Drugs Used to Treat Spasticity - UNMC

DISEASE MANAGEMENT 

Drugs 2000 Mar; 59 (3): 487-495 

0012-6667/00/0003-0487/$25.00/0 

© Adis International Limited. All rights reserved. 

Drugs Used to Treat Spasticity 

Mariko Kita and Donald E. Goodkin 

Department of Neurology, University of California at San Francisco, School of Medicine UCSF/Mt 

Zion Multiple Sclerosis Center, San Francisco, California, USA 

Contents 

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 487 

1. Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488 

2. Rationale for Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488 

3. Pharmacotherapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489 

3.1 Baclofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489 

3.2 Diazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490 

3.3 Tizanidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490 

3.4 Clonidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491 

3.5 Dantrolene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491 

3.6 Gabapentin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492 

3.7 Botulinum Toxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492 

3.8 Intrathecal Baclofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492 

4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493 

Abstract 

Spasticity is a common and disabling symptom for many patients with upper 

motor neuron dysfunction. It results from interruption of inhibitory descending 

spinal motor pathways, and although the pathophysiology of spasticity is poorly 

understood, the final common pathway is overactivity of the alpha motor neuron. 

Therapy for spasticity is symptomatic with the aim of increasing functional capacity 

and relieving discomfort. Any approach to treatment should be multidisciplinary, 

including physical therapy, and possibly surgery, as well as 

pharmacotherapy. It is important that treatment be tailored to the individual patient, 

and that both patient and care giver have realistic expectations. Pharmacotherapy 

is generally initiated at low dosages and then gradually increased in an 

attempt to avoid adverse effects. Optimal therapy is the lowest effective dosage. 

Baclofen, diazepam, tizanidine and dantrolene are currently approved for use in 

patients with spasticity. In addition, clonidine (usually as combination therapy), 

gabapentin and botulinum toxin have shown efficacy, however, more studies are 

required to confirm their place in therapy. Intrathecal baclofen, via a surgically 

implanted pump and reservoir, may provide relief in patients with refractory 

severe spasticity. 

Spasticity, a clinical sign of upper motor neuron 

dysfunction, results from interruption of inhibitory 

descending spinal motor pathways. As observed in 

numerous neurological disorders such as cerebral 

palsy, spinal cord injury, stroke, and multiple sclerosis 

(MS), spasticity is defined as a velocity-dependent 

increase in tonic stretch reflexes, [1] where faster 

passive movements meet with increasing resis-

488 Kita & Goodkin 

tance. A clasp-knife phenomenon may be seen with 

dissipation of resistance during stretch. Additional 

signs associated with spasticity include weakness, 

increased muscle tone, impaired dexterity and coordination, 

hyper-reflexia, extensor plantar responses, 

spontaneous muscle spasms, and contractures. 

[2] Spasticity worsens in the setting of 

noxious stimuli such as infection, urolithiasis, urinary 

or faecal retention, decubitus ulcers, tight or 

misfitting clothing or misfitting orthotics. The 

symptoms of spasticity can greatly interfere with a 

patient’s functional capacity. 

1. Pathophysiology 

The pathophysiology of spasticity is poorly understood 

but the final common pathway underlying 

the mechanism is overactivity of the alpha motor 

neuron. Descending spinal pathways (corticospinal, 

reticulospinal, vestibulospinal) exert control over 

alpha motor neurons via mono- and poly-synaptic 

pathways. 

The muscle spindle is the complex sensory structure 

of the muscle conveying information about 

muscle length. Spindles lie in parallel with extrafusal 

fibres (large muscle fibres that effect gross 

movement), so when the muscle is lengthened, the 

spindle is stretched causing Ia afferent fibres to 

send impulses to the spinal cord. Shortening of the 

extrafusal muscle results in shortening of the spindle 

and silencing of the Ia afferents. The intrafusal 

muscle fibres of the spindle complex are innervated 

by gamma motor neurons in the anterior 

horns of the spinal cord, which act to increase the 

tension of the intrafusal fibre when it is shortened. 

This resets the spindle after shortening so it is again 

sensitive to changes in muscle length. 

When the muscle is lengthened by tendon tap or 

stretch, Ia afferents produce excitatory postsynaptic 

potentials (EPSPs) on agonist motoneurons. Although 

this monosynaptic connection plays a role 

in the reflex, most excitatory activity in the stretch 

reflex is mediated by oligosynaptic and polysynaptic 

pathways. [2] Interneurons play a major role in 

the reflex arc. Antagonist muscle spindles also send 

Ia afferents to produce EPSPs on agonist interneurons 

which subsequently produce inhibitory postsynaptic 

potentials (IPSPs) on motoneurons. The 

firing of the motoneuron depends on the summation 

of EPSPs and IPSPs. Additional inhibitory interneurons 

act on Ia afferents to produce a presynaptic 

inhibition of the afferent signal. γ-Aminobutyric 

acid (GABA) is the neurotransmitter involved in 

this selective presynaptic inhibition. 

