Review of drug treatments of spasticty 2002 by Clark1968

Abstract: Systemic pharmacologic treatments may be indicated in conditions in which the distribution of muscle overactivity is diffuse. Antispastic drugs act in the CNS either by suppression of excitation (glutamate), enhancement of inhibition (GABA, glycine), or a combination of the two. Only four drugs are currently approved by the US FDA as antispactic agents: baclofen, diazepam, dantrolene sodium, and tizanidine. However, there are a number of other drugs available with proven antispastic action. This chapter reviews the pharmacology, physiology of action, dosage, and results from controlled clinical trials on side effects, efficacy, and indications for 21 drugs in several categories. Categories reviewed include agents acting through the GABAergic system (baclofen, benzodiazepines, piracetam, progabide); drugs affecting ion flux (dantrolene sodium, lamotrigine, riluzole); drugs acting on monoamines (tizanidine, clonidine, thymoxamine, beta blockers, and cyproheptadine); drugs acting on excitatory amino acids (orphenadrine citrate); cannabinoids; inhibitory neuromediators; and other miscellaneous agents. The technique, advantages, and limitations of intrathecal administration of baclofen, morphine, and midazolam are reviewed. Two consistent limitations appear throughout the controlled studies reviewed: the lack of quantitative and sensitive functional assessment and the lack of comparative trials between different agents. In the majority of trials in which meaningful functional assessment was included, the study drug failed to improve function, even though the antispastic action was significant. Placebo-controlled trials of virtually all major centrally acting antispastic agents have shown that sedation, reduction of global performance, and muscle weakness are frequent side effects. It appears preferable to use centrally acting drugs such as baclofen, tizanidine, and diazepam in spasticity of spinal origin (spinal cord injury and multiple sclerosis), whereas dantrolene sodium, due to its primarily peripheral mechanism of action, may be preferable in spasticity of cerebral origin (stroke and traumatic brain injury) where sensitivity to sedating effects is generally higher. Intrathecal administration of antispastic drugs has been used mainly in cases of muscle overactivity occurring primarily in the lower limbs in nonambulatory, severely disabled patients, but new indications may emerge in spasticity of cerebral origin. Intrathecal therapy is an invasive procedure involving long-term implantation of a foreign device, and the potential disadvantages must be weighed against the level of disability in each patient and the resistance to other forms of antispastic therapy. In all forms of treatment of muscle overactivity, one must distinguish between two different goals of therapy: improvement of active function and improvement of hygiene and comfort. The risk of global performance reduction associated with general or regional administration of antispastic drugs may be more acceptable when the primary goal of therapy is hygiene and comfort than when active function is a priority. ÂŠ1997 John Wiley & Sons, Inc. Spasticity:Etiology, Evaluation, Management, and the Role of Botulinum Toxin Type A, MF Brin, editor. Muscle Nerve 1997; 20 (suppl 6):S92-S120. Key words: spasticity, muscle overactivity, GABAergic drugs, baclofen, benzodiazepines, dantrolene, tizanidine, intrathecal delivery, botulinum toxin

Traditional Pharmacological Treatments for Spasticity Part II: General and Regional Treatments Jean-Michel Gracies, MD, PhD; Elie Elovic, MD; John McGuire, MD; David Simpson, MD Systemic pharmacologic treatments may be indicated in conditions in which the distribution of muscle overactivity is diffuse, such as anoxic, toxic, metabolic, inflammatory, vascular, traumatic, or degenerative encephalopathies or myelopathies. Multiple sclerosis and spinal cord injury are common causes of diffuse or regional muscle overactivity where the number of affected muscle groups may not be amenable to local treatments. As noted in the accompanying review of local pharmacological treatments,1 there are several peripheral causes of aggravated muscle overactivity which require treatment before consideration of pharmacological therapies. Such aggravation may be a consequence of the stimulation of afferents Department of Neurology (Jean-Michel Gracies, MD, PhD, and David Simpson, MD), The Mount Sinai Medical Center, New York, NY. Center for Head Injuries (Elie Elovic, MD), JFK Johnson Rehabilitation Institute, Edison NJ. Rehabilitation Institute of Chicago (John McGuire MD), Chicago, IL. Correspondence to: Jean-Michel Gracies, MD, PhD, Department of Neurology, 1 Gustave L. Levy Place New York, NY 10029

General and regional treatments

other than the stretch receptors, such as flexor reflex afferents.2 This may be due to heterotopic ossification, urinary tract infection, urolithiasis, stool impaction, pressure sore, fracture, dislocation, ingrown toenail, excessively restrictive clothing, or condom drainage appliance.

General Pharmacologic Treatments Medications with a proven efficacy in reducing stretch reflexes are numerous, but none has been established as uniformly useful in reducing the disability due to muscle overactivity in patients with lesions to central motor pathways.3,4,5 In addition, all drugs have potentially serious side effects. These negative features should be carefully weighed when beginning a patient on any drug, so that its continued use is contingent on a clear net beneficial effect. Efficacy, side effects, and dosage of centrally acting drugs are summarized in Tables 1-3. The mechanisms and anatomic sites of action of the available antispastic drugs are not completely understood. It is currently thought that they either alter the function of transmitters or neuromodulators in the cen-

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Table 1.

Efficacy of Antispastic Agents in Specific Patient Populations MS

SCI

Baclofen (oral)

+/-

Tizanidine

Diazepam

+/-

Clorazepate

Dantrolene

Ketazolam

TBI

CP +

Strength unimportant, cognitively fragile

Night administration

Piracetam

Progabide

Clonidine

Cyproheptadine Thymoxamine (IV)

Hand function and ambulation improved

Preparation for PT sessions?

Flexor reflexes reduced

Orphenadrine (IV) Baclofen (intrathecal)

Comments

+ +

Clonazepam

Stroke

Legend: +: The antispastic efficacy and tolerance of the drug in the condition indicated have been established in a double-blind protocol. ++: The antispastic efficacy and tolerance of the drug in the condition indicated have been demonstrated to be greater than one of the standard drugs in double-blind comparative studies (e.g., baclofen ++ versus diazepam + in MS). +/-: The overall improvement was mitigated in the double-blind trials in which the drug was analyzed, usually because of bothersome side effects while the antispastic efficacy was good. +?: Open trials have been promising but the efficacy has not been established in a double-blind protocol. An empty box means that the drug has not been investigated to our knowledge in the condition indicated in the column. * We indicate important features of the drugs that may relate to the patient population in which they seem most appropriate (e.g., dantrolene), or to the most adequate timing of administration (e.g., diazepam, clonazepam), or to a particular feature in their efficacy (e.g., thymoxamine, orphenadrine). MS=multiple sclerosis; SCI=spinal cord injury; TBI=traumatic brain injury; CP=cerebral palsy; PT=physical therapy

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Figure 1. Similarities Among Chemical Structures of GABA Agonists

tral nervous system (CNS) or have an action on peripheral neuromuscular sites. The CNS actions could include suppression of excitation (via glutamate), enhancement of inhibition (via GABA or glycine), or both. Only four pharmaceutical agents are approved by the United States Food and Drug Administration (FDA) for the treatment of spasticity related to a disorder of the central nervous system. These are baclofen (in adults), diazepam, dantrolene sodium, and tizanidine. While available in Europe for several years, the latter has only recently been released in the U.S. market.

