity, thanks to its better efficacy and safety profile with respect to systemic approach with drugs. Different from baclofen or tizanidine, the efficacy of BTX type A has been demonstrated in self-care improvement (in particular for washing and dressing) and in active movements for the leg, with gait improvement if possible. Except for using kinematic analysis, no improvement was possibly shown in active movement or function in the upper limb. Pain was also reduced by BTX treatment as demonstrated in literature. Four forms of BTX are currently available in Europe: three type As (BOTOX®, Allergan; Dysport®, Ipsen-Pharma; Xeomin®, Merz) and one type B (Neurobloc®, Elan-Pharma). It is absolutely recommended to keep in mind that the units of these four toxins are different, being

**123**

*Spasticity and Dystonia: A Brief Review DOI: http://dx.doi.org/10.5772/intechopen.91780*

it should be considered:

**2.5 Alcohol and phenol**

• Per session: 1500 MU Dysport® 600 U BOTOX®.

It is notable that these dosages are identified relatively to acceptable side effects, in order to be safe. Moreover, each product could be effective with different doses for each patient, in terms of both efficacy and safety [61]. As well as the cannabinoid, there is a strong recommendation of the use of BTX to reduce muscle tone in

Localised and loco-regional spasticity may effectively be treated by selective neurolysis. Coagulation and denaturing of proteins induced by phenol perineurally injected lead to cellular and axonal damage. Unfortunately, this chemical denervation is irreversible; moreover, the effects of phenol are not selective because also vascular and sensory structures can be destroyed [62]. In fact, the main recommendation choosing this approach is to identify preferably the nerves to be treated with a low sensory activity and a high motor predominance (i.e. obturator or musculocutaneous nerves, etc.). However, this focal treatment is usually not used as a first-line therapy, except in the case of particularly problematic overactivity affecting a big area under a single motor nerve control, for example, musculocutaneous nerve for biceps brachii muscle or obturator nerve for thigh adductor muscles. This may allow to use in the same patient BTX to treat other muscles, without the risk of an overdose. Electrical stimulation is used to identify a nerve, in order to perform injection on it. Firstly, a transient motor block may be a plan, in order to evaluate if chemical neurolysis might be significantly effective and safe. In fact, the efficacy and/or advantages eventually deriving from alcohol or phenol treatment could be evaluated before, in particular with respect

• Per site: 125 MU Dysport® 50 U BOTOX®.

spasticity do to multiple sclerosis [42].

specific for each one. Injection sites are better detected, using electrical stimulation, as anatomical markers alone may induce to an inaccurate target. The use of ultrasound guidance, particularly in children, in identifying muscle site injection, is an interesting study object; however, this technique has not been evaluated with respect to electrical stimulation guidance for its efficiency. Generally, there are no immediate postinjection complications (except for a little pain as a side effect related to injection itself). Above all, during the first 3 weeks after each injection treatment, there would be a low risk of adverse events (swallowing disorders and botulism-like syndrome), so patients and caregivers must be warned as well as encouraged to eventually consult if necessary. The effects of treatment could be assessed 1–6 weeks after the injection, based on personalised goals decided before treatment. The effect of the toxin is not permanent, so repeated injections are often needed; nevertheless, a long-lasting effect is also observed. No repeated treatment is recommended without a specific assessment. When and if needed according to functional evaluation, a minimum delay of 2–3 months between injections must be respected, in order to reduce the risk of an immunologic reaction that may induce a permanent inefficacy of subsequent treatments. Each subsequent treatment should be planned after an accurate functional evaluation according to the pre-therapeutic identified goals and task, as well as tolerance. So, a review of the dose and treated muscles could be scheduled. If therapeutic effects continue to be evident, repeated injections can be planned [33, 56–60]. Physical therapy has to be considered after BOTOX injections. Regarding maximum doses, according to European Consensus,

### *Spasticity and Dystonia: A Brief Review DOI: http://dx.doi.org/10.5772/intechopen.91780*

*Neurostimulation and Neuromodulation in Contemporary Therapeutic Practice*

anaesthesia [52].

*2.3.6 Cannabinoids*

recommendation is strong [42].