Thus, the spinal segmental reflexes require the 

participation of muscle spindles, fusimotor innervation 

(gamma motor neurons), Ia primary afferents, 

and alpha motor neurons, as well as Renshaw 

recurrent inhibition, disynaptic reciprocal inhibition, 

nonreciprocal autogenic Ib inhibition, presynaptic 

inhibition and remote inhibition/excitation of alpha 

motor neurons. [2] Spasticity results from a prolonged 

disinhibition of components of this system 

but the exact mechanism remains unclear. 

2. Rationale for Treatment 

The goal of therapy is to increase functional capacity 

and relieve discomfort. Before initiating treatment 

one must first evaluate the functional consequences 

of reducing spasticity. For some patients 

with proximal leg weakness, increased extensor 

tone in the legs offers necessary stability and support 

during transferring and walking. For other patients, 

hyper-reflexia and clonus interfere with normal 

ambulation. In non-ambulatory patients, flexor 

spasms may be painful and debilitating. Patients 

with spasticity may exhibit further increase in tone 

or spontaneous spasm in the setting of an underlying 

infection, such as a urinary tract infection, or 

other noxious stimulus. These secondary causes 

should be ruled out before altering a given therapeutic 

regimen. The approach to treating spasticity 

should be multimodal. Physical therapy is an essential 

component of antispasticity regimens and 

in the most patients with refractory spasticity, surgical 

intervention (e.g. posterior rhizotomy or tendon 

release procedures) may be beneficial. In this 

review we will focus on pharmacological treatment 

of spasticity. 

© Adis International Limited. All rights reserved. Drugs 2000 Mar; 59 (3)

Drug Treatment of Spasticity 489 

3. Pharmacotherapies 

Medications frequently used in the treatment of 

spasticity include baclofen, benzodiazepines, tizanidine, 

clonidine, dantrolene, gabapentin, and botulinum 

toxin. Of these, only baclofen, diazepam, 

tizanidine and dantrolene are approved for the 

treatment of spasticity. A general rule is to initiate 

treatment at low dosages and to increase them 

gradually to avoid adverse effects. The lowest dosage 

that proves to be effective for an individual 

patient is considered optimal. Table I outlines the 

use of frequently used oral antispasticity agents. 

3.1 Baclofen 

Baclofen is a structural analogue of GABA, and 

inhibits monosynaptic and polysynaptic spinal reflexes. 

It binds to the GABA B receptor which is 

coupled to calcium and potassium channels, and 

occurs both pre and postsynaptically. [3] By binding 

at the presynaptic site the membrane is hyperpolarised, 

and influx of calcium into presynaptic 

terminals is restricted resulting in a decrease in 

neurotransmitter release in excitatory spinal pathways 

and a decrease in alpha motor neuron activity. 

[4] In addition, postsynaptic binding on the Ia 

afferent terminal increases potassium conductance, 

hyperpolarising the membrane and enhancing the 

presynaptic inhibition. Activation of GABA B receptors 

may also result in inhibition of gamma motor 

neuron activity and decreased muscle spindle 

sensitivity. [5] 

Several trials have examined the efficacy of 

baclofen in patients with spasticity secondary to 

MS and spinal cord pathology. [6-14] In the patients 

with MS, baclofen has been found to be effective 

in reducing spasticity, decreasing frequency and 

severity of sudden painful spasms, and improving 

the range of joint movement. However, increased 

weakness was a common complaint. In patients with 

spinal cord injuries, baclofen has been reported to 

be particularly helpful in reducing flexor spasms. 

In post-stroke patients, it appears to be less beneficial. 

[15,16] Specifically, patients were found to have 

amodestdecreaseinmuscletonewhichwasinterpreted 

subjectively as only a slight improvement 

Table I. Oral agents commonly used to treat spasticity 

Agent Starting dosage Maximum recommended 

dosage 

Baclofen 5 mg/day 

80 mg/day in divided doses Muscle weakness, 

increasingto15 

sedation, fatigue, 

mg/day in 3 divided 

dizziness, nausea 

doses 

Diazepam 2 mg/day bid or 5 

mg qhs 

40-60 mg/day in divided 

doses 

Adverse effects Monitoring Special attention 

Sedation, cognitive 

impairment, depression 

Tizanidine 2-4 mg/day 36 mg/day in divided doses Drowsiness, dry mouth, 

dizziness, reversible 

dose-related elevated 

liver transaminases 

Clonidine 0.1 mg/day Not approved for spasticity; 

in patients with hypertension, 

doses as high as 2.4mg in 

divided doses have been 

studied but rarely employed; 

Usual dose in hypertension 

0.2-0.6 mg/day 

Bradycardia, hypotension, 

dry mouth, drowsiness, 

constipation, dizziness, 

depression 

Dantrolene 25 mg/day 400 mg/day in divided doses Hepatotoxicity (potentially 

irreversible), weakness, 

sedation, diarrhoea 

Gabapentin 100mg tid 3600 mg/day in divided doses Stomach upset 

bid = twice daily; qhs = at bedtime; tid = three times daily. 

Periodic liver 

function tests 

Dependence 

potential 





Abrupt cessation 

associated with 

seizures 

Withdrawal 

syndrome 

Nottobeusedwith 

antihypertensives 

or clonidine 

Add-on agent 

Hypotension may 

result 

Nottobeusedwith 

tizanidine 

Hepatotoxicity 



in the feeling of stiffness. No effect was noted on 

hyper-reflexia or clonus. [16] 

Baclofen is rapidly absorbed after oral administration 

but CNS penetration is relatively limited. 