General and regional treatments

Agents Acting Through the GABAergic System Gamma-amino butyric acid (GABA) and glycine are the main inhibitory neurotransmitters in the CNS, typically used by small interneurons to mediate presynaptic inhibition in the spinal cord. However, they are also ubiquitous in inhibitory synapses of the brain stem, cerebellum, basal ganglia, and cerebral cortex. Localized spinal ischemia is a typical experimental paradigm that eliminates GABA cells and leaves long tracts intact. The reverse is true for spinal transection, which does not diminish the number of GABA interneurons below the level of transection. When GABA is released by interneurons, it binds to receptors on the post-synaptic membranes.

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Receptors for GABA have been divided into two main types. The more prominent is GABAA, which is a ligand-gated chloride ion channel. Bicuculline and picrotoxine are the most useful GABA antagonists for confirming GABAergic mediation through GABAA receptors. The second receptor, GABAB, is less well characterized. It is a member of the G protein-coupled receptor family, coupled both to biochemical pathways and to regulation of ion channels. It is insensitive to bicuculline. The GABAA receptor has at least three subunits, termed alpha, beta, and gamma, that surround a chloride channel. Once GABA is released from presynaptic neurons, the receptor is activated, opening the chloride ionophore channel and causing membrane hyperpolarization. In the situation of presynaptic inhibition, where an axoaxonal connection exists between a GABAergic interneuron and the terminal of a Ia afferent, hyperpolarization of the Ia membrane decreases its excitability and decreases transmitter release from the Ia afferent to the motor neuron. Hence, presynaptic inhibition of the afferent neuronal terminal reduces motor neuron output without direct motor neuron inhibition. GABA agonists GABA itself does not cross the blood-brain barrier so it cannot be administered orally, but several analogs are available that increase GABA receptor activity within the CNS. Stuctures of GABA and its analogs are shown in Figure 1.

Baclofen (Lioresal®) Pharmacology and precautions Baclofen (4-amino-3 (4-chlorophenyl) butanoic acid) is a structural analog of GABA. There is wide intersubject variation in baclofen absorption and elimination, but on average it is rapidly and extensively absorbed after oral administration. The mean therapeutic half-life of baclofen is approximately 3.5 hours (range 2 to 6 hours). Baclofen is excreted mainly by the kidney in unchanged form, although 15% is metabolized in the liver. Therefore, the dose should be reduced in patients with impaired renal function, and liver function parameters should be monitored periodically during baclofen treatment. Intrathecal administration of baclofen is discussed later in this review. Physiological action Baclofen does not bind to the classical GABAA receptor, but rather to the recently discovered bicuculline-insensitive “B” receptor. GABAB receptors occur both pre- and post-synaptically. Upon binding with the presynaptic terminal of the GABAergic interneuron, membrane hyperpolarization occurs, the influx of calcium into the presynaptic terminal is restricted, and endogenous transmitter release is reduced.3,6 However, post-synaptic binding on the Ia sensory afferent terminal also causes membrane hyperpolarization and increases potassium conductance, so that presynaptic inhibition is enhanced. Baclofen activation of GABAB receptors may also cause inhibition of gamma motor neuron activity and reduced muscle spindle sensitivity.7 The net effect is inhibition of monosynaptic and polysynaptic spinal reflexes.

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Table 2.

Side Effects of Antispastic Agents Decreased Muscle ambulation weakness speed

Sedation

Others

Precautions

Hepatotoxicity

Monitor liver function

Dantrolene

Baclofen (oral)

Difficulty in seizure control

+/-

Dry mouth, liver function

Tizanidine Diazepam

Clorazepate

Cognitive

+/-

Ketazolam

Clonazepam

Piracetam

Nausea

Progabide

Clonidine Cyproheptadine

Thymoxamine (IV)

Hepatotoxicity

Monitor liver function

Depression, hypotension

Blood pressure monitoring

Dry mouth Risk of hypotension

Orphenadrine (IV) Baclofen (intrathecal)

Monitor liver function

Seizure control Pump dysfunction

Legend: +: The side effect has been demonstrated as statistically more frequent with the drug than with placebo in double-blind protocols ++: A major problem +/-: A minor problem 0: The side effect has been looked for but has not been more frequent than with placebo at the doses used in double-blind protocols. An empty box means that the side effect has not been investigated with a double-blind protocol.

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Side effects Baclofen can produce adverse effects related to central depression, including sedation, drowsiness, and fatigue, and patients should be cautioned regarding activities made hazardous by decreased alertness (such as operation of automobiles or other dangerous machinery). Baclofen may interfere with attention and memory in elderly and braininjured patients, and cause confusion, nausea, and dizziness. It may also provoke muscle weakness, an effect that can be more troublesome for the more functional patient than for the severely disabled. For example, baclofen has been reported to deteriorate walking ability in ambulatory multiple sclerosis (MS) patients9 for whom this can lead to drug discontinuation.8 It can also cause hypotonia, ataxia, and paresthesia, and it may potentiate the effects of antihypertensive agents. In some patients, seizure control has been lost during treatment with baclofen, and abrupt discontinuation of baclofen can produce seizures, confusion, hallucinations, and rebound muscle overactivity with fever.10,11 This possibility makes oral administration of the drug hazardous in patients with compromised gastrointestinal function or those whose cognitive status may interfere with regular self-administration. The effects of chronic baclofen treatment during human pregnancy are largely unknown. Finally, oral baclofen is widely prescribed worldwide and there are a few reports of major toxicity. An adult who ingested 2 grams (25 times the maximum recommended daily dose) developed coma with hypoventilation. Low blood pressure, small pupils, absence of tendon reflexes, and unresponsiveness were also noted.12

Clinical efficacy Most studies on baclofen have involved patients with spinal pathology or multiple sclerosis.8,13-30 The majority of MS patients showed a reduction in spasticity and in sudden and painful spasms.28,29 Baclofen was also reported to be particularly effective for the flexor spasms in spinal cord lesions.8,18,19,21,25,26 It has been shown to be safe in long-term use and to remain effective.28 However, some studies failed to find positive effects on clonus25 or deep tendon reflexes.18,25 Most importantly, most studies failed to document positive drug effect on ambulation and activities of daily living (ADL) performances.8,25 In the study by Pedersen et al., ambulation and strength even deteriorated during baclofen treatment.8 There have been very few open studies investigating the effect of baclofen in spasticity of cerebral origin,31-33 and to our knowledge only one double-blind study.7 Compared to those with other etiologies, stroke patients appeared to benefit less from treatment and experience significant side effects.33 Additional effects of baclofen include an anxiolytic effect which may contribute to its antispasticity action, and an improvement of bladder control by decreasing hyperreflexive contraction of the external urethral sphincter, although this has not been consistently reported.9 In conclusion, and as we will see for the other medications reviewed, benefits of baclofen for reduction of positive symptoms such as spasms, clonus, and resistance to stretch are far more clear than on functional skills such as mobility or ADLs.

