Chapter 30 Spasticity Management

Patricia W. Nance, Lalith Satkunam, Karen Ethans

Spasticity is a common sequela to an insult to the upper motor neuron (UMN) in the central nervous system.

The definition of spasticity is most commonly cited as follows ¹³⁵:

Spasticity is a motor disorder that is characterized by a velocity dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex, as one component of the upper motor neuron syndrome.

American Academy of Neurology (1990)²

The specific behavioral features of the UMN syndrome can vary depending on the underlying cause, for example spinal cord injury (SCI) versus cerebral vascular damage. Spinal interneurons, sensory afferents, and modulatory and motor efferent pathways normally interact to control, coordinate, and modulate spinal motor neuronal activation. The medical literature supports the notion that insufficient descending inhibition results in structural and physiologic reorganization of segmental circuits following injury or dysfunction within the UMN pathways, such as alterations of intrinsic and extrinsic properties of motor neurons and interneurons.

From a clinical standpoint, it is important to distinguish between the positive symptoms related to the UMN syndrome (e.g., spastic dystonia, flexor spasms, exaggerated cutaneous reflexes, and autonomic hyperreflexia) and the negative symptoms (e.g., paresis, loss of fine dexterity, and fatigability).²⁴⁵ This difference relates directly to the expectations of outcome following treatment for a positive symptom of spasticity, without necessarily worsening the negative symptom of weakness.²⁴⁶

The successful management of spasticity can be a therapeutic challenge. When severe, spastic muscular movements can be violent and uncontrolled, resulting in severe complications such as chronic pain, contractures, long bone fracture, joint dislocations, and chronic skin ulceration. Undesirable complications such as these can be anticipated, prevented, and treated with appropriate management. The effects of spasticity, however, might not always be negative. For example, spasticity can assist weakened legs, allowing the person to stand or transfer and have improved bed mobility.

This review focuses on a rehabilitative approach to spasticity treatment. One must first establish whether there is a functional problem caused by the spasticity and what are the related goals of treatment. All spasticity-aggravating factors must be treated, and the medical therapy must be matched to the specific needs of the patient. Finally, one must reevaluate the patient to ensure that the goal of therapy has been met.

Causes of Spasticity

Like the UMN syndrome, spasticity can accompany diffuse or localized cerebral or spinal pathology. Anoxic, toxic, or metabolic encephalopathies can cause diffuse cerebral abnormalities,² whereas localized cerebral injury can occur with tumor, abscess, cyst, vascular malformations, infarction, hemorrhage, or trauma. Trauma, inflammation, demyelinating disease, and degenerative and familial disorders, as well as compression by a mass (e.g., neoplasm, infection, or cyst) are examples of spinal cord disorders. An example of a combination of UMN and lower motor neuron pathology is amyotrophic lateral sclerosis, where spasticity can be the dominant feature in some patients. Spasticity is often cited as a significant problem in multiple sclerosis (see Chapter 52), traumatic brain injury (see Chapter 49), cerebral palsy (see Chapter 53), SCI (see Chapter 55), and stroke (see Chapter 50). Problematic spasticity occurs in 40% to 60% of patients with SCI and multiple sclerosis, which results in a significant impact on activities of daily living and patient independence. Almost two thirds of patients with cerebral palsy present with “spastic diplegia.”^∗

Changes in the characteristics of a person’s regular spasticity can help to alert those affected and caregivers of problems in parts of the body where the patient no longer has voluntary movement or sensory appreciation; for example, an increase in spasm frequency in a person with complete tetraplegia who has developed an otherwise asymptomatic urinary tract infection. In neurolathyrism, a rare disorder, spasticity can be the main presenting symptom.¹⁶⁶ Physiatrists are often asked to evaluate the patient who presents with the sudden worsening of spasticity, possibly a result of the onset of a new pathologic process, such as a urinary tract infection, urolithiasis, stool implication, pressure sore, fracture, dislocation, ingrown toe nail, excessively restrictive clothing, irritating condom drainage appliance, or even thyrotoxicosis.²⁰⁸ If there is a remediable cause of spasticity, it must be discovered and treated. If problematic spasticity persists in the absence of a remediable cause, then it is appropriate to pursue treatment until a therapeutic response is obtained. Inevitable complications are the natural history of suboptimal treatment of severe spasticity. These complications include skin breakdown, infection, bone fracture or dislocation, and more frequent inpatient hospitalization.^17,¹⁸⁰

Evaluation and Measurement

Of the many clinical monitoring tools described in the literature to assess the severity of spasticity, most researchers agree that assessment tools should be tailored to meet the individual characteristics of a given patient. A number of spasticity-measuring tools are used, which range from simple questionnaires and goniometry evaluations to more technologically complicated electromyographic and biomechanical analysis of limb resistance to mechanical displacement, and even video monitoring assessments of joint mobility.^32,^43,^98,¹⁸⁶

