Baclofen. This g-aminobutyric acid (GABA)-B receptor agonist acts mainly on the presynaptic and postsynaptic terminals of primary fibres of the spinal cord to reduce the release of amino acids and to antagonize their actions. It is particularly useful in the treatment of painful spasms and increased tone of spinal origin, although functional benefits have been more difficult to demonstrate. In a large study of 759 patients with MS, 70 percent showed marked improvement in spasticity (defined as a two-step reduction on the five-step Ashworth Scale) and flexor spasms. A beneficial effect on spasms and hypertonicity was also seen in a small, double-blind, placebo-controlled, crossover study that involved 22 patients, 11 of whom had MS. The efficacy of baclofen has been shown to be equal to, if not greater than, that of diazepam. Baclofen is given three times a day, and should be started at a very low level with gradually increasing steps of 5 to 10 mg until the desired effect is achieved and/or side effects such as drowsiness, fatigue, and muscle weakness become unacceptable, usually reaching a dose of between 40–80 mg a day. Side effects are reported to affect up to 45 percent of patients. Abrupt discontinuation may result in severe withdrawal symptoms, which include hallucinations and seizures.

Tizanidine. This imidazoline derivative, which is closely related to clonidine, acts by stimulating b2-adrenergic receptors in the spinal cord. A number of studies have suggested that its efficacy is similar to that of baclofen. More recently, it was evaluated in two double-blind, placebo-controlled trials in the United Kingdom and the United States involving 187 and 220 patients, respectively. In the American trial, tizanidine reduced spasms and clonus significantly, but had no effect on spasticity as measured on the Ashworth Scale, and although the patients rated the drug significantly better on efficacy, the assessing physician did not. In the UK trial, a 20 percent reduction in spasticity was reported, and 75 percent of patients receiving the drug reported a subjective benefit without an increase in muscle weakness. However, no improvement in mobility-related activities of daily living was found. The suggestion that it may not cause weakness may be of therapeutic value. It is suggested that it be started at a low dose, 2 mg three times a day, and gradually increased up to a maximum of between 18–36 mgs. A long acting preparation that may be taken once daily is available in some countries. The most frequent side effects are tiredness (a major problem in patients who already suffer from fatigue), drowsiness, and dry mouth. Liver function tests must be checked before and after treatment because hepatotoxicity may occur.

Dantrolene. Few studies have evaluated the role of this agent or its efficacy in the management of spasticity. However, because dantrolene has a peripheral target of action and exerts its effect within the muscle itself by inhibiting the release of calcium ions from the sarcoplasmic reticulum, thereby preventing muscle contraction, it is theoretically a useful additional agent if centrally acting drugs are not effective. It is thought to be more effective in treating spasms and clonus than hypertonicity, and long-term benefit has been documented. However, it is poorly tolerated. Side effects include drowsiness, weakness, fatigue, and occasionally hepatotoxicity, which may be irreversible.

Benzodiazepines. Benzodiazepines have three potential anti-spasticity actions: suppression of sensory impulses from muscle and skin receptors, potentiation of GABA action post-synaptically, and inhibition of excitatory descending pathways. The efficacy of diazepam has been evaluated in a small, doubleblind, cross-over trial of 21 patients with spastic paraparesis. It may be used as additional therapy in resistant cases of spasticity. Its role is limited by side effects, including drowsiness and dependence.

Cannabinoids. (See also Chapter 5.) There has been increasing pressure to evaluate the role of cannabinoids in spasticity in MS. A recent study evaluated the potential benefit of cannabinoids on spasticity and other symptoms related to MS. It was a randomized, placebo-controlled trial that enrolled 667 patients with stable MS and muscle spasticity; 630 participants were treated at 33 UK centres with oral cannabis extract (n=211), Delta9-tetrahydrocannabinol (Delta9-THC; n=206), or placebo (n=213). The trial duration was 15 weeks. The primary outcome measure was change in overall spasticity as measured by the Ashworth scale. Analysis was by intention to treat; 611 of 630 patients were followed up for the primary endpoint. No treatment effect of cannabinoids on the primary outcome was seen (p=0.40). The estimated difference in mean reduction in total Ashworth score for participants taking cannabis extract compared with placebo was 0.32 (95 percent CI −1.04 to 1.67), and for those taking Delta9-THC versus placebo it was 0.94 (−0.44 to 2.31). A treatment effect on patient-reported spasticity and pain was seen (p=0.003), and patients reported improvement in spasticity in 61 percent, 60 percent, and 46 percent of participants on cannabis extract, Delta9-THC, and placebo, respectively. However, the study showed evidence of a placebo effect, and there was also an element of patient un-blinding.

A 12-month follow-up, which included data on 502 patients, was subsequently reported. There was evidence of a treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12-months follow-up in an intention to treat analysis, (p=0.04). In the group taking Delta9-THC, the Ashworth score was significantly reduced compared to those taking either cannabis extract or placebo.

Another, smaller study carried out in a rehabilitation setting failed to show an objective benefit on spasticity, and an earlier, double-blind, placebo-controlled, twofold, crossover trial of oral tetrahydrocannabinol (THC) and Cannabis sativa plant extract in 16 patients showed no benefit, and both treatments worsened the global impression of the patients. Thus, the current evidence evaluating the use of cannabinoids in the treatment of spasticity in MS is variable, and may relate in part to the poor responsiveness of the outcome measure and the difficulty in blinding. Further research into cannabinoids is warranted and is currently underway

Other Drugs. A range of other drugs has been tried in MS-related spasticity, and reports involving small numbers have appeared in the literature. They include clonazepam, memantine, glycine, L-threonine, vigabatrin, and gabapentin.