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Table 3.

Daily Dosages of Antispastic Agents Initial Dantrolene

Maximum

25 mg

Doses per Day 100 mg x 4

3 mg/kg 30 to 60 mg

Baclofen (oral)

5 mg x 3

80 mg

Tizanidine

2 to 4 mg

36 mg

2 to 3

Diazepam

5 mg or 2 mg x 2

60 mg

Clorazepate

5 mg x 4

5 mg x 2

Ketazolam

10 mg x 3

30 to 60 mg

0.5 mg

3 mg

Clonazepam

Maximum in Children

0.8 mg/kg

1 to 3

Piracetam

50 mg/kg

Progabide Clonidine Cyproheptadine

45 mg/kg

0.05 mg x 2

0.1 mg x 4

2 to 4

4 mg

36 mg

Thymoxamine (IV)

0.1 mg/kg

Orphenadrine (IV)

60 mg

Baclofen (intrathecal)

25 Âľg

0.5 mg/kg

500 to 1000 Âľg

The doses indicated are those used in double-blind studies in which the antispastic efficacy has been demonstrated or in the open studies in which it has been strongly suggested (see Table 1).

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Dosage Baclofen may be initiated with 5 mg three times per day and increased gradually, by 5 mg increments every 4 to 7 days, to a therapeutic level. The recommended maximum dose is 80 mg per day in 4 divided doses; however, higher doses, up to 150 mg, have been used successfully.34,35 While baclofen is not approved by the FDA for use in children, physicians have prescribed baclofen with doses initiated at 2.5-5 mg per day, with maximum doses of 30 mg (children 27 years of age) to 60 mg (children 8 years or older).

Benzodiazepines Physiology of action of benzodiazepines The pharmacologic and antispasticity effects of benzodiazepines are mediated by a functionally coupled benzodiazepine-GABAA receptor chloride ionophore complex.36,37,38 They have no direct presynaptic GABAmimetic effect, but exert it indirectly postsynaptically when GABA transmission is functional. The benzodiazepine action results in an increase in presynaptic inhibition and then a reduction of mono- and polysynaptic reflexes.39-42 There exist high and low affinity receptors as well as longand short-acting benzodiazepines. The length of action is related to the rate of metabolism of the parent compound, as well as the production and elimination of pharmacologically active metabolites. Diazepam, chlordiazepoxide, and clonazepam are considered to be long-acting benzodiazepines, whereas oxazepam, alprazolam, and lorazepam are short-acting without significant production of active metabolites.

Diazepam (Valium速) Diazepam is the oldest antispasticity medication still in widespread clinical use. Pharmacology Diazepam is well absorbed after an oral dose, with a peak blood level in 1 hour. It is metabolized in the liver to active compounds: N-desmethyldiazepam (nordazepam) then oxazepam. Diazepam is 98% protein-bound and has a half-life (including active metabolites) of 20 to 80 hours. The extent of protein binding is clinically significant, since low serum albumin, as often occurs in spinal cord injured and stroke patients, may increase susceptibility to side effects. Other benzodiazepines are also metabolized extensively, mostly by the microsomal enzymes of the liver. They cross the placental barrier and they are secreted into breast milk. Physiology Diazepam binds in both the brain stem reticular formation and spinal polysynaptic pathways, but the former seems to be more sensitive to the drug effects,44 leading to the prediction of less drug response in complete spinal cord lesions.5 Adverse effects Three major classes of adverse effects have been described. Effects related to central nervous system depression: Diazepam produces depression of the central nervous system which is synergistic with alcohol. Thus it can suppress behavioral arousal, provoke sedation, reduce motor coordination, and impair intellect, attention, and memory.39-42,45,46 In two studies in hemiplegic patients, one of which involved only a small dose of 6 mg/day, ambulation speed deteriorated slightly but significantly on diazepam.44,45 In the second, placebo-controlled study, grip strength was also shown to be adversely affected by

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diazepam.45 The possibility of deterioration of walking ability has also been reported in MS patients.9 Intoxication: Benzodiazepines have a wide margin of safety but the potential for overdose still exists. The signs of diazepam intoxication are somnolence progressing to coma. One review reported the rate of fatal benzodiazepine poisoning in Britain over a decade as 5.9 per million prescriptions.43 Near-term infants born with benzodiazepine intoxication are particularly at risk. A benzodiazepine antagonist, flumazenil, has been used with some success in such cases.47 Withdrawal syndrome: True physiologic addiction may occur. If diazepam is tapered too rapidly or discontinued abruptly, withdrawal symptoms may appear. The onset of symptoms occurs 2 to 4 days after diazepam is stopped. Symptoms may include anxiety, agitation, restlessness, irritability, tremor, muscle fasciculation and twitching, nausea, hypersensivity to touch, taste, smell, light, and sound, insomnia, nightmares, seizures, hyperpyrexia, psychotic manifestations, and death.48 The intensity of the symptoms is related to the prewithdrawal dose. Symptoms of withdrawal from low-dose diazepam (<40 mg per day) are more likely if the patient has taken the drug consistently for more than 8 months. With short-acting benzodiazepines, onset of symptoms occurs after 1 to 2 days after the drug is withdrawn. Even when benzodiazepines are withdrawn slowly over 4 to 6 weeks, withdrawal symptoms may persist for 6 months.48

General and regional treatments

Clinical efficacy and dosage Diazepam has been used most extensively in patients with muscle overactivity of spinal cord origin, and its antispastic efficacy has been demonstrated in these conditions by double-blind protocols49,50 with a dosedependent antispastic effect.50 It remains controversial whether the antispastic effectiveness of diazepam is greater for complete or incomplete spinal cord lesions.51,52 In children with cerebral palsy, diazepam has also been demonstrated to have clinical efficacy for athetosis as well as against spasticity.53,54 Much of the improvement was attributed to general relaxation. In hemiplegic spasticity, the effects of diazepam appear to be less dramatic, or at least more often overshadowed by adverse effects. Double-blind comparative studies of the efficacy of diazepam and baclofen for spasticity were carried out in MS patients.9,55,56 No significant difference in efficacy for spasticity was found. Tolerance was also equivalent but qualitatively different: Sedation was much more common on diazepam, whereas side effects were equal in number but more varied on baclofen. Nonetheless, patients and physicians preferred baclofen in two studies out of three,9,55 which may reflect the fact that sedation was a more troubling side effect than those experienced on baclofen. Diazepam therapy may be initiated with a bedtime dose of 5 mg, and increased to 10 mg as needed. Daytime therapy can be initiated with 2 mg twice a day. Diazepam may be slowly titrated up to 60 mg or more per day, in divided doses. Pediatric doses range from 0.12 to 0.8 mg/kg per day in divided doses. Because of the central depression, diazepam as antispastic medication is often used at night to suppress spasms that disturb sleep.