The Ashworth Scale,^10,^73,¹³⁹ Oswestry Scale of Grading,⁹¹ and Degree of Adductor Muscle Tone²²⁴ are some of the tone intensity scales used to assess spasticity in SCI. As proposed originally, the Ashworth Scale is a simple five-point Likert scale in which the observer’s subjective opinion of the subject’s resting muscle tone ranges from “normal” at the lowest grade to “rigid” at the highest¹⁰ (Table 30-1). The original scale was modified by adjusting the lowest number from 0 to 1 and the highest scale from 4 to 5. Another modification from the original scoring scheme was the addition of a point between 1 and 2, where 1 was a “catch” at the end of joint motion range and 1+ was a catch earlier in the joint motion range nearer to midpoint.²⁴ The Ashworth Scale has the advantage of ease of use in the clinical setting. This asset has been used in a number of pharmaceutical trials of antispasticity medications in which a simple measurement tool can be used easily by the participating clinicians to assess the efficacy of the intervention. A recent comprehensive review of engineering and medical literature concluded that the Ashworth Scale is in common use and has significant interrater agreement and good reliability, but it is not a functional outcome measure and can be biased by evaluator subjectivity.⁷³ A monitoring test should be able not only to assess the change in spasticity during therapy but also to assess the functional effects of interventions. Such a test should have a well-defined scoring system, be reliable and sensitive to change, and have standard instructions.¹⁸⁶

Table 30-1 The Ashworth Scale

Score	Definition
0	No increase in muscle tone
1	Slight increase in muscle tone, manifested by a catch and release
2	More marked increase in muscle tone through most of the range of motion, but affected limb is easily moved
3	Considerable increase in muscle tone—passive movement difficult
4	Limb rigid in flexion or extension

Another method of observing the spasticity phenomenon is to assess the number of episodic spasms as reported by the patient. The Penn Spasm Frequency Score ¹⁹⁵ is an ordinal ranking of the frequency of leg spasms per day and per hour. One problem with this scale is that patients usually report that the number of spasms occurring per hour is often affected by their activity at the time. For example, they tend to report few spasms if resting comfortably or more if physically active. The duration of each spasm is also not considered.

The casual observation of the free swing of the knee in the “pendulum test” was formalized and provided objective data by the use of videomotion analysis. The advantages of videomotion analysis of the pendulum test include the ability to do the analysis anywhere a video recorder is available, freedom from the attachment of cumbersome recording devices to the patient, and processing by a nonbiased “blinded” observer who has had no contact with the patient.^105,¹⁷⁹

Pain can be assessed, whether or not it is associated with spasticity, by a self-administered test such as the Pain Intensity Descriptor Scale ⁹⁵ or by using a 10-cm visual analog scale.^40,¹¹⁷ It is important to decipher whether the pain is from the spasticity itself or caused by other factors such as with neuropathic pain in SCI or multiple sclerosis, thalamic pain syndromes, or frozen shoulder in stroke. Standardized assessments of functional ability or caregiver burden might or might not be sensitive to changes in relative levels of spasticity. These include the Sickness Impact Profile,²² the 36-Item Short-Form Health Survey,⁶ the functional independence measure (FIM),⁵ and the Caregiver Dependency Scale.⁴ The Canadian Occupational Performance Measure (COPM)²⁰⁰ and the Goal Attainment Scale (GAS) have been shown to be sensitive to detect changes following intervention in cerebral palsy.⁴⁹ The GAS has been shown to have potential of detecting functional changes.⁹ A multicenter trial of intrathecal baclofen with 138 patients reported improvement in both the performance and satisfaction scores on the COPM.¹⁰¹

Physiologic Mechanisms

No single pathophysiologic mechanism accounts for all the observable aspects of spasticity. Dysfunction within the central nervous system of descending pathways to and within the spinal cord causes a UMN syndrome that is often associated with exaggerated reflexes and spasticity, which includes velocity-dependent increased muscle tone.¹³⁵ Although enhanced reflexes are sufficiently common and associated with the spasticity phenomenon to be part of its definition, measurement of the reflex amplitude in some patients (such as patients with stroke or neurologically complete SCI) has shown reductions compared with that in able-bodied subjects.^176,^178,²⁰⁷

Although the spinal α-motor neuron is considered to be the final common pathway for expression of spasticity, one should consider the more complex motor pathways involved in the disordered movements of spastic brain-injured patients. Spastic hypertonia encompasses a variety of conditions, including dystonia, rigidity, myoclonus, muscle spasm, clonus, cocontraction, posturing, and spasticity.^109,^158,¹⁷⁴ The following sections briefly review the physiology of segmental reflexes.

The Monosynaptic Reflex

The physiologic components involved in the spinal stretch reflex response include the muscle spindle stretch receptor, the myelinated sensory neuron, the synapse, the homonymous α-motor neuron, and the muscle it innervates. As originally described in the decerebrate cat model, the stretch reflex shows a dramatic increase in extensor muscle tone on passive flexion of the extended hindlimbs. This stretch reflex has two components: a brisk, short-acting phasic component that responds to the initial dynamic change in length, and a weaker, longer-acting tonic component that responds to the steady stretch of the muscle at a new length.¹⁴⁴

A change in muscle length can evoke a stretch reflex. Modified muscle fibers (intrafusal receptor organs) that detect changes in muscle length are called muscle spindles. Nuclear bag fibers and nuclear chain fibers are two types of specialized muscle spindle fibers (Figure 30-1). Nuclear bag fibers are further subdivided into dynamic and static nuclear bag fibers. Dynamic nuclear bag fibers are highly sensitive to the rate of change in muscle length, providing velocity sensitivity to muscle stretch.¹⁵¹ Static nuclear bag fibers and nuclear chain fibers are more sensitive to the steady-state, static or tonic, muscle length. The structural differences between these fibers are responsible for the physiologic differences in their sensitivities and for the two different components, phasic and tonic, of the stretch reflex. Intracellular muscle fibers are observed to undergo changes as a result of spasticity, as does the extracellular matrix.¹⁴⁵

FIGURE 30-1 Nuclear bag and nuclear chair fibers of the muscle spindle.