**2.4 Botulinum toxin**

traumatic brain injuries, and spinal cord lesions. As shown for baclofen, also for dantrolene, there are many evidences of efficacy and safety of its antispastic effect proven vs. placebo, but no studies focused on functional changes in activities of daily living. It's notable that dantrolene is also used to prevent muscle stiffness and spasms caused by malignant hyperthermia (a rapid rise in body temperature and severe muscle contractions) that can occur during surgery with certain types of

It is known, from many evidences, that the psychoactive ingredient in cannabis, delta-9-tetrahydrocannabinol (delta-9-THC), is able to treat muscle spasticity and pain. Two types of cannabinoid receptors can be described: CB1 and CB2. CB1s are located both in the central and peripheral neurons. CB1 and CB2 receptors are equally activated by delta-9-THC, a cannabinoid receptor agonist [53, 54]. On the contrary, cannabidiol, a natural cannabinoid, is inactive on the CB1 receptor. Some studies reported that cannabis extracts, containing approximately equal concentrations of delta-9-THC and cannabidiol administered through sublingual way, can significantly reduce spasticity. During the last years, several studies investigated and argued on the efficacy and safety of oral cannabinoid administration in MS patients as an add-on treatment for spasticity. A multicentre, double-blind, placebo-controlled trial showed that in MS spasticity treatment, cannabinoid may help to treat MS-related spasticity and pain [53]. However, according to the results from clinical trials, it is not allowed to use cannabinoids in MS as a general use. In a recent study, 630 MS patients affected by muscle spasticity were randomised to be treated with oral delta-9-THC, cannabis extract, or placebo for up to 12 months. The results showed a controversial effect; in fact, there was a small treatment effect on muscle spasticity and disability as functional independence measure, but patients' sensation was that these drugs were helpful in treating their disease [54]. Adverse side effects are generally mild, in particular dry mouth, somnolence, dizziness, nausea, and rarely intoxication. However, there is a need of longer-term studies to evaluate other, well-known, adverse side effects of cannabinoid such as risks of lung cancer and other respiratory dysfunctions. A recent multicentre observational study confirmed the efficacy and safety of delta-9-THC in clinical practice, as an effective and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs [55]. In a recent consensus, a significant recommendation for the use of cannabinoids in spasticity emerged, particularly for oromucosal spray nabiximols, as treatment of spasticity in MS; the strength of the

BTX type A is considered as the first-line treatment of multifocal muscle overactivity, thanks to its better efficacy and safety profile with respect to systemic approach with drugs. Different from baclofen or tizanidine, the efficacy of BTX type A has been demonstrated in self-care improvement (in particular for washing and dressing) and in active movements for the leg, with gait improvement if possible. Except for using kinematic analysis, no improvement was possibly shown in active movement or function in the upper limb. Pain was also reduced by BTX treatment as demonstrated in literature. Four forms of BTX are currently available in Europe: three type As (BOTOX®, Allergan; Dysport®, Ipsen-Pharma; Xeomin®, Merz) and one type B (Neurobloc®, Elan-Pharma). It is absolutely recommended to keep in mind that the units of these four toxins are different, being

**122**

specific for each one. Injection sites are better detected, using electrical stimulation, as anatomical markers alone may induce to an inaccurate target. The use of ultrasound guidance, particularly in children, in identifying muscle site injection, is an interesting study object; however, this technique has not been evaluated with respect to electrical stimulation guidance for its efficiency. Generally, there are no immediate postinjection complications (except for a little pain as a side effect related to injection itself). Above all, during the first 3 weeks after each injection treatment, there would be a low risk of adverse events (swallowing disorders and botulism-like syndrome), so patients and caregivers must be warned as well as encouraged to eventually consult if necessary. The effects of treatment could be assessed 1–6 weeks after the injection, based on personalised goals decided before treatment. The effect of the toxin is not permanent, so repeated injections are often needed; nevertheless, a long-lasting effect is also observed. No repeated treatment is recommended without a specific assessment. When and if needed according to functional evaluation, a minimum delay of 2–3 months between injections must be respected, in order to reduce the risk of an immunologic reaction that may induce a permanent inefficacy of subsequent treatments. Each subsequent treatment should be planned after an accurate functional evaluation according to the pre-therapeutic identified goals and task, as well as tolerance. So, a review of the dose and treated muscles could be scheduled. If therapeutic effects continue to be evident, repeated injections can be planned [33, 56–60]. Physical therapy has to be considered after BOTOX injections. Regarding maximum doses, according to European Consensus, it should be considered:


It is notable that these dosages are identified relatively to acceptable side effects, in order to be safe. Moreover, each product could be effective with different doses for each patient, in terms of both efficacy and safety [61]. As well as the cannabinoid, there is a strong recommendation of the use of BTX to reduce muscle tone in spasticity do to multiple sclerosis [42].