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Clorazepate Dipotassium (Tranxene®)

Clonazepam (Klonopin®, Rivotril®)

Clorazepate is a benzodiazepine analogue which is immediately transformed in gastric juice into desmethyldiazepam, a major metabolite of diazepam. The half-life of clorazepate is 1-3 hours, but the half-life for desmethyldiazepam is as long as 106 hours. Desmethyldiazepam probably has greater potency and duration of antispastic effect than diazepam.57 In a promising doubleblind study in multiple sclerosis and stroke patients, clorazepate has been shown to be effective in decreasing phasic stretch reflexes (response to quick stretch).57 Sedation appeared much less prominent than with diazepam. However, as with many other studies, no functional assessment was carried out. The oral dose was 5 mg twice a day, with a loading dose because of the potential delay until steady state. Clorazepate could have therapeutic advantages over diazepam since the plasma concentration of desmethyldiazepam seems steadier, and unlike diazepam it has not been reported to impair learning and memory.58,59 No study on clorazepate in spasticity after 1985 has been identified. Clorazepate is available in 3.75 mg or 7.5 mg capsules.

Clonazepam is a well known medication in North America for the suppression of myoclonic, akinetic, or petit mal seizure activity or for control of dystonia. It is also commonly used in Europe parenterally for treatment of seizures and status epilepticus. Its use in spasticity is less common, primarily for the suppression of nighttime spasms. It has been compared to baclofen in an open trial only, in a population composed mainly of MS patients.62 In this study, the two drugs were reported to be comparable in antispastic efficacy, but sedation, confusion, and fatigue were greater problems with clonazepam and more frequently resulted in drug discontinuation. Clonazepam is well absorbed after an oral dose, with maximum blood concentrations occurring in 1 to 2 hours. It is 98% bioavailable, with less than 1% excreted in the urine and 86% bound in plasma. The half-life of clonazepam is 18-28 hours. It is most commonly prescribed as 0.5 or 1.0 mg at night, but doses can go up to 3 mg per day according to tolerance.62 For patients who find morning sedation excessive, the tablet can be broken in half and 0.25 mg taken at night.

Ketazolam (Loftran®)

Tetrazepam (Myolastan®)

Like its congeners, ketazolam has anxiolytic, sedating, and muscle relaxant properties, and it may have a similar pharmacologic action. In a double-blind crossover study of patients with spasticity due to MS, stroke, or head injury, ketazolam has been reported to be equally effective and slightly less sedating than diazepam.60,61 In that study, stroke patients tolerated higher dose levels better than MS patients. Ketazolam was given as 10 mg three times per day for the first week, and then doubled, but it can actually be administered in a single 30-60 mg per day dose.61 Ketazolam is available in Canada but is not yet approved in the United States.

Tetrazepam is a benzodiazepine derivative which is reported to reduce the tonic muscle overactivity in spastic patients, with little effect on tendon hyperreflexia, and no influence on muscle strength.63

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Conclusion Only diazepam and clonazepam have been compared to baclofen. They appear to be of similar antispastic efficacy in MS patients, but they also appear to be more sedating than baclofen. However, no assessments of meaningful function were included in these studies5 and comparative data on spinal cord injury and spasticity of cerebral origin are lacking. Clorazepate appears promising but needs further investigation.

Piracetam Piracetam is chemically related to GABA and baclofen and effectively crosses the bloodbrain barrier. It is used in Europe (Nootropyl速) but is not approved yet in the United States. In 1978, a double-blind cross-over study investigated its effects in children with cerebral palsy, at the dose of 50 mg/kg/day.64 This well-designed study was one of the very few in this literature to include meaningful functional assessments. Global improvement was statistically greater in the piracetam phase of the trial for resistance to passive motion, hand function, ambulation, and standardized assessment of filmed behavior. In the patients affected, athetoid movements improved dramatically. Side effects were minimal (nausea and transient vomiting in one patient). Surprisingly, this preliminary trial has not been followed by further investigations in other patient groups or by comparative studies with other antispastic agents.

Progabide This GABA agonist is still investigational in the United States. It has specific and potent binding to both GABAA and GABAB receptors. It was studied in MS patients in two double-blind placebo-controlled cross-over designs, at doses from 15 to 30 and from 30 to 45 mg/kg/day.64a-66 In the first study, the authors rated spasticity with the sensitive

General and regional treatments

assessment of the angle of muscle catch, similar to the Tardieu scale.65,67,68 Significant reduction in spasticity scores and in flexor spasms were seen in both studies, but no significant effects were observed in functional measures of ambulation,66 or fine motor function66 or in voluntary power.64-66 Both clinicians and patients subjectively favored progabide. In the second trial, 10 of the 25 patients who completed the study chose to pursue the medication.66 However, the drug had frequent adverse effects and had to be discontinued in one third of the patients because of elevation of liver function tests.66

Drugs Affecting Ion Flux Dantrolene Sodium (Dantrium速) Pharmacology Dantrolene sodium is a hydantoin derivative. The oral formulation is prepared as a hydrated sodium salt to enhance absorption (approximately 70%), which occurs primarily in the small intestine. Dantrolene sodium is lipophilic and crosses cell membranes well, achieving wide distribution and significant placental concentration in the pregnant patient. It is metabolized largely in the liver. After oral administration of the drug, it is eliminated in urine and bile, with urinary elimination of 15% to 25% of the nonmetabolized drug followed by urinary excretion of the metabolites. After a dose of 100 mg, the peak blood concentration of the free acid, dantrolene, occurs in 3 to 6 hours and the active metabolite, 5-hydroxydantrolene, occurs in 4 to 8 hours. The half-life of dantrolene sodium is approximately 15 hours after an oral dose, and 12 hours after an intravenous dose.69,70

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Physiology of action Unique among systemic antispasticity agents, dantrolene sodium acts peripherally at the muscle fiber rather than at the neural level. It reduces muscle action potentialinduced release of calcium from the sarcoplasmic reticulum of skeletal muscle, partially uncoupling motor nerve excitation and skeletal muscle contraction, thereby decreasing the force produced by excitation-contraction coupling.69-72 It reduces the activity of phasic stretch reflexes more than tonic ones, in a dose-dependent manner.70 Dantrolene has its greatest effect on the force of contraction in fast twitch fibers, at lower frequencies of neural stimulation, and at shorter muscle lengths.73 It is assumed that this is because more available calcium can build up at high rates of stimulation or in slow twitch fibers, which may partly neutralize the drug effect.5 Similarly, in voluntary contraction, the patient may sense the decrement in force and compensate through greater recruitment.5 For unknown reasons, dantrolene seems to have little effect on smooth and cardiac muscle tissues. It also affects both extrafusal and intrafusal fibers,5 which leaves open the possibility that part of its antispastic efficacy may be related to alterations in spindle sensitivity. As can be expected from its mechanism of action, dantrolene sodium does not reduce the evoked electromyographic (EMG) activity in response to either tendon tap or nerve stimulation.74 However, it does modestly reduce maximal voluntary power (to 93% of baseline).74,75