The mean half-life is fairly short with an average 

of approximately 3.5 hours. Because it is partially 

metabolised by the liver (15%) and excreted by the 

kidney, the dosage should be decreased in patients 

with known hepatic or renal impairment. There 

have been reports of elevated liver enzyme levels 

in patients receiving baclofen. As such, screening 

liver function tests should be performed when initiating 

treatment with baclofen and every 6 months 

thereafter. Treatment is often initiated at 5mg once 

daily increasing to 3 times daily as tolerated. Thereafter, 

the dosage can be increased slowly at increments 

of 5mg/day as needed. It may be helpful to 

initiate treatment and increments at night to minimise 

adverse effects. The highest recommended dosage 

is 80mg daily in divided doses, but for some 

patients, this dosage may not be sufficient to relieve 

symptoms. Higher dosages should be prescribed 

with caution as adverse effects are likely to 

be more prominent. 

Typical adverse effects are related to CNS depression 

and include drowsiness, fatigue, weakness, 

nausea, and dizziness. Abrupt cessation of sustained 

treatment should be avoided because sudden 

withdrawal of baclofen has been associated with 

hallucinations and seizures. 

3.2 Diazepam 

The action of the benzodiazepines is mediated 

by the coupling of the benzodiazepine-GABA A 

receptor-chloride ionophore complex. [17] Binding 

of benzodiazepine to the GABA A receptor increases 

chloride conductance resulting in presynaptic 

inhibition in the spinal cord. [18,19] Diazepam 

is the most commonly used benzodiazepine in the 

treatment of spasticity. Early trials have demonstrated 

efficacy in treating spasticity in patients 

with spinal cord injury, hemiplegia, and MS. [20-23] 

From and Heltberg [24] studied 17 patients with MS 

in a double-blind, crossover trial with baclofen and 

diazepam. Each patient received 4 weeks therapy 

with each drug. No differences were seen in efficacy 

of reducing spasticity, clonus, flexor spasms, 

or improvement in gait or bladder function. The 

adverse effect profiles differed slightly, with more 

patients reporting sedation while receiving diazepam, 

but the severity of adverse effects was similar 

in both groups. When patients, still masked to treatment 

assignment, were asked which agent they preferred, 

baclofen was significantly favoured. [24] Other 

studies have confirmed comparable antispasticity 

effects of baclofen and diazepam in reducing muscle 

tone and frequency of spasms. However, baclofen 

was not necessarily favoured by patients over 

diazepam. [25,26] In clinical practice, diazepam is 

frequently used as an adjunct to baclofen in treating 

spasticity, [27] andislesscommonlyusedasasingle 

agent. 

Diazepam is well absorbed after oral administration 

and reaches a peak concentration after approximately 

1 hour. It is 98% protein-bound and is 

metabolised by the liver to active compounds nordazepam 

and oxazepam. In patients with hepatic 

dysfunction, initial dosages should be titrated carefully. 

Total half-life can range between 20 and 80 

hours. Treatment may be initiated at 2mg twice 

daily increasing as needed to obtain a desired effect. 

Alternatively, single 5mg doses at night may be 

effective for nocturnal symptoms. Adverse effects 

include sedation and cognitive impairment, and 

there is a potential for dependence. A withdrawal 

syndrome is associated with the benzodiazepines 

and abrupt cessation of diazepam has been associated 

with seizures. 

3.3 Tizanidine 

Tizanidine is an imidazole derivative and is a 

centrally acting α 2 -adrenergic agonist which inhibits 

the release of excitatory amino acids in spinal 

interneurons. It may also act by facilitating the action 

of glycine. Tizanidine has demonstrated potent 

muscle relaxing properties in animal models of 

spasticity, [28] anditwasfoundtosuppressthepolysynaptic 

reflex in the spinal-transected cat. [29,30] In 

addition, tizanidine has been shown to enhance 

vibratory inhibition of the H-reflex in humans and 



reduces abnormal co-contraction which may also, 

in part, contribute to antispasticity effects. [31] In 

placebo-controlled trials, tizanidine has been shown 

to reduce muscle tone and frequency of muscle 

spasms in both patients with MS and spinal cord 

injury. [32-34] Similar efficacy was noted when tizanidine 

open-label was tested in patients who had 

experienced a stroke. [35] Although tizanidine was 

found to reduce spasticity without altering muscle 

strength, it has shown no consistent positive effect 

on functional measures, such as timed ambulation, 

upper extremity function or activities necessary in 

activities of daily living (ADLs). [32] When compared 

with baclofen or diazepam in early trials, 

tizanidine demonstrated similar efficacy and better 

tolerability. [30,33,36-43] When compared with baclofen, 

night-time insomnia was reported more frequently 

with tizanidine, and weakness was also reported 

but less frequently than with baclofen. [36] 

There have been no controlled trials investigating 

the use of tizanidine in combination with baclofen. 

Tizanidine undergoes first-pass hepatic metabolism 

and is subsequently eliminated by the kidney. 