Group Ia and group II fibers are two types of myelinated sensory afferent fibers that innervate intrafusal fibers. Group Ia, or primary sensory, afferents convey both phasic and tonic stretch information. Group II fibers innervate static nuclear bag and nuclear chain fibers and convey information on the tonic or static change in muscle length. Contained within the muscle spindle unit are contractile elements that stiffen the region of the nuclear bag fibers. These contractile elements maintain spindle sensitivity during skeletal muscle contraction. They are innervated by special motor neurons known as the γ-motor neurons.

The Inverse Stretch Reflex

The Golgi tendon organ is sensitive to intramuscular tension and is innervated by myelinated Ib sensory afferents. The Golgi tendon organ is particularly sensitive to muscle tension created by active muscle contraction but has a high threshold for detecting passive stretch. Stimulation of Ib afferents leads to inhibition of the homonymous α-motor neuron and of its synergists. The excitation of its antagonistic motor neurons also stimulates Ib afferents. This behavior has been called the inverse myotactic reflex because its actions oppose those of the stretch (myotactic) reflex. It is also called Ib nonreciprocal inhibition. It should be noted that this reflex is stimulated by muscle tension, whereas the stretch reflex is stimulated by a change in muscle length. The Golgi tendon organ has been hypothesized to function as part of a muscle tension feedback system.¹³⁷

Elevated Reflex Activity

The stretch reflex can be viewed as a feedback system with muscle length as the regulated variable. Normally the gain, or input–output relationship, of the stretch reflex to a given change in muscle length is kept low by descending influences when the individual is at rest. The gain is enhanced when physical demand for performance is needed. Hyperreflexia is an example of segmental reflex dysregulation associated with an upper motor lesion. Hyperreflexia can theoretically result from a number of mechanisms, including decreased spinal inhibitory mechanisms from brain centers, hyperexcitability of α-motor neurons, peripheral nerve sprouting, and increased γ-fiber activity.

Long-term reductions in inhibition can contribute to hyperreflexia. Examples of inhibition types are as follows: recurrent Renshaw inhibition, reciprocal Ia inhibition, presynaptic inhibition, nonreciprocal Ib inhibition, and inhibition from group II afferents. Various lines of research have supported deficient presynaptic and nonreciprocal inhibition as significant contributors to spasticity. The supportive evidence for it being caused by deficient group II afferent-related and Renshaw inhibition is lacking.¹⁵³ Presynaptic inhibition is mediated via a γ-aminobutyric acid (GABA)ergic mechanism that decreases the efficacy of Ia afferent transmitter release. Inhibitory interneurons synapse with the presynaptic terminal of the Ia afferent via an axoaxonic synapse where GABA is the neurotransmitter. Inhibitory interneurons involved in presynaptic inhibition are modulated by descending pathways. The loss or reduction of rostral control can reduce tonic levels of descending facilitation on inhibitory interneurons, leading to increased α-motor response to normal Ia afferent input.²⁴⁵

The Ia afferent presynaptic inhibitory interneurons are normally controlled by descending excitatory pathways. Reciprocal Ia inhibition decreases the chance for cocontraction of antagonistic and agonistic muscles during the stretch reflex or during voluntary movement. Evidence exists for decreased excitability of the inhibitory neurons after rostral lesions of the central nervous system. This dysfunction could lead to an increased cocontraction and weakness of voluntary movement.⁴⁴ Nonreciprocal Ib inhibition has been found to be decreased or even replaced by facilitation in patients with spastic paresis and spastic dystonia, in this case both stroke and SCI subjects, but not in subjects without spastic dytonia.⁵⁹

Patients with spastic paresis from SCI show increased rather than decreased levels of recurrent Renshaw inhibition. Renshaw cells are inhibitory neurons that are stimulated by collateral axons from α-motor neurons. When an α-motor neuron fires, it stimulates a Renshaw cell that in turn inhibits the initiating motor neuron and its synergists. The Renshaw cell also inhibits the IIa afferents presynaptic inhibitory interneuron associated with the initiating motor neuron. Because the Renshaw cell inhibits the inhibitory interneurons as well as agonist α-motor neurons, increased Renshaw cell activity might contribute to spasticity by decreasing reciprocal Ia inhibition.²¹¹ Hyperexcitability of α-motor neurons might contribute to spasticity. Examples of primary changes in membrane properties that would be expected to produce increased α-motor neuron discharge include a reduction in the area of dendritic membranes, deafferentation dendritic hyperexcitability, and an increase in the number of excitatory synaptic inputs as a result of sprouting (Figure 30-2).²⁴⁵

FIGURE 30-2 Influences on the stretch reflex.

(Redrawn from Satkunam LE: Rehabilitation medicine. 3. Management of adult spasticity, CMAJ 169:1173-1179, 2003.)

Multisynaptic Segmental Connections

The majority of spinal segmental connections are polysynaptic. In addition to the muscle spindle afferents making direct contact with the α-motor neuron of the agonist muscle, interposed interneurons connect these afferents and antagonistic α-motor neurons to opposing muscle groups, resulting in a polysynaptic connection. As mentioned above, the Golgi tendon organ contributes to this via Ib nonreciprocal inhibition. These reflex pathways coordinate muscle action around the joint. Interneurons also receive excitatory and inhibitory signals from descending pathways. Supraspinal centers can control joint stiffness through the modulation of excitatory and inhibitory input to segmental interneurons and interneuronal networks.^41,¹⁰⁸

The interneurons that mediate Ib nonreciprocal inhibition connect inhibitory agonist and excitatory antagonistic motor neurons. At rest, Ib nonreciprocal inhibition opposes the actions of the stretch reflex. Convergent input from Ia spindle afferents is received by Ib interneurons, along with low-threshold cutaneous afferents and joint afferents and excitatory and inhibitory inputs from descending pathways. The Golgi tendon organ afferents make polysynaptic connections via the Ib inhibitory interneuron with the homonymous α-motor neurons and via other interneurons with the antagonist motor neurons. Because of Golgi tendon organ sensitivity to active muscle tension and the short-latency convergent input from Ia spindle afferents that Ib interneurons receive, cutaneous afferents, joint afferents, modulating descending pathways, and spinal interneuronal networks are likely to play an important role in exploratory movements of the limbs. A functional example of this network organization would be the reduction of muscle contraction if a limb encountered an unexpected obstacle. The interneuron receiving Ib afferent information would mediate the inhibition of the agonist, which would reduce the force against the impediment. Ib inhibition could also function to decrease muscle contraction at the extreme range of joint motion. The net effect of Ib inhibition during volitional activity depends on inputs from multiple sources.

Recurrent Renshaw inhibition takes place via polysynaptic connections to α-motor neurons. Renshaw cells not only directly inhibit the homonymous α-motor neuron but also disinhibit the antagonist α-motor neuron via Ia inhibitory interneurons. The Renshaw cells are also influenced by the descending pathways. These polysynaptic connections also help to coordinate the action of muscles around a joint.

The majority of group II afferent connections are polysynaptic and involve several classes of interneurons. These interneurons typically arise from muscle spindles, but some afferents originate as free nerve endings or in other types of receptors. Their activation tends to activate flexor synergistic muscles and inhibit physiologic extensors. Unopposed, group II-mediated activity produces tonic activation of physiologic limb flexors. Group III (Aδ fibers) and IV (C fibers) afferents originate from deep muscle and cutaneous receptors. Group III fibers are thinly myelinated. Group IV fibers are small-diameter afferents, often unmyelinated, and originate as free nerve endings serving nociceptive and thermoregulatory functions. Both types of fibers convey impulses generated by extreme pressure, heat, and cold. Similar to type II responses, the reflex responses to these stimuli are bilateral flexion predominantly and are typically proportionate to the stimulus intensity.

The afferent fibers that produce generalized reflexive flexor movements have become known collectively as flexor reflex afferents. Interestingly, the response to cutaneous stimuli is not always one of generalized flexion. The vestibulocollic and cervicocollic reflexes produce patterns of coordinated ipsilateral limb flexion accompanied by contralateral limb extension with activation of group II and III fibers to either keep the head level during body tilt or to oppose a fall. Different modalities of stimuli can have differential effects, particularly evident after a neurologic injury. For example, after certain neurologic lesions, pressure applied to the plantar surface of the foot produces a marked extension of the leg, known as extensor thrust. In contrast, a pinprick in the same area leads to flexion withdrawal of the limb. The spinal circuits responsible for ipsilateral flexion and crossed limb extension also receive descending inputs and coordinate voluntary limb movements.

A cutaneous stimulus can modulate the activity of particular motor neurons. Touching an area of skin can cause a reflex contraction of specific muscles, usually those beneath the area of stimulation. This is an example of an exteroceptive response. Cutaneous stimuli might not always produce observable contractions. They can have subthreshold or facilitative effects. Proprioceptive information is transmitted from muscle spindles and Golgi tendon organs via group Ia, II, and Ib afferents. Finally, there are indications that pathway connectivity and neurotransmitter distribution might account for differential responses comparing the upper limbs with the lower limbs.¹⁵⁹

Goal Setting

Because spasticity results from neurologic dysfunction within several regions in the central nervous system, the associated loss of voluntary motor function can be highly variable among patients with symptomatic spasticity. Prediction of the functional impact resulting from the presence of spasticity consequently can be challenging. Compare an individual with C4 tetraplegia who uses a mouth stick or suck and puff actuator to operate a computer, telephone, and numerous adapted electronic devices, as well as a head controller to operate an electric wheelchair, for example, with a person with T10 paraplegia. The presence of mild to moderate spasticity can alter the sitting position so that the control over the adaptive devices is lost for the person with tetraplegia, whereas the paraplegic person does not experience the same functional impact to that level of spasticity intensity. The functional goal for spasticity treatment should be one within the ability of the patient when the performance of the function is limited mainly by spasticity. Common examples of spasticity-limited functional goals are to improve speed and safety of wheelchair transfers, to improve the performance of activities of daily living such as dressing, and to facilitate perineal hygiene by reducing thigh adductor or pectoral muscle spasticity, thus facilitating ease of caregiver assistance. One must consider also the extent to which the spasticity helps the individual functionally; therefore the goal of functional improvement must consider the balance of treatment effects. Spasticity can be protective against skeletal muscle atrophy and indirectly affect functional independence, ambulation, and incidence of fracture.⁹³ Spasticity has been reported to increase glucose uptake and thereby reduce the risk for diabetes in those with SCI.²⁰

One potential functional goal might be the improvement of gait. Although patients with spasticity are reported to have disturbances of gait speed, timing, kinematics, and electromyographic patterns, the relative impact of spasticity on gait remains controversial.^76,^78,^133,¹⁹⁶ Although it seems logical that knee extensor muscle torque should correlate with the speed of “comfortable” walking, by experimental measurement it accounts for only 30% of the variance in gait speed in spastic stroke patients.²³ Young²⁴⁴ concluded that not all abnormalities underlying “spastic gait” are caused by spasticity, and consequently are not affected by antispasticity drug treatment.

Pain and fatigue are examples of other factors that can contribute to functional limitations. Spasticity can be caused or exacerbated by pain. The presence of pain is widely acknowledged as a significant negative contributor to the quality of life. The time and energy required to complete a task also could change more with the presence of spasticity and its treatment than with the actual ability or inability to complete the task. Spasticity can significantly disturb sleep, contributing even more to fatigue. If there are treatable goals such as improving function, hygiene, ease of care, and seating and positioning, as well as decreasing pain, contractures, or sleep disturbance, then treatment options can be offered as follows.

Nonpharmacologic Treatments

A regular exercise routine that includes daily range of motion exercise must be done, with a focus on muscle stretching. This can be accomplished with assistance from a therapist in the short term, but in the long term the exercise should be taught to be done by self or caregivers.^31,^102,¹⁹⁷ Immediate reduction in spasticity can be seen objectively from passive movements or from stretch.^187,²²⁰ Any spasticity-aggravating factors (e.g., urinary tract infection, constipation, skin ulceration, ingrown nails, and fractures) must be identified and treated.

A number of other helpful physical treatments can be used. Casting a joint with the muscle in a lengthened position can help maintain muscle length, with serial casting allowing for progressive improvement in joint range. With this treatment, however, one must be extremely vigilant not to cause skin breakdown from pressure points in the insensate limb. Externally applied repetitive cycling movements to the lower limbs using a motorized exercise bicycle has allowed some subjective improvements but no objective changes in torque resistance response to movement.¹²¹ Another approach to spasticity reduction is hippotherapy, which involves the rhythmic movements associated with riding a horse to regulate muscle tone. The short-term effect of hippotherapy has been shown in decreasing spasticity of the lower limb as noted by the Ashworth Scale and self-reported spasticity with a small crossover randomized clinical trial.¹³⁸ In a recent review of the literature pertaining to randomized trials of antispasticity treatments for amyotrophic lateral sclerosis, the recommended treatment included individualized, moderate-intensity, endurance-type exercises for the trunk and limbs.¹¹ Electrical stimulation of the spinal cord has been reported to result in reduction of spasticity,^15,¹⁰³ although the measurement of spasticity in these studies has been questioned.⁶¹ Several investigators have shown that electrical stimulation of the peripheral nerves can decrease spasticity in patients with SCI, stroke, or traumatic brain injury.^∗ Other physical modalities that have been reported to ameliorate spasticity include application of tendon pressure,¹⁴⁰ cold, warmth, vibration, splinting, bandaging, massage, low-power laser, and acupuncture.^90,⁹⁶ Some success has also been reported with magnetic stimulation over the thoracic spinal cord¹⁸⁵ and topical application of 20% benzocaine,²⁰⁶ although these are not mainstays of therapy at this point.

Pharmacologic Treatments

The first treatment that usually springs to mind for spasticity is pharmacologic. It is hoped that, after reading the preceding paragraphs, what also comes to mind is excellent medical management, treatment of aggravating factors, and use of physical modalities. Nevertheless, pharmacologic treatment is often required in the management of spasticity, and it is important to have a thorough understanding of the various effects of the medications in this class of therapeutics. The specific pharmacologic effects can be directed toward alteration of transmitters or neuromodulators by suppression of excitation (glutamate), enhancement of inhibition (GABA or glycine), a combination of noradrenaline (norepinephrine), serotonin, adenosine, and various neuropeptides, or action on peripheral neuromuscular sites. Although numerous substances have potential antispasticity effects, the USA Food and Drug Administration (FDA) has approved only four prescription pharmaceuticals for the treatment of spasticity related to central nervous system disorder. These are baclofen, tizanidine, dantrolene sodium, and diazepam. These four agents will be discussed first, followed by other pharmaceuticals with similar pharmacologic actions but without an FDA-approved antispasticity indication.

Enhancement of Segmental Inhibition via GABA

The main inhibitory neurotransmitters in the central nervous system are GABA and glycine. The physiologic action of GABA on the Ia-mediated spinal reflex is by presynaptic inhibition, as was shown in the 1940s by Sir John Eccles. GABA-containing cells are typically small interneurons. Localized ischemia is a common experimental methodology for eliminating these small GABA-containing interneurons while leaving long tracts intact. A spinal transection, on the other hand, disrupts long tract function but does not decrease the number of GABA interneurons or the concentration of GABA in spinal tissue below the level of transection. Once GABA is released by GABAergic interneurons, free GABA is released to bind to receptors on the postsynaptic membrane. The classic GABA_A receptor has been characterized as having a number of cell membrane protein subunits: α, β, and γ. GABA binding activates the receptor, which stimulates the chloride ionophore channel, resulting in membrane hyperpolarization. When an axonal connection exists between a GABAergic interneuron and the terminal of a Ia afferent, then hyperpolarization of that membrane will result in decreased excitability, decreased excitatory transmitter release, and subsequently reduced motor neuron firing. For this reason, presynaptic inhibition of the afferent neuronal terminal reduces motor neuron output without direct inhibition of motor neuron excitability. Because GABA does not cross the blood-brain barrier, it would not be useful as an oral antispasticity agent.

Medications With GABA-Mimetic and GABA-Like Actions

Baclofen (Lioresal)

Baclofen is β-4-chlorophenyl GABA, which binds to and activates the bicuculline-insensitive GABA_B receptors. Bicuculline is a toxin that antagonizes the inhibitory effects of endogenous GABA at GABA_A receptors, which cause treated animals to convulse. Once a presynaptic GABA_B receptor is activated, potassium conductance is altered, resulting in a net membrane hyperpolarization and a reduction in endogenous transmitter release.^53,¹¹² For example, in a presynaptic sensory neuron, release of GABA by a local interneuron and binding at the receptor on the sensory neuron produce inhibition of the primary afferent terminal, and result in a decrease in excitatory neurotransmitter release. Baclofen activation of receptors postsynaptically inhibits calcium conductance and causes inhibition of γ-motor neuron activity, reduced drive to intrafusal muscle fibers, and reduced muscle spindle sensitivity.²³⁴ The overall inhibitory effect of baclofen administration at the spinal cord level reduces sensory and motor neuron activation. It also reduces the activation of monosynaptic spinal reflexes and, to a lesser extent, polysynaptic spinal reflexes. Numerous clinical reports note the antispasticity effects of oral baclofen for patients with multiple sclerosis or SCI.^∗ Orally delivered baclofen has recently been studied in patients with cerebral disorders and was found to have selective efficacy on lower limb spasticity but not on spasticity in the upper limbs.¹⁵⁹ Short-term studies with multiple sclerosis patients suggest that gait enhancement is observable with effective spasticity treatment in selected patients.^189,²²²

Baclofen absorption after oral administration occurs mainly in the proximal small intestine. This probably involves two different amino acid transporter systems as a result of competitive inhibition of absorption by the neutral and β amino acids. The kidney normally excretes the baclofen essentially unchanged, but the liver can metabolize as much as 15% of a given dose. This is why periodic liver function testing is advisable during baclofen treatment, and the dosage should be reduced in patients with impaired renal function. The average therapeutic half-life of baclofen is 3.5 hours but ranges from 2 to 6 hours. Baclofen dosing is usually initiated as 5 mg three times per day and increased gradually to a therapeutic level. The recommended maximum dosage is 80 mg/day in four divided doses.¹²⁷ Reports of improved therapeutic effects with higher dosages have been published.^1,^128,²²² Because baclofen treatment can produce sedation, patients should be cautioned regarding the operation of automobiles or other dangerous machinery and activities made hazardous by decreased alertness. Baclofen is excreted by the kidneys, so patients with renal impairment will likely require a lower dosage. The effects of chronic baclofen treatment during human pregnancy are largely unknown. In some patients, seizure control has been lost during treatment with baclofen.¹³¹ Abrupt discontinuation of baclofen can produce seizures, confusion, hallucinations, and rebound muscle spasticity with fever.²³¹

Oral baclofen is a widely prescribed pharmaceutical in North America, and there are few reports of major toxicity. Massive overdose with oral baclofen has been reported, however, including a case report of a 57-year-old woman who ingested 2 g of baclofen, causing coma and hypoventilation. She was given naloxone, 50% dextrose, and activated charcoal. Initially her blood pressure was low, and later systolic hypertension was noted, followed 16 hours later by bradycardia and hypotension. Her pupils were small and unresponsive, and muscle stretch reflexes were absent. Plasma baclofen concentrations over time showed first-order elimination kinetics and a half-life of 8 hours.⁸⁹

Modulating the Monoamines

Tizanidine (Zanaflex)

Tizanidine is an imidazoline derivative and agonist that binds to α₂-receptor sites both spinally and supraspinally,^46,²¹⁰ similar to the α₂-adrenergic agonist clonidine (see description following). The medical literature supports the notion that the pharmacologic effects include the restoration or enhancement of presynaptic inhibitory modulation of spinal reflexes in patients with spasticity.^57,^175,^182,²²⁷ Tizanidine has been shown to decrease reflex activity, especially polysynaptic reflex activity.^54,^55,²²⁷ Tizanidine also has an antinociceptive effect as shown in animal models.⁵⁴^–⁵⁶ ¹²² Several European and American studies have shown that tizanidine is equal in effectiveness to baclofen and diazepam but with a more favorable tolerability profile. The main advantage appears to be fewer complaints of treatment-related weakness. Furthermore, two clinical trials demonstrated that patients with spasticity improved muscle strength during tizanidine treatment.^129,¹⁶² Gelber et al.⁸⁷ describe a statistically significant improvement in upper limb spasticity, pain intensity, and quality of life in stroke patients by titrating dosages in 2-mg intervals, mindful of withdrawal rebound effects.

Tizanidine has been tested in a number of clinical trials in Europe and has been found to be safe, well tolerated, and beneficial in treating spasticity of various etiologies.⁷⁴ Tizanidine is an α₂ agonist like clonidine but has a much reduced potency and does not consistently induce a reduction in blood pressure or pulse, as clonidine does.³³ Symptomatic hypotension has been reported when tizanidine is taken with an antihypertensive drug; thus the concomitant administration of tizanidine and antihypertensive drugs should be avoided. An important drug interaction between ciprofloxacin, an antibiotic, and tizanidine has prompted the USA FDA to approve safety labeling. As a result of ciprofloxacin-induced inhibition of cytochrome P450 1A2, hepatic metabolism of tizanidine is decreased. The resulting increase in tizanidine plasma concentration and clinically significant adverse events is a contraindication to the coadministration of tizanidine, taken orally, and ciprofloxacin, given intravenously.

Tizanidine is well absorbed after an oral dose, with extensive first-pass hepatic metabolism to inactive compounds that are subsequently eliminated in the urine. Therefore tizanidine should be used with caution in patients with known liver abnormality. Because the most common side effects reported during the clinical trials with tizanidine include dizziness and drowsiness, it is recommended that tizanidine therapy begin with a single dose of 2 to 4 mg at bedtime. The titration of tizanidine should be tailored to the patient. The maintenance dosage is the one at which the therapeutic goals have been met with the fewest side effects. The scored tizanidine tablets contain 4 mg. Dosage increases of 2 to 4 mg every 2 to 4 days are recommended; most clinicians experienced with tizanidine, however, recommend a slower and more gradual upward titration. This is particularly the case for patients with multiple sclerosis, who tend to experience side effects at lower dosages. The maximum recommended dosage is 36 mg/day. All trials, including those in people with SCI, multiple sclerosis, or cerebral disorders, have reported somnolence consistently in 42% to 46% of the patients.^162,^179,²²¹

Alteration of Ion Channels

Dantrolene Sodium (Dantrium)

Dantrolene sodium is a hydantoin derivative whose primary pharmacologic effect is to reduce calcium flux across the sarcoplasmic reticulum of skeletal muscle. This action uncouples motor nerve excitation and skeletal muscle contraction.^71,²³⁸ It is indicated for use in chronic disorders characterized by skeletal muscle spasticity, such as SCI, stroke, cerebral palsy, and multiple sclerosis. The oral formulation is prepared as a hydrated sodium salt to enhance absorption (approximately 70%), which occurs primarily in the small intestine. After a dose of 100 mg, the peak blood concentration of the free acid, dantrolene, occurs in 3 to 6 hours. The compound is hydroxylated, and the active metabolite, 5-hydroxydantrolene, peaks in 4 to 8 hours. Dantrolene sodium has been shown to produce a dose-dependent decrease in the stretch reflex¹⁰⁹ and a percentage decrease of grip strength.⁷⁹ Dantrolene is lipophilic and crosses cell membranes well, achieving wide distribution and significant placental concentration in the pregnant patient. Liver metabolism by mixed function oxidase and cytochrome P450 produces a 5-hydroxylation of the hydantoin ring and reduction of the nitro group to an amine, which is then acetylated. Urinary elimination of 15% to 25% of the unmetabolized drug is followed by urinary excretion of the metabolites after oral administration of the drug. The median elimination half-life is 15.5 hours after an oral dose and 12.1 hours after an intravenous dose.

The majority of placebo-controlled clinical trials of dantrolene have shown a reduction of muscle tone, stretch reflexes, and increased passive motion. The most consistent finding has been a reduction of clonus in patients with clonus.¹⁹⁸ Mixed conclusions have been drawn regarding the effects of dantrolene sodium on gross motor performance and strength. In comparative trials with spasticity of different etiologies, some have suggested that the best responders to dantrolene sodium are those with stroke and cerebral palsy, and that patients with SCI improve the least, if at all. Most investigators agree, however, that patients with multiple sclerosis do not generally benefit from dantrolene treatment.¹⁴⁸ In four trials of children with cerebral palsy, dantrolene sodium was found to be superior to placebo. The degree of improvement appeared greater in children than in adults. One study found dantrolene to be superior to baclofen, and another suggested equal efficacy to diazepam. In addition to its antispasticity effects, dantrolene has been used in the treatment of malignant hyperthermia and the neuroleptic malignant syndrome.²³¹ Dantrolene has also been reported to be useful in the treatment of hyperthermia following abrupt baclofen withdrawal.^126,¹⁴⁸

At least 13 clinical reports of overt hepatotoxicity appear in the literature, five of which report hepatonecrosis. The overall incidence of hepatotoxicity in a large group of patients receiving dantrolene sodium for more than 2 months is reported to be 1.8%, with symptomatic hepatitis occurring in 0.6% and fatal hepatitis in 0.3%. The greatest risk was in women older than 30 years who were taking more than 300 mg/day for more than 60 days. Initiation of antispasticity treatment with dantrolene sodium should begin with 25 mg once daily, increasing every 4 to 7 days by 25-mg increments to 100 mg four times per day. The dosage at which the anticipated therapeutic response occurs with the fewest side effects should be the maintenance dose.

Benzodiazepines

The pharmacologic and antispasticity effects of benzodiazepines are generally mediated by a functionally coupled benzodiazepine–GABA receptor chloride ionophore complex.^45,^188,²¹² As described above, the GABA_A receptor supramolecular structure is envisioned as a heteropentameric glycoprotein of about 275 kDa, whose subunits react with GABA, benzodiazepines, steroids, barbiturates, and picrotoxin-like convulsants.¹⁴⁶ More specifically, the duration of action is related to the receptor and pharmacodynamics; certain benzodiazepine subunits are either high-affinity or low-affinity receptors, as well as long-acting and short-acting benzodiazepines. Benzodiazepines enhance GABA_A receptor current, which increases the opening frequency of the chloride ionophore without altering channel conductance or open duration.²²⁸ The relative length of action is also related to the duration of activity and rate of metabolism of the pharmacologically active metabolites. Examples of long-acting benzodiazepines are diazepam, chlordiazepoxide, and clonazepam. Oxazepam, alprazolam, and lorazepam are considered to be short acting without significant production of active metabolites. Benzodiazepines cross the placental barrier and are secreted into breast milk. Microsomal enzymes of the liver metabolize the benzodiazepines extensively.

Diazepam (Valium)

Diazepam is a benzodiazepine that is sedating, reducing agitation and anxiety. It decreases polysynaptic reflexes and has muscle relaxant, sedation, and antispasticity effects.^58,^148,¹⁹³ Long used as a treatment for stiff person syndrome, its effects diminish over time, requiring alternative treatment such as intravenous propafol.¹⁰⁷ Diazepam is usually started with a bedtime dose of 5 mg, increased to 10 mg as needed for adults, but is found to be effective when given 0.1 to 0.05 mg/kg and excessively sedating in children when given in excess of 1 mg/kg.¹⁵⁰ Diazepam is well absorbed after an oral dose, with the peak blood level occurring typically in 1 hour. Diazepam is metabolized to the active compound N-desmethyldiazepam (nordiazepam) and then to oxazepam. The half-life of diazepam and its active metabolites is 20 to 80 hours, and it is 98% to 99% protein-bound. In patients with low serum albumin and lower protein-binding capacity, such as is often the case in patients with SCI or stroke, the incidence of undesirable sedation is increased. Daytime therapy is initiated with 2 mg and increased as needed; a clinical trial of children with cerebral palsy, however, suggests that a single bedtime dose was sufficient to improve passive stretching exercises throughout the day with the additional benefit of being a relatively low-cost pharmaceutical.¹⁵⁰ Intravenous diazepam is reported to have been effective in the attenuation of intrathecal baclofen withdrawal.⁴⁸

Diazepam intoxication causes a range of symptoms from somnolence to coma. Although it is generally regarded as having a wide margin of safety, treatment of patients with myelopathy has been linked to increased body weight.⁸⁴ Benzodiazepine poisoning also has been reported.²¹⁴ Near-term infants born with benzodiazepine intoxication are at risk. A case report notes a young mother at term who consumed a diazepam overdose of 250 to 300 mg and became drowsy but responsive. The fetal heart rate showed decreased variability and absence of accelerations. The benzodiazepine antagonist flumazenil, 0.3 mg, was given to the mother intravenously. Within 5 minutes, behavioral arousal in the mother and improved fetal heart rate variability were observed.²²⁵

Typical symptoms of patients in withdrawal from high-dose diazepam (>40 mg/day) are anxiety and agitation; restlessness; irritability; tremor; muscle fasciculation; twitching; nausea; hypersensitivity to touch, taste, smell, light, and sound; insomnia; nightmares; seizures; hyperpyrexia; and psychosis. The intensity of the symptoms and risk for death are related to the prewithdrawal dose. Symptoms of withdrawal from low-dose benzodiazepine (<40 mg/day) are more likely if the patient has taken the drug consistently for more than 8 months. Long-term usage of diazepam is common. In a study of 23 SCI treatment facilities with the Department of Veterans Affairs, 70% routinely used diazepam as an antispasticity treatment, and 67% of patients had been using it for more than 6 years.²⁹ Onset of withdrawal symptoms occurs 1 to 2 days after a short-acting benzodiazepine is stopped or 2 to 4 days for a long-acting benzodiazepine. Even when the benzodiazepines are withdrawn slowly over 4 to 6 weeks, withdrawal symptoms can persist for 6 months.⁸⁸

< div class='tao-gold-member'>

Only gold members can continue reading. Log In or Register to continue