Efficacy and indications The majority of placebo-controlled trials of dantrolene have shown a reduction of muscle tone, tendon reflexes, and clonus, and an increase in range of passive motion.72,76 As in studies of local treatments, the proportion of patients who improved in ADL function was usually much smaller than the proportion who had reduced clonus or improved â&#x20AC;&#x153;overall clinical response.â&#x20AC;?77,78 There have been mixed conclusions regarding the effects of dantrolene sodium on motor performance and strength. In one study in stroke patients, loss of strength and difficulty in stair climbing were more prominent during dantrolene treatment.79 Excessive muscular contraction is the final pathway in motoneuronal hyperexcitability of all causes, and consequently dantrolene is potentially of use in all types of lesions of the CNS. However, as an antispasticity medication dantrolene sodium is more commonly recommended in spasticity of cerebral origin, although this favored indication remains controversial. Some authors have indeed suggested that the best responders to dantrolene sodium are stroke patients,76,79 whereas others suggest that spinal cord injured patients improve most.80 Benefit from dantrolene treatment in multiple sclerosis patients has been less clear.81,82 In children with cerebral palsy, dantrolene sodium was superior to placebo in four trials.83 The degree of improvement appeared greater in children than in adults. Dantrolene sodium and diazepam have been compared in MS in a double-blind crossover design,84 in children with cerebral palsy85 and in a mixed population including cerebral and spinal causes of spasticity.86 Control of clinically assessed spasticity was slightly better for dantrolene, as was the profile of side effects. Patients on dantrolene experienced more weakness, while patients on diazepam had more drowsiness and ataxia. Patients tended to favor dantrolene overall in two studies out of three.83,84 The com-

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bination of both drugs was preferable to each drug separately in the two studies that made this comparison.85,86 One study found dantrolene sodium to be superior to baclofen. In addition to its antispasticity effects, dantrolene sodium has been reported to be useful in the treatment of hyperthermia following abrupt baclofen withdrawal,87,11 and it has been used in the treatment of malignant hyperthermia and the neuroleptic malignant syndrome.69 In conclusion, dantrolene is generally preferred in muscle overactivity subsequent to supraspinal injury such as hemiplegia or cerebral palsy. For some authors, it is also useful after spinal cord injury, although many use it secondarily to baclofen or diazepam. Its most pronounced effect is probably the reduction in clonus and muscle spasms resulting from innocuous stimuli. Because weakness may be a problematic adverse effect of treatment, dantrolene sodium is likely to be of most use in patients with good strength, limited by their spasticity, or conversely in those with complete paralysis in whom additional weakness is not of concern.5 In addition, it may be a better drug than compounds primarily active in the CNS (baclofen and especially benzodiazepines) for patients with coordination problems or marginal cognitive status.5 However, dantrolene is not free of central impact (see below), and more comparative research on dantrolene and baclofen is needed.

side effect is hepatotoxicity. At least 13 reports appeared in the literature, five of which report hepatonecrosis. In a large group of patients receiving dantrolene sodium for more than 2 months, the overall incidence of hepatotoxicity was 1.8%, symptomatic hepatitis occurred in 0.6% and fatal hepatitis in 0.3%, with the greatest risk in females, older than 30 years of age, taking more than 300 mg per day for more than 60 days, and in patients taking other medications simultaneously, especially those metabolized in the liver.69 Therefore, liver function tests should be performed before beginning a regimen of dantrolene sodium and monitored periodically, and the drug should be tapered or discontinued if enzyme elevations are noted since most cases are reversible on prompt discontinuation.88

Dosage Dantrolene dosage is initiated at 25 mg per day and may be slowly increased up to 100 mg 4 times per day (for example by 25 mg increments every 4 to 7 days). Higher doses are occasionally effective and can be tried when monitoring for hepatotoxicity and other side effects. However, clinical results are not clearly related to dose and may plateau at a dose of 100 mg/day. In addition, the manufacturerâ&#x20AC;&#x2122;s recommended dose is not to exceed 400 mg per day, to limit the risk of hepatotoxicity and weakness. The dose at which the anticipated therapeutic response occurs with the fewest adverse effects should be the maintenance dose. Side effects Pediatric doses begin with 0.5 mg/kg twice Dantrolene is mildly sedating and may cause daily, increasing the frequency and dosage malaise, nausea and vomiting, dizziness, until maximum effect is reached. The maxidiarrhea, and paresthesia.5 However, in mum dose is generally 3 mg/kg q.i.d. or less comparison to baclofen or diazepam, it is than 100 mg q.i.d. less likely to cause lethargy or cognitive disturbances. Although dantrolene can weaken muscles (including respiratory muscles), the effects on spasticity are not generally accompanied by significant impairment of motor performance, except in patients with marginal strength. The most important

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Lamotrigine (Lamictal速) The mechanisms of the effects of lamotrigine on muscle overactivity are still unclear. Lamotrigine is a phenyltriazine and it is thought to act at voltage-sensitive sodium channels to stabilize neuronal membranes. In particular, lamotrigine inhibits the release of excitatory amino acid transmitters from excitatory neurons. It has anticonvulsant and analgesic properties in animal models of acute and chronic pain.89 Recently, clinical trials with lamotrigine have shown promise in the treatment of muscle overactivity and chronic central pain.90

Riluzole (Rilutek速) Riluzole blocks the action of voltage-sensitive sodium channels, thereby preventing release of excitatory amino acids (in particular, glutamate). It is an approved treatment for amyotrophic lateral sclerosis,91 and is associated with a reduction in stiffness in this disease.

Drugs Acting on Monoamines Tizanidine and clonidine are imidazoles that affect alpha-2 noradrenaline receptors. Their antispasticity properties may be due to restoration or enhancement of noradrenergic presynaptic inhibition in spastic patients.92,93 Descending alpha-adrenergic fibers may also play a role in the regulation of fusimotor drive.94

Tizanidine (Zanaflex速, Sirdalud速) Pharmacology Tizanidine is well absorbed after an oral dose with extensive first pass hepatic metabolism by liver microsomal enzymes to inactive compounds that are subsequently eliminated in the urine. Its peak effect occurs 1 to 2 hours following administration and its half-life is 2.5 hours. Physiology of action Tizanidine is an imidazoline derivative which has an agonistic action at central alpha-2 adrenergic receptor sites both spinally and supraspinally. It also binds to imidazoline receptors sites.95,96 It prevents the release of excitatory amino acids (i.e., glutamate and aspartate) from the presynaptic terminal of spinal interneurons and it may facilitate the action of glycine, an inhibitory neurotransmitter. These mechanisms may result in inhibition of facilitatory coeruleospinal pathways. Tizanidine reduces tonic stretch reflexes and polysynaptic reflex activity in the spinal transected cat, possibly presynaptically.97,98 These findings have been bolstered by the observation that tizanidine has an antinociceptive effect in animal models.99-101 Finally, tizanidine enhances vibratory inhibition of H reflex in humans and reduces abnormal co-contraction, effects which have been correlated with clinical improvements of spasticity in patients.102 Side effects and precautions As with other antispasticity medications, side effects are dose-related and may be minimized by dose titration. The most common side effects of tizanidine reported during controlled clinical trials are dry mouth and sedation, with possibility of drowsiness, tiredness, and dizziness.103 Unlike clonidine, tizanidine has not been found to induce a consistent change in blood pressure.104-106 However, the risk of symptomatic hypotension exists with tizanidine, and concomitant

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administration of tizanidine and antihypertensive drugs (especially clonidine) should be avoided. In cases where spasticity is satisfactorily treated by a dose which provokes symptomatic orthostatic hypotension, it is possible to use fludrocortisone acetate, a mineralocorticoid that enhances the reabsorption of sodium ions from tubular fluid into the plasma. Other side effects include visual hallucinations (3% of subjects) and elevated liver function tests (5% of subjects) both responding to dose reduction.104-106 Nighttime insomnia, which can be partly responsible for daytime somnolence, was reported more frequently by patients receiving tizanidine than by those receiving baclofen in a comparative study in MS patients.107 Conversely, weakness was also reported but less often than on baclofen.107 Since tizanidine has first pass hepatic metabolism, it should be used with caution in patients with known liver abnormality. Measurement of SGOT/AST and SGPT/ALT is recommended at baseline and at months 1, 3, and 6 of tizanidine treatment. Recently a modified release form of tizanidine has been formulated which allows for once or twice daily dosing.108 Clinical efficacy and dosage Placebo-controlled studies have established the antispasticity action of tizanidine in multiple sclerosis and spinal cord injury,103,104,109,110 but no definite functional changes were seen.103 Several trials have shown that tizanidine (6 to 36 mg/day) is safe and similar in efficacy to baclofen (15 to 90 mg/day) in patients with MS or forms of spinal cord pathology.92,98,107,111-117 Particularly, no differences were found in functional measures.107,118 Tizanidine has also been compared to diazepam in controlled trials in patients with spastic hemiplegia caused by stroke and head trauma.105 Tizanidine had a significantly better result regarding walking distance on flat ground, and was preferred overall by the investigators. Tizanidine also had a favorable tolerability profile, although sedation was a

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prominent side effect in both groups.105 Thus tizanidine emerges as a potentially useful option in spasticity of spinal and cerebral origin in those patients in whom the potential for sedation is less a concern than weakness.5 Tizanidine therapy may be initiated with a single dose of 2 to 4 mg at bedtime (4 mg tablets) and should be titrated upward very gradually, particularly for multiple sclerosis patients. Dose increases of 2 to 4 mg every 2 to 4 days are conventional, until a maintenance dose meeting the therapeutic goals with the least side effects. The maximum recommended dose is 36 mg per day.

Clonidine (Catapres速, Dixirit速, Catapressan速) Pharmacology Clonidine is 95% bioavailable after an oral dose, with peak plasma level at approximately 3 to 5 hours. About half the absorbed dose is metabolized in the liver and the other half is excreted in the urine as unchanged drug. The half-life is 5-19 hours except in patients with impaired renal function in whom it can increase up to 40 hours. Physiology of action Clonidine probably acts at multiple levels in the CNS, including as an alpha-2 agonist in the brain, the brain stem, and the substantia gelatinosa of the dorsal horns in the spinal cord.5 It is thought that clonidine lowers blood pressure and heart rate via an alpha-2 mediated inhibition of locus coeruleus neurons. It thereby reduces their discharge rate, which decreases tonic facilitation upon sympathetic preganglionic fibers.119,120 Clonidine also has a spinal site of action that is alpha-2 selective. Autoradiographic binding of H3clonidine occurs in the dorsal horns of the spinal cord and can be blocked by yohimbine.121 In the spinalized cat, clonidine markedly inhibits the short latency response of alpha-motoneurons to group II muscle

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afferent stimulation.122 The mechanism times per day dose regimen. The patch of could be an augmentation of presynaptic Catapres® has two dose formulations, 0.1 inhibition. Indeed, the antispasticity effect of mg or 0.2 mg, and is designed to deliver the clonidine treatment in humans with spinal indicated amount of clonidine daily for cord injury has been consistent with seven days. enhancement of alpha-2 mediated presynaptic inhibition of sensory afferents.93,123,124 Other Adrenergic Blocking Adverse effects and precautions Bradycardia, hypotension, and depression are important side effects of clonidine. In one open trial, these adverse effects led to discontinuation of the drug in two of the four patients included.124 Blood pressure and pulse rate should be monitored periodically during treatment. Other frequent side effects include dry mouth, drowsiness, dizziness, constipation, and ankle edema. Efficacy and Dosage Clinical experience with clonidine as an antispastic treatment is limited, and to our knowledge no double-blind study has been published. Open-label case reports found clonidine effective in reducing spasms and resistance to stretch in four patients with spinal cord pathology, when given doses of 0.2 mg/day.124 In another open trial, clonidine was added to the existing baclofen regimen in 55 patients with spinal cord injury.123 Only 31 responded to the drug, and most of the nonresponders withdrew because of adverse effects. No patient was able to substitute clonidine for baclofen, but baclofen doses could be reduced in many responders. In addition to the oral form, a transdermal patch has also been reported to have efficacy in the treatment of spasticity.125,126 Since some patients may be very sensitive to the effects of clonidine, the initial dose should be low. In the United States, the smallest tablet of Catapres® contains 0.1 mg, but the other oral formulation available in Canada (Dixirit®) allows a more gradual start. Dixirit® can be initiated at 25 µg orally twice a day and then increased every three days by 25 µg per day as a three or four

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Agents: Thymoxamine and Beta Blockers

Thymoxamine is also an alpha-adrenergic blocking drug that has been studied as an antispasticity medication, both intravenously (single dose of 0.1 mg/kg)94,127 and orally in doses up to 80 mg six times daily.128 In adouble-blind protocol vs. placebo and diazepam in SCI and MS patients, only intravenous administration was reported able to reduce resistance to passive movement, ankle jerk amplitude,94 and stretchelicited EMG activity.127 The reduction of stretch-evoked EMG tended to be greater than with diazepam. However, flexor spasms may increase with this drug.94,127 No functional assessment was included in this study. It was assumed that the discrepancy between the results after oral and intravenous administration was due to reduced bioavailability by the oral route. Beta-adrenergic blocking agents may also have some influence on the stretch reflex. Propanolol given intravenously appeared to reduce clonus in 13 of 16 patients studied.94

Cyproheptadine (Periactin®) Cyproheptadine is a histamine and a serotonin antagonist with anticholinergic and sedative effects. It may have a direct inhibitory effect on the motor neurons by neutralizing the spinal and supraspinal serotoninergic excitatory inputs.129 In open trials in patients with spasticity due to spinal cord injury or multiple sclerosis, cyproheptadine decreased clonus129 and voluntary EMG,129 and increased walking speed in patients whose gait was limited by clonus,130 but it did not reduce the amount of EMG of

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co-activated antagonists during maximal voluntary movements.129 In a comparative clinical trial, cyproheptadine had similar antispasticity efficacy to clonidine and baclofen in spinal cord injured patients.131 The drug was well tolerated at the doses used. In principle, adverse reactions can be related to CNS depression and anticholinergic properties and may include sedation and dry mouth. Cyproheptadine may be initiated as 4 mg (1 tablet) at bed time, increasing by a 4 mg dose every 3 to 4 days. The most commonly effective and tolerable dose is 16 mg in divided doses. The maximum recommended dose is 36 mg per day.

Drugs Acting on Excitatory Amino Acids Orphenadrine Citrate (Norflex®) Orphenadrine citrate is a compound related to orphenadrine hydrochloride (Disipal®), an anticholinergic drug. Patch clamp and binding studies have revealed that orphenadrine is an uncompetitive Nmethyl-D-aspartate (NMDA) type glutamate antagonist. In a double-blind placebo-controlled study in spinal cord injured patients, single intravenous injections of 60 mg orphenadrine citrate showed some efficacy as a fast-acting antispasticity treatment, with onset of effects within 30 minutes.132 It also increased the threshold of the flexion reflex in the lower limbs.132 No side effects were noted in this trial. Such treatment may be of use in rehabilitation work to prepare spastic patients for a subsequent physical therapy session with joint ranging and stretching, provided that the session is performed within the hour after the injection.

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Cannabinoids Cannabis (Cesamet®, Marinol®) The main active alkaloid of the cannabis sativa plant is delta-9-tetrahydrocannabinol (THC), available as a prescription pharmaceutical, dronabinol (Marinol®), or as the synthetic cannabinoid, nabilone (Cesamet®). The antispasmodic action of cannabis was recognized by Western doctors more than a century ago.133,134 In the modern era, there have been anecdotal reports of the relaxing effect that recreational smoking of marijuana has on muscles, in patients with spasticity due to multiple sclerosis, spinal cord injury, or stroke.135,136 Some literature supports the hypothesis that this is due to a specific antispastic effect rather than a general relaxation response.136,137 In a double-blind trial of oral THC in 9 MS patients, in doses of 5 and 10 mg, the 10-mg dose proved superior to the 5-mg dose, and both were superior to placebo in reduction of EMG response to stretch (interference pattern by visual inspection) and subjective gradings of spasticity.136 While antispastic effects peaked at 3 hours after ingestion, the usual delay for psychological effects, the number of patients who reported “feeling high” was equivalent on THC and placebo (one in each group). Unfortunately, functional effects were not assessed. Dronabinol is 4% to 12% available after an oral dose; less than 1% is excreted via the urine and 95% of the drug is bound to plasma proteins. The half-life is 20 to 44 hours. It is formulated as 2.5 mg, 5 mg, or 10 mg capsules. Nabilone is formulated as a pulvule containing 1 mg, with a recommended dose of 1-2 mg twice a day. The systemic effects, tolerance, and addictive properties of these compounds have not been evaluated in spastic patients, but the potential for these long-term effects mandates caution in their use. However, THC derivatives with fewer psychotropic and addictive properties may prove beneficial in the future.

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Inhibitory Neuromediators: Glycine and Precursors As mentioned above, glycine is a prominent inhibitory neurotransmitter of the CNS, particularly in the brain stem and spinal cord. The glycine receptor shares many features with the GABAA receptor. We have identified no double-blind study of the effect of glycine or its precursors in spasticity. In seven case reports of patients treated with oral glycine 3 to 4 g/day (with 1 to 2 g/day of sodium bicarbonate), the authors described a subjective improvement in “spasticity, tonus and paresis.”138 Threonine is a precursor of glycine. An open study of threonine supplementation (500 mg/day) over a 12-month period in patients with genetic spasticity syndromes reported decreased spasticity, with some regression 4 months after cessation of treatment.139 Controlled trials on supplementation of glycine and precursors in spasticity are needed.

Miscellaneous Drugs The drugs reviewed below have been tested for their effects in spasticity but have proven either relatively ineffective at the trial doses or to have unacceptable adverse effects. We mention them here for the research potential some of their derivates may hold, especially if chemical modifications allow the development of forms that produce fewer side effects. Cyclobenzaprine (Flexeril®) This medication is sometimes prescribed in general practice for “muscle spasm.” A double-blind cross-over study of its antispastic efficacy at the dose of 60 mg/day was carried out in patients with spinal and cerebral spasticity.140 At that dose, the drug did not prove superior to placebo; however, doses up to 150 mg/day decreased spasticity with a dose-response relationship in one SCI patient. No further trials of this compound were identified.

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Phenytoin (diphenylhydantoin, Dilantin®, Diphenylan®, Dihydan®) Before the emergence of the benzodiazepines, phenytoin was more commonly used as an antispastic treatment, along with the phenothiazines (see below). It has an inhibitory effect on repetitive firing of action potentials.140a This inhibition is mediated by a slowing of the rate of recovery of voltageactivated sodium channels from inactivation. These effects are selective on sodium channels when phenytoin is used at therapeutic ranges (10-20 µg/mL).140a The antispastic efficacy of phenytoin was evaluated in a controlled trial in patients with a variety of diagnoses.141 Six of 10 patients had tone reduction from phenytoin at serum levels greater than 7 µg/mL, but with no doseresponse relationship beyond this threshold.The bothersome side effects of this drug are well known and it is unclear whether there is a patient population (apart from those already treated by phenytoin for associated epilepsy) that may benefit more from phenytoin than from more modern antispastic agents with less serious side effects.5 Phenothiazines The antispastic effect of chlorpromazine and some of its derivates has been clearly established in controlled studies141-144 and may be related to alpha-adrenergic blockade (see above). Sedation was consistently a significant problem. In addition, the frequency and severity of the long-term adverse effects (tardive dyskinesia, parkinsonian syndrome) of classical phenothiazine derivatives have not been evaluated in patients with damage to central motor pathways and should prohibit their use in spasticity before more information is available. They may, however, be useful in spastic patients with psychiatric disturbances for whom treatment with phenothiazines is indicated.

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Intrathecal Administration of Antispastic Drugs When patients with spasticity fail to obtain relief from oral medications, two of the classes described above are also used in intrathecal administration. This is especially true in nonambulatory patients when most of the disabling muscle overactivity occurs in the lower limbs, as for instance flexor spasms due to spinal cord dysfunction.145-147 Intrathecal administration has been used more recently in cerebral palsy and brain injured patients.148,149 A pump can be implanted subcutaneously in the abdominal wall, with a catheter surgically placed into the subarachnoid space. By delivering the drug directly to the spinal cord, the desired site of action, higher concentrations can be placed near the target with lower doses than the oral route. Hence, central nervous system side effects associated with increased oral intake are partially avoided. The pump may be refilled as needed (usually on a monthly basis) by transcutaneous injection. The drug dose is adjusted to provide maximal spasm relief while minimizing weakness. The development of reliable implantable delivery systems has permitted chronic slow infusion of drugs into the intrathecal space. There are two types of pumps available. With the mechanical gas-powered bellows type, drug can be infused only at a constant rate, and thus dose titration occurs primarily at the time of refill. In addition, the administration rate may be sensitive to temperature and pressure changes. The most satisfactory pumps are electronic. In contrast to the gas-powered model, they may be programmed to change rates several times daily via a built-in computer, allowing precise and flexible titration of the drug. For example, tone can be reduced to relieve spasms at night, but the dose can be tapered 1 hour before meals to improve sitting position or transfers. The built-in computer can

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be adjusted by an external laptop computer equipped with a programming wand. Battery life is presently about 4 to 5 years. In the future, patients with a pump in place may be able to switch medications should the original fail to provide relief. Preimplantation evaluation The patient should be free from active infection and pressure sores. The skin over the back should be intact and there should be an anterior abdominal wall suitable for pump placement. The sites of abdominal procedures such as colostomies, ileal conduits, or feeding tubes must be distant from the pump site. In patients who have a potential block of cerebrospinal fluid flow, myelography may be required to ensure that there is a communication between the proposed site of infusion and the level of the suspected source of muscle overactivity. Since some patients may not respond,145 a short trial is suggested with the proposed intrathecal drug via percutaneous lumbar catheter preferably in combination with an external continuous infusion pump, in order to know whether intrathecal administration of the drug will be effective and if so at what dose. Complications Complications may include infection, pump dysfunction (dislodgement, disconnection, kinking, or blockage), pump failure, and consequently drug overdose or withdrawl symptoms. It is possible that some of the surgical complications might be minimized by epidural rather than intrathecal administration,150 but studies comparing these two approaches are needed.5 The main limits of this potentially effective therapy are its invasiveness and cost (approximately $6500 for the pump alone, plus the cost of the drug and implantation surgery).

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Baclofen (Lioresal®) Efficacy The US Food and Drug Administration has approved intrathecal administration of baclofen via pump for spasticity. Although few controlled studies have been done, several have reported efficacy of intrathecal baclofen for the treatment of spasticity related to CNS damage.145-156 The initial open trials were carried out in patients with severe spasticity who either had not benefitted from oral baclofen or did not tolerate its adverse effects. A small number of patients with MS, transverse myelitis, traumatic cord injury, and cerebral anoxia all showed dramatic reductions of spasticity,151 and subsequent double-blind placebo-controlled crossover studies with SCI and MS patients confirmed these results.145,146 Patients whose sleep was disrupted by spasms were also studied in a sleep laboratory and showed reduced nighttime arousals on baclofen.5,145 Intrathecal baclofen may also have beneficial effects on bladder management. However, other functional data were not reported. Dosage and risks The intrathecal dose is approximately 1% of the oral dose.151 Baclofen is initially infused continuously at 25 µg per day. The dose is titrated up to an average of 400-500 µg per day or until satisfactory reduction in spasticity has been achieved. Some authors report experience with doses as high as 1500 µg per day.153 While the dose may escalate early in the course of intrathecal baclofen, it generally reaches a plateau 6 months following implantation. Baclofen pumps can be refilled up to 3 months apart. The most common side effects of intrathecal baclofen include drowsiness, dizziness, nausea, hypotension, headache, and weakness, similar to those seen in oral administration. Reversible coma due to baclofen toxicity has been reported157 which mandates caution to avoid inadvertent overdose. However, patients suffering from respiratory depres-

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sion due to accidental intrathecal bolus injection were reversed with physostigmine 2 mg administered intravenously. Withdrawal syndrome is a possibility with intrathecal as with oral baclofen, and requires the same management. The half-life of intrathecal baclofen is approximately 5 hours.

Morphine (InfumorphTM) A single 1-2 mg intrathecal or epidural dose of morphine may cause a marked reduction in spasticity and pain in patients with spinal cord pathology.158,159 Pump implantation can follow the evaluation, with an ultimate daily morphine dose of 2 to 4 mg.159 Patients with spasticity alone (with no pain associated) were not reported to develop tolerance and no bladder atony was produced.159 However, tolerance, pruritis, nausea, hypotension, urinary retention, and respiratory depression can still occur with an intrathecal morphine bolus dose of as little as 0.4 mg.160,161 Patient populations in which intrathecal morphine would have advantages over intrathecal baclofen remain to be determined.

Midazolam (Versed®) Intrathecal midazolam has been reported to be effective but is limited by sedation.162

Conclusion Spasticity (exaggeration of stretch reflexes) is one component of the muscle overactivity that disables patients with lesions to central motor pathways. This symptom usually appears in the context of inappropriate cocontractions, permanent tonic muscle activity in the absence of any stretch or volitional command (spastic dystonia), and other disabling factors such as weakness and muscle shortening. Most treatments reducing spasticity also reduce global muscle overactivity including unwanted co-contractions. The degree to which muscle overactivity contributes to functional impairment and dis-

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comfort must be carefully assessed before considering a pharmacologic treatment reducing motoneuron, reflex, or muscle excitability. Once this assessment is made, the goal of antispasticity treatment must be specified: It may be an increase in active function, by enabling new activities or improving their speed, or may relate to improvement of hygiene and comfort. According to the goal sought, different treatment modalities may be offered, including physical therapies, local or general pharmacologic treatments, or surgery. General pharmacologic treatment may be indicated when the distribution of overactivity is diffuse. Common side effects of each drug must be an important criteria of selection. For example, excess weakness or sedation is not tolerable if there is a hope for improvement in active function. It is also essential to formulate the goals of antispasticity treatment in advance in order to help the patient, family, and health care team to understand what benefits may be realistically expected from treatment. Basic principles in the management of muscle overactivity in spastic patients include the avoidance of noxious stimuli and provision of sustained muscle stretch in overactive muscle groups. Training of antagonists may soon also be demonstrated as an essential step in this care. Pharmacological therapy of muscle overactivity can then be implemented, only as an adjunct to these basic measures.

of the drug near the site of action, which limits side effects but has the disadvantages of an invasive procedure with a foreign body in place. More functionally oriented research on comparative drug selection in homogeneous patient populations is needed in order to make the best match between drug and patient and to rigorously determine whether functional benefits of can be expected. When a pharmacologic treatment of muscle overactivity is elected, two points remain critical: - Spasticity rating scales, which are currently suboptimal, help in following the efficacy of these treatments but may be meaningless without primary functional assessment. - Treatment of muscle overactivity must be placed in the context of global functional care of a patient with damage to the central motor pathways. The comprehensive analysis of each case should enable the clinician to identify where treatment of muscle overactivity itself is only one of the relevant strategies, and where as much effort should be directed toward motor learning with task-specific training, or learning of compensatory strategies.

Baclofen, dantrolene sodium, diazepam, tizanidine, and ketazolam remain commonly used oral systemic agents in the treatment of muscle overactivity, but there are several additional drugs that may be promising. All are nonselective and therefore may cause general adverse effects, including sedation, weakness, and changes in mood and cognition. Intrathecal administration of antispastic medications can be considered especially in nonambulatory patients. This type of administration allows high concentrations

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20. Castaigne P, Held JP, Laplane D, PierrotDeseilligny E, Bussel B, Macquart-Moulin J: Étude de l’effet du Liorésal dans la spasticité. Revue Neurol (Paris) 1973; 128(4):245-250.

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21. Ashby P, White D: “Presynaptic” inhibition in spasticity and the effect on ß-(4-chlorophenyl) GABA. J Neurol Sci 1973; 20:329-338.

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