Its half-life is approximately 2.5 hours and the peak 

effect is seen 1 to 2 hours after administration. Liver 

function tests should be checked at baseline, months 

1, 3 and 6 of treatment, and periodically thereafter. 

Treatment is initiated at 2 to 4 mg/day, increasing 

every 3 days by 2 to 4 mg/day. The total dosage 

shouldnotexceed36mg/dayin3divideddoses. 

There is little experience with single doses greater 

than 8mg. Adverse effects include dry mouth (45%), 

drowsiness (54%) and dizziness, and were seen 

primarily when dosages exceeded 24 mg/day. Visual 

hallucinations (3%) and elevated liver function 

tests (5%) were reversible with dosage reduction. 

[32] Tizanidine has not been found to have 

consistent effects on blood pressure, but because 

of its central α 2 -adrenergic activity and risk of potential 

hypotension, concomitant use of antihypertensives, 

especially clonidine, should be avoided. 

3.4 Clonidine 

Clonidine is a centrally acting α 2 -adrenergic agonist 

that is frequently used to treat hypertension 

as well as opiate withdrawal. The central α-adrenergic 

activation is thought to decrease sympathetic 

outflow. Clonidine has been shown to decrease the 

vibratory inhibition index in patients with spinal 

cord injury, [44] to reduce muscle tone in patients with 

brain injuries (stroke, trauma, haematoma, cerebral 

palsy), [45] and has shown modest benefit as a 

supplement to baclofen. [46] Clonidine is rarely used 

as a single agent in the treatment of spasticity. It is 

available in 0.1mg tablets, but the patch formulation 

(0.1mg and 0.2mg) is designed to deliver the 

specified dose daily and must be changed every 7 

days. Adverse effects include bradycardia, hypotension, 

dry mouth, drowsiness, constipation, dizziness, 

and depression. 

3.5 Dantrolene 

Dantrolene is a hydantoin derivative. It acts directly 

on muscle contractile elements decreasing 

the release of Ca 2+ from skeletal muscle sarcoplasmic 

reticulum, which interferes with excitationcontraction 

coupling that is necessary to produce 

muscle contraction. [47-49] Theeffectismostpronounced 

on extrafusal fibres, but there is a minor 

effect on intrafusal fibres as well. Whether this effect 

may alter spindle sensitivity is unclear. [50] 

Dantrolene has a greater effect on fast-twitch fibres 

(those that produce rapid contraction and high tension, 

but fatigue relatively easily) than on slowtwitch 

fibres (those that contract tonically, producing 

less tension, but are more resistant to fatigue). [51] 

Placebo-controlled trials of dantrolene have 

demonstrated effective reduction of muscle tone and 

hyper-reflexia. [49,52-54] When dantrolene was compared 

with diazepam in a double-blind, crossover 

designed trial in 42 patients with MS, both drugs 

were found to decrease spasticity, clonus and hyperreflexia, 

as well as diminish muscle stiffness and 

cramping. [55] Similar trials have been performed in 

children with cerebral palsy [56] and in patients with 

spasticity secondary to varying causes of cerebral 

and spinal disorders. [57] Spasticity was slightly better 

controlled with dantrolene than with diazepam 

and adverse effects were reported to be more tolerable 

with dantrolene. 



The half-life for oral dantrolene is approximately 

15 hours, with peak concentrations occurring 

within 3 to 6 hours. It is metabolised largely by the 

liver. Dantrolene therapy is initiated at 25 mg/day 

and slowly titrated upwards by increments of 25 

mg/day every 5 to 7 days, with a recommended 

maximum of 400 mg/day in divided doses. Because 

its site of action is peripheral, the most common 

adverse effect of dantrolene is weakness. For 

this reason, dantrolene may be most appropriate for 

those patients who are non-ambulatory with severe 

spasticity. Other adverse effects include drowsiness, 

diarrhoea and malaise. Hepatotoxicity, which 

can be irreversible, is the major concern with dantrolene 

and those patients who are being considered 

for therapy should have liver function tests 

checked prior to initiating therapy and on a regular 

basis (every 3 months) thereafter. 

3.6 Gabapentin 

Gabapentin was first introduced in 1994 as a 

new treatment option for patients with partial seizures. 

[58] It is structurally similar to GABA, exerting 

GABAnergic activity by binding receptors in 

the neocortex and hippocampus. However, it does 

not bind conventional GABA A , GABA B ,glycine, 

glutamate, benzodiazepine or N-methyl aspartate 

receptors. [59,60] It is easily absorbed, reaching peak 

plasma concentrations in 2 to 3 hours, it is not protein 

bound, does not undergo metabolism, and is 

excreted unchanged in the urine. It is well tolerated 

indosagesupto3600mg/day. [61] Recent studies 

and reports have suggested it might be effective as 

another tool in treating spasticity [61,62] but further 

studies will be necessary to confirm efficacy. 

3.7 Botulinum Toxin 

Botulinum toxin is a product of Clostridium botulinum, 

and ingestion of the organism or its spores 

results in botulism. Botulinum toxin blocks presynaptic 

release of acetylcholine from the nerve 

terminal. Seven immunologically distinct toxins 

(type A through G) have been purified. Local intramuscular 

injection of botulinum toxin A has been 

approved for the treatment of strabismus and 

blepharospasm associated with dystonia. When injected, 

the agent spreads through muscle and fascia 

approximately 30mm, binding presynaptic cholinergic 

nerve terminals, resulting in a chemical denervation. 

Botulinum toxin injection has been studied as a 

treatment for severe spasticity caused by stroke, traumatic 

brain injury and other causes, [63-66] and has 

been found to be effective in reducing muscle tone 

and spasms. Snow et al. [67] studied botulinum toxin 

A in 9 patients with advanced MS (wheelchair- or 

bed-bound) in a randomised, crossover, doubleblind 

study. Muscle tone, frequency of spasms and 

hygiene/self-care scores were used to assess efficacy. 

Botulinum toxin injection produced a significant 

reduction in spasticity and improvement in ease 

of nursing care, with no adverse effects. [67] Botulinium 

toxin injection was found to be a promising 

therapy for the treatment of spasticity in children 

with cerebral palsy. [68,69] Judicious use of botulinum 

toxin may permit surgery to be delayed until children 

reach a more suitable age. 

Although botulinum toxin injection is off-label 

for treatment of spasticity, it may be an appropriate 

option for selected patients with severe localised 

spasms. Physicians using botulinum toxin should 

be trained in its use with attention to relevant topical 

anatomy and kinesiology. Onset of focal muscle 

fibre paralysis begins in 24 to 72 hours with a 

maximal effect seen at 5 to 14 days. The paralysis 

is transient lasting 12 to 16 weeks. Localising specific 

muscles with electromyographic guidance 

may be necessary to produce optimal effects. Injection 

site reactions can occur and antibodies may 

develop to specific immunological strains, thus 

limiting efficacy. Because the delivery of toxin is 

not entirely contained, the paralysis of muscles 

may not be exact. Excessive weakness, though ultimately 

reversible, may result. 

3.8 Intrathecal Baclofen 

When treatment with oral medication fails in a 

patient with persistent severe spasticity, intrathecal 

administrationofbaclofenshouldbeconsidered.A 

pump with reservoir is surgically implanted in the 



subcutaneous tissue of the abdominal wall. A catheter 

is threaded into the subarachnoid space allowing 

delivery of baclofen directly into the CSF. This 

allows as much as 4 times the concentration of drug 

to be delivered at only 1% of the oral dosage, without 

concomitant elevation of serum concentrations, 

and thereby reducing unwanted cerebral adverse 

effects. [70] Penn et al. [70] conducted a double-blind, 

placebo-controlled, 3-day crossover study in 20 

patients (10 with MS and 10 with spinal cord injury). 

All patients had decreased muscle tone and frequency 

of spasms while treated with baclofen. All 

patients were subsequently enrolled in a long term 

nonblind trial of continuous infusion, with a mean 

follow-up period of 19 months. Using the Ashworth 

scale [71,72] (a standardised scale to assess muscle 

tone), all patients exhibited normal tone and spasm 

frequency was diminished to the point that there 

was no interference with ADLs. Seven of 8 patients 

also experienced improvement in bladder function. 

[70] Others have found equally dramatic results. 

[73-75] Well tolerated and effective long term 

follow-uphasbeenreportedinpatientsupto84 

months. [76] 

Pump implantation is considered only after a 

patient undergoes a trial of intrathecal baclofen to 

establish responsiveness. Treatment is started at a 

dosage of 25 µg/day, increasing up to an average of 

400 to 500 µg/day, although dosages as high as 

1500 µg/dayhavebeenreported. [77] The half-life 

of intrathecal baclofen is approximately 5 hours. 

Many patients require increased dosages during 

the first 6 months’treatment and tolerance has been 

reported. [71,78] Most adverse effects tend to occur 

during the titration phase and include drowsiness, 

headache, nausea, weakness, and hypotension. Reversible 

coma has been reported in baclofen overdosing. 

[79] Other complications may be due to mechanical 

problems (dislodgment, disconnection, 

kinking, blockage), pump failure or infection. Intrathecal 

baclofen is a costly treatment and although 

useful, should only be considered in patients 

with severe functional limitations who have 

not responded satisfactorily to other treatments. 

4. Conclusion 

As with any symptomatic therapy, the treatment 

of spasticity should be individualised. Goals for 

therapy and realistic expectations should be established 

by both care provider and patient. Conservative 

measures should be incorporated into treatment 

regimens for spasticity. Stretching, massage 

and passive range of motion exercises are extremely 

important in preventing muscle shortening 

and the formation of contractures. Guidance on 

proper positioning and posture, as well as how to 

avoid specific positions that may elicit clonus or 

spasms, can result in increasing functional. Patients 

should also be evaluated for adaptive equipment 

such as ambulatory aids, reachers and other 

devices, and be instructed on the appropriate use 

of these tools. Direct effects of muscle relaxation 

from physiotherapy are often short-lived and for 

many patients, these conservative measures alone 

are insufficient to treat their symptoms. Most patients 

experience symptomatic improvement with 

physiotherapy in combination with one or more 

antispasticity agents. Patients refractory to these 

treatment options may respond to intrathecal baclofen. 

An understanding of the mechanism of action 

of these therapies should aid in developing 

individualised regimens for patients. 

References 

1. Lance JW. Symposium synopsis. In: Feldman RG, Young RR, 

Koella WP, editors. Spasticity: disordered motor control. Chicago 

(IL): Year Book Medical Publishers, 1980: 485-94 

2. Young RR. Spasticity: a review. Neurology 1994; 44 Suppl. 9: 

12S-20S 

3. Bormann J. Electrophysiology of Gaba-a and Gaba-b receptor 

subtypes. Trends Neurol Sci 1988; 11: 112-6 

4. Davidoff RA. Antispasticity drugs: mechanism of action. Ann 

Neurol 1985; 17: 107-17 

5. Van Hemet JCJ. A double-blind comparison of baclofen and 

placebo in patients with spasticity of cerebral origin. In: Feldman 

RG, Young RR, Koella WP, editors. Spasticity: disordered 

motor control. Chigaco (IL): Year Book Medical 

Publishers, 1980 

6. Jerusalem F. A double-blind study on the antispastic action of 

beta-(4-chlorophenyl)-gamma-amino butyric acid in multiple 

sclerosis, Nervenarzt 1968; 39: 515 

7. Jones RF, Burke D, Morasszeky JE, et al. A new agent for the 

control of spasticity. J Neurol Neurosurg Psychiatry 1970; 33: 

464-8 

8. Hudgson P, Weightman D. Baclofen in the treatment of spasticity. 

BMJ 1971; 4: 15-17 



9. Basmajan JV. Lioresal (baclofen) treatment of spasticity in multiple 

sclerosis. Am J Phys Med 1975; 54 (4): 175-7 

10. Duncan GW, Shahani BT, Young RR. An evaluation of baclofen 

treatment for certain symptoms in patients with spinal cord 

lesions. Neurology 1976; 441: 446 

11. Levine IM, Jossmann PB, DeAngelis V. Lioresal, a new muscle 

relaxant in the treatment of spasticity: a double blind quantitative 

evaluation. Dis Nerv Sys 1977; 38: 1011-5 

12. Sawa GM, Paty DW. The use of baclofen in treatment of spasticity 

in multiple sclerosis. Can J Neurol Sci 1979; 6 (3): 351-4 

13. Hinderer SR, Lehman JF, Price R, et al. Spasticity in spinal cord 

injured persons: quantitative effects of baclofen and placebo 

treatments. Am J Phys Med Rehabil 1990; 69 (6): 311-7 

14. Smith CR, LaRocca NG, Giesser BS, et al. High dose oral baclofen: 

experience in patients with multiple sclerosis. Neurology 

1991; 41: 1829-31 

15. Pedersen E, Arlien-Soborg P, Mai J. The mode of action of the 

BAGA derivative baclofen in human spasticity. Acta Neurol 

Scand 1974; 50: 665-80 

16. Milanov IG. Mechanisms of baclofen action on spasticity. Acta 

Neurol Scand 1992; 85: 305-10 

17. Costa E, Guidotti A. Molecular mechanisms in the receptor action 

of the benzodiazepines. Ann Rev Toxicol 1979; 19: 531-45 

18. Schwarz M, Turski L, Janiszewski W, et al. Is the muscle relaxant 

effect of diazepam in spastic mutant rats mediated through 

GABA-independent benzodiazepine receptors Neurosci Lett 

1983; 36: 175-80 

19. Pedersen E. Clinical assessment and pharmacologic therapy of 

spasticity. Arch Phys Med Rehabil 1974; 55: 344-54 

20. Kendall PH. The use of diazepam in hemiplegia. Ann Phys Med 

1964; 7: 225-8 

21. Neill RW. Diazepam in the relief of muscle spasm resulting 

from spinal-cord lesions. Ann Phys Med 1964; Suppl.: 33-8 

22. Nathan PW. The action of diazepam in neurological disorders 

with excessive motor activity. J Neurol Sci 1970; 10: 33-50 

23. Corbett M, Frankel HL, Michaelis L. A double-blind cross-over 

trial of valium in the treatment of spasticity. Paraplegia 1972; 

10: 19-22 

24. From A, Heltberg A. A double-blind trial with baclofen and 

diazepam in spasticity due to multiple sclerosis. Acta Neurol 

Scand 1975; 51: 158-66 

25. Roussan M, Terrence C, Fromm G. Baclofen versus diazepam 

for the treatment of spasticity and long term follow-up of 

baclofen therapy. Pharmatherapeutica 1987; 4 (5): 278-84 

26. Cartlidge NE, Hudgson P, Weightman D. A comparison of baclofen 

and diazepam in the treatment of spasticity. J Neurol Sci 

1974; 23: 17-24 

27. Mitchell G. Update on multiple sclerosis therapy. Med Clin 

North Am 1993; 77: 231-49 

28. Coward DM. Selective muscle relaxant properties of tizanidine 

and an examination of its mode of action. Triangle 1981; 20: 

151-58 

29. Davies J. Selective depression of synaptic transmission of spinal 

neurones in the cat by a new centrally acting muscle relaxant, 

5-chloro-4-(2-imidazolin-2-yl-amino)-2,1,3-benzothiadazole 

(DS 103 282). Br J Pharmacol 1982; 76: 473-81 

30. Newman PM, Nogues M, Newman PK, et al. Tizanidine in the 

treatment of spasticity. Eur J. Clin Pharmacol 1982; 23: 31-5 

31. Delwaide PJ. Electrophysiological testing of spastic patients: 

it’s potential usefulness and limitations. In: Delwaide PJ, 

Young RR editors. Clinical neurophysiology in spasticity. 

Amsterdam: Elsevier, 1985: 185-203 

32. United Kingdom Tizanidine Study Group. A double-blind placebo-controlled 

trial of tizanidine in the treatment of spasticity 

caused my multiple sclerosis. Neurology 1994; 44 Suppl. 

9: 70-9 

33. Lapierre Y, Bouchard S, Tansey C, et al. Treatment of spasticity 

with tizanidine in multiple sclerosis. Can J Neurol Sci 1987; 

14: 513-7 

34. Nance PW, Bugaresti J, Shellenberger K, et al. Efficacy and 

safety of tizanidine in the treatment of spasticity in patients 

with spinal cord injury. Neurology 1994; Suppl. 9: 44S-52S 

35. Milanov I, Georgiev D. Mechanisms of tizanidine action on 

spasticity. Acta Neurol Scand 1994; 89: 274-9 

36. Bass B, Weinshenker B, Rice GPA, et al. Tizanidine versus 

baclofen in the treatment of spasticity in patients with multiple 

sclerosis. Can J Sci 1988; 15 (1): 15-9 

37. Stein R, Nordal HJ, Oftendal SI, et al. The treatment of spasticity 

in multiple sclerosis: a double-blind clinical trial of a new 

anti-spasticity drug tizanidine compared with baclofen. Acta 

Neurol Scand 1987; 75: 190-4 

38. Smolenski C, Muff S, Smolenski-Kauts S. A double-blind comparative 

trial of a new muscle-relaxant, tizanidine (DS102- 

282) and baclofen in the treatment of chronic spasticity in 

multiple sclerosis. Curr Med Res Opin 1981; 7 (6): 374-83 

39. Hoorgstraten MC, van der Ploeg RJO, Van der Burg W, et al. 

Tizanidine versus baclofen in the treatment of multiple sclerosis 

patients. Acta Neurol Scand 1988; 77: 224-30 

40. Eyssette M, Rohmer F, Serratrice G, et al. Multi-centre, doubleblind 

trial of a novel antispastic agent, tizanidine, in spasticity 

associated with multiple sclerosis. Curr Med Res Opin 1988; 

10 (10): 699-708 

41. Pagano MA, Ferreiro ME, Herskovits E. Comparative study of 

tizanidine and baclofen in patients with chronic spasticity. 

Rev Neurol Argent 1988; 14 (4): 268-76 

42. Rinne UK. Tizanidine treatment of spasticity in multiple sclerosis 

and chronic myelopathy. Curr Ther Res 1980 Dec 1; 28 

(6): 827-36 

43. Bes A, Eyssette M, Pierrot-Deseilligny E, et al. A multi-centre, 

double-blind trial of tizanidine, a new anti-spastic agent, in 

spasticity associated with hemiplegia. Curr Med Res Opin 

1988; 10: 709-18 

44. Nance PW, Shears AH, Nance DM. Reflex changes induced by 

clonidine in spinal cord injured patients. Paraplegia 1989; 4: 

296-301 

45. Dall JT, Harmon RL, Quinn CM. Use of clonidine for treatment 

of spasticity arising from various forms of brain injury: a case 

series. Brain Injury 1996; 10 (6): 453-8 

46. Donovan WH, Carter RE, Rossi CD, et al. Clonidine effect on 

spasticity: a clinical trial. Arch Phys Med Rehabil 1988; 69 (3 

Pt 1): 193-4 

47. Herman R, Mayer N, Mecomber SA. Clinical pharmaco-physiology 

of dantrolene sodium. Am J Physical Med 1972; 51: 

296-311 

48. Ellis KO, Carpenter JF. Mechanisms of control of skeletal muscle 

contraction by dantrolene sodium. Arch Phys Med Rehabil 

1974; 55: 362-9 

49. Pinder RM, Brodgen RN, Speight TM, et al. Dantrolene sodium: 

a review of its pharmacological properties and therapeutic 

efficacy in spasticity. Drugs 1977; 13: 3-23 

50. Whyte J, Robinson KM. Pharmacologic management. In: Glenn 

M, Whyte J, editors. The practical management of spasticity 

in children and adults. Philadelphia (PA): Lea & Febiger, 

1990: 201-26 

51. Monster AW, Tamai Y, McHenry J. Dantrolene sodium in spasticity. 

Acta Neurol Scand 1979; 59: 309-16 

52. Gelenberg AJ, Poskanzer DC. The effect of dantrolene sodium 

on spasticity in multiple sclerosis. Neurology 1973; 23: 1313-5 



53. Tolosa ES, Soll RW, Loewenson R. Treatment of spasticity in 

multiple sclerosis with dantrolene. JAMA 1975; 233 (10): 1046 

54. Katrak PH, Cole A, Poulos CJ, et al. Objective assessment of 

spasticity, strength and function with early exhibition of dantrolene 

sodium after cerebrovascular accident: a randomized 

double-blind study. Arch Phys Med Rehabil 1992; 73: 4-9 

55. Schmidt RT, Lee RH, Spehlman R. Comparison of dantrolene 

sodium and diazepam in the treatment of spasticity. J Neurol 

Neurosurg Psychiatry 1976; 39: 350-6 

56. Nogen AG. Medical treatment for spasticity in children with 

cerebral palsy. Child’s Brain 1976; 2: 304-8 

57. Glass A, Hannah A. A comparison of dantrolene sodium and 

diazepam in the treatment of spasticity. Paraplegia 1974; 12: 

170-4 

58. US Gabapentin Study Group. The long-term safety and efficacy 

of gabapentin (Neurontin) as add-on therapy in drug-resistant 

partial epilepsy. Epilep Res, 1994 May, 18 (1): 67-73 

59. Fromm GH. Gabapentin. Epilepsia 1994; 35 Suppl. 5: 77-80S 

60. McLean MJ. Gabapentin. Epilepsia 1995; 36 Suppl. 2: 73S-86S 

61. Priebe MM, Sherwood AM, Graves DE, et al. Effectiveness of 

gabapentin in controlling spasticity: a quantitative study. Spinal 

Cord 1997; 35: 171-5 

62. Dunevsky A, Perel A. Gabapentin for relief of spasticity associated 

with multiple sclerosis. Am J Phys Med Rehabil 1998; 

77: 451-4 

63. Yablon SA, Agana BT, Ivanhoe CB, et al. Botulinum toxin in 

severe upper extremity spasticity among patients with traumatic 

brain injury: an open label trial. Neurology 1996; 47: 

939-44 

64. Simpson DM, Alexander DN, O’Brien CF, et al. Botulinum 

toxin type A in the treatment of upper extremity spasticity: a 

randomized, double-blind, placebo-controlled trial. Neurology 

1996; 46: 1306-10 

65. Burbaud P, Wiart L, Dubos JL, et al. Arandomized, double blind 

placebo controlled trial of botulinum toxin in the treatment of 

spastic foot in hemiparetic patients. J Neurol Neurosurg Psychiatry 

1996; 61: 265-9 

66. Das TK, Park DM. Effect of treatment with botulinum toxin on 

spasticity. Postgrad Med J 1989; 65: 208-10 

67. Snow BJ, Tsui JKC, Bhatt MH, et al. Treatment of spasticity 

with botulinum toxin: a double-blind study. Ann Neurol 1990; 

28: 512-5 

68. Cosgrove AP, Corry IS, Graham HK. Botulinium toxin in the 

management of the lower limb in cerebral palsy. Dev Med 

Child Neurol 1994; 36 (5): 386-96 

69. Koman LA, Mooney III JF, Smith BP, et al. Management of 

spasticity in cerebral palsy with botulinum-A toxin: report of 

a preliminary, randomized, double-blind trial. J Pediatr Orthop 

1994; 14 (3): 299-303 

70. Penn RD, Savoy SM, Corcos D, et al. Intrathecal baclofen for 

severe spinal spasticity. N Engl J Med 1989; 320: 1517-21 

71. Ashworth B. Preliminary trial of carisprodol in multiple sclerosis. 

Practitioner 1964; 192: 540-2 

72.LeeKC,CarsonL,KinninE,etal.TheAshworthScale:a 

reliable and reproducible method of measuring spasticity. J 

Neuro Rehab 1989; 3: 205-9 

73. Ochs G, Struppler A, Meyerson BA, et al. Intrathecal baclofen 

for long-term treatment of spasticity: a multi-centre study. J 

Neurol Neurosurg Psychiatry 1989; 52: 933-9 

74. Albright AL, Barron WB, Fasick MP, et al. Continuous intrathecal 

baclofen infusion for spasticity of cerebral origin. JAMA 

1993; 270: 2475-7 

75. Dralle D, Muller H, Zierski J, et al. Intrathecal baclofen for 

spasticity [letter]. Lancet 1985; II 8462: 1003 

76. Penn RD. Intrathecal baclofen for spasticity of spinal origin: 

seven years experience. J Neurosurg 1992; 77: 236-40 

77. Nance PW, Schryvers OI, Schmidt BJ, et al. Intrathecal baclofen 

therapy for adults with spinal spasticity: therapeutic efficacy 

and effect on hospital admission. Can J Neurol Sci 

1995; 22: 122-9 

78. Nanninga JB, Frost F, Penn R. Effect of intrathecal baclofen on 

bladder and sphincter function. J Urol 1989; 142: 101-5 

79. Siegfried J, Rea GL. Intrathecal application of drugs for muscle 

hypertonus. Scand J Rehab Med 1988; 17 Suppl.: 145-8 

Correspondence and offprints: Dr Mariko Kita, Department 

of Neurology, University of California at San Francisco, 

School of Medicine UCSF/Mt Zion Multiple Sclerosis Center, 

1701 Divisadero Suite 480, San Francisco, CA 94115- 

1642, USA. 

E-mail: kita@itsa.ucsf.edu

Drugs Used to Treat Spasticity - UNMC

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?