CHAP 33 - SKELETAL MUSCLE RELAXANT

REHABILITATION FOCUS
● 2 major therapeutic groups affecting the skeletal muscles
1. Neuromuscular blockers - used as adjuncts to general anesthesia to produce the muscle paralysis
necessary for surgery, tracheal intubation and control of ventilation.
- Nicotinic antagonists at the neuromuscular junction and lack CNS activity.
2. Skeletal muscle relaxants or spasmolytics
- 2 groups:
1. Reduce spasticity in neurologic conditions
2. Reduce muscle spasm – ff. muscle injury or inflammation.
- Called CENTRALLY ACTING SKELETAL MUSCLE RELAXANTS – because it
acts at multiple sites in the CNS than Neuromuscular end plate
- SPASMODIC DRUGS: (1) Dantrolene (2) Botulinum Toxin — acts in or near
skeletal muscle with no significant central effects.

PATHOPHYSIOLOGY OF SPASTICITY AND MUSCLE SPASM

● Spasticity is characterized by an increase in tonic stretch reflexes and flexor muscle spasms (ie, increased basal
muscle tone), together with muscle weakness and a reduction in viscoelastic muscle properties.
● Spasticity is frequently associated with cerebral palsy, multiple sclerosis, spinal cord injury, and stroke
- These conditions often involve abnormal function of the bowel and bladder as well as skeletal muscle.
The mechanisms underlying spasticity in these types of neurologic injury involve the stretch reflex arc
itself (Figure 33-2) and higher centers in the CNS.
● After an upper motor neuron (UMN) lesion, damage to descending pathways in the spinal cord results in loss of
supraspinal inhibition to alpha and gamma motor neurons in the anterior horn of
the spinal cord.
● When UMNs from the cerebral cortex and brainstem nuclei are no longer
able to modulate spinal reflexes or activate spinal cord inhibitory interneuron
pools, decreased activity of inhibitory interneurons results in increased excitability
of alpha motor neurons in the spinal cord. Figure 33-3 illustrates descending
polysynaptic input onto alpha motor neurons from many CNS centers, drawing
attention to the normal considerable inhibitory input
● Some of the signs and symptoms of neurologic injury spasticity may be
improved by pharmacologically modifying the stretch reflex or by interfering
directly with skeletal muscle (ie, excitation-contraction coupling).
● Drugs that modify the reflex arc may modulate excitatory or inhibitory
synapses (Chapter 12). To reduce the hyperactive stretch reflex, it is desirable to
reduce the activity of la sensory afferent ft.hers providing information from the
muscle spindle, enhance the activity of the inhibitory interneurons, and/or directly
decrease the activity of alpha motor neurons. Figure 33-4 illustrates select sites of
action for various skeletal muscle relaxants.
 ● Muscle spasms are distinct from spasticity in that these localised tonic contractions result from a peripheral injury
rather than an UMN injury. Muscle spasms are sustained contractions of specific muscles that often occur after
musculoskeletal injuries and inflammation secondary to nerve impingement, muscle strains, or muscle overuse.
- They may also result from chemical or mechanical stimuli in the peripheral nervous system.
● Noxious nociceptive stimuli set in motion a pain-spasm-pain cycle that can be interrupted by enhancing the activity
of inhibitory interneurons to promote muscle relaxation.
● Regardless of whether the origin of hyperexcitable skeletal muscle is neurologic spasticity or muscle spasm,
skeletal muscle relaxants have the overall effect of decreasing the activity of skeletal muscle.
● For both spasticity and muscle spasms, the pharmacotherapeutic goal is to normalize muscle excitability.
However, skeletal muscle relaxants produce a nonspecific depression of all synapses involved in the stretch
reflex-reducing not only the undesirable excitatory transmission, but also the desired inhibitory input transmission
(Figure 33-3).
- In addition, excessive depression of synapses at the level of the spinal cord segments can result in a loss
of voluntary muscle activity. Thus, selective enhancement of inhibitory or selective depression of
excitatory transmission is needed.
● Currently available drugs can provide significant relief from spasticity (antispasticity drugs) as well as painful
muscle injury spasms (anti spasm drugs).
- In spite of this, the ultimate goal of normalizing muscle excitability without a significant decrease in
voluntary muscle activity and patient function is largely unfulfilled.
- This challenge can be partially met by effective communication between the healthcare providers (often
physical and occupational therapists) observing effects on patients' function and the prescribers that can
make appropriate adjustments in medications, dosages, and/or methods of administration

ANTISPASTICITY DRUGS
● DIAZEPAM
- benzodiazepines facilitate the action of y-aminobutyric acid (GABA), the primary inhibitory
neurotransmitter in the CNS.
- Diazepam (Valium) is the benzodiazepine most commonly used as a spasmolytic agent.
➔ Diazepam acts at all GABA A synapses, but its action in reducing spasticity is at least partly
mediated in the spinal cord (Figure 33-4).
➔ It is somewhat effective in treating spasticity resulting from cord transection and spasticity due to
cerebral palsy.
➔ Diazepam is also used to treat muscle injury spasm of almost any origin, including local muscle
trauma.
➔ Diazepam produces sedation in most patients at the dose required to significantly reduce muscle
tone. Other benzodiazepines have been used as spasmolytics, but experience with them is much
more limited.
● BACLOFEN
- Baclofen (p-chlorophenyl-GABA) is an orally active GABAmimetic gent and exerts its spasmolytic activity
at GABA B receptors. Activation of central GABA B receptors by baclofen results in hyperpolarization by
increasing K+ conductance in postsynaptic neurons.
➔ Hyperpolarization of presynaptic terminals reduces calcium influx, which decreases release of
excitatory transmitters in the brain and spinal cord (Figure 33-4). Baclofen inhibits activity of la
sensory afferents
➔ in muscle spindles, spinal interneurons, and motor neurons. Baclofen may also reduce pain in
individuals with spasticity, perhaps by inhibiting the release of substance P in the spinal cord.
➔ Baclofen is at least as effective as diazepam and tizanidine (discussed below) in reducing
spasticity due to neurologic injury and it produces much less sedation and weakness than
diazepam.
➔ Baclofen is rapidly and completely absorbed after oral administration. Adverse effects include
drowsiness (to which patients may become tolerant with chronic administration) and generalized
muscle weakness at higher doses.
- Increased seizure activity has been reported in epileptic patients, especially upon
withdrawal of the drug. Therefore, withdrawal of baclofen must be done very slowly.
● Chronic infusion of baclofen via an implantable intrathecal pump can control severe spasticity for
individuals unresponsive to oral baclofen or those who experience intolerable adverse effects at effective
spasmolytic doses.
● Intrathecal administration is becoming more widely used for two main reasons.
1. Baclofen does not readily leave the spinal canal, so the frequency of systemic adverse effects is
lower. However, cases of excessive somnolence, respiratory depression, and even coma have
been reported with high doses.
2. Intrathecal catheter can be placed to more selectively target baclofen delivery to appropriate
spinal cord segments.
- Partial tolerance to the antispastic effect of the drug may occur after several months of
therapy but can be overcome by upward dosage adjustments. A major disadvantage of
this therapeutic approach is the difficulty of maintaining the drug-delivery catheter in the
subarachnoid space. Recently, it has been noted that the observed partial tolerance to
baclofen may be due to unrecognized catheter malfunction.
- To address this concern, instructions provided to patients include the avoidance of
sudden, excessive, or repeated movements such as bending, twisting, bouncing, or
stretching. These movements may interrupt or stop drug delivery by damaging the pump
(located subcutaneously in the anterior abdominal wall) or dislodging, kinking or blocking
the intrathecal catheter.
- Long-term intrathecal baclofen therapy can improve the quality of life for patients with
severe spasticity associated with multiple sclerosis, stroke, and cerebral palsy.
- Oral baclofen has been studied in severl other medical conditions. Off-label uses (uses
outside of what is approved by the Food and Drug Administration [FDA]) include
intractable hiccups, intractable low back pain, trigeminal neuralgia, cluster
headache, and the management of drug and alcohol dependence.

● TIZANIDINE
- a-adrenoceptor2 agonists (eg, clonidine) have a variety of CNS effects that are not fully understood.
Among these effects is the ability to reduce muscle spasm.
- Tizanidine (Zanaflex) has significant a2-adrenoceptor agonist effects, but lacks the antihypertensive
efficacy of clonidine. Studies in animals and humans suggest that tizanidine reinforces both presynaptic
and postsynaptic inhibition in the spinal cord (Figure 33-4).
 - Tizanidine also inhibits nociceptive transmission in the spinal dorsal horn. Oral tizanidine is just as
effective in relieving spasticity as diazepam, baclofen, and dantrolene, but produces significantly less
muscle weakness.
➔ For this reason, tizanidine may be a better choice for reducing spasticity while maintaining
adequate muscle strength for transfers, ambulation, and general activity.
➔ Tizanidine is relatively short-acting, so individuals may reserve dosing for activities of daily living
and times when relief of spasticity is most important.
➔ Since tizanidine induces drowsiness that may impair function, some individuals take the drug at
night. Dry mouth and asthenia are also common. Hypotension is a less frequent adverse reaction.
● OTHER CENTRALLY ACTING SPASMOLYTIC DRUGS
- Gabapentin (Neurontin) and its newer analog pregabalin (Lyrica) have no activity at GABA A or GABA B
receptors.
➔ These drugs bind to a subunit of voltage-gated calcium channels, though their exact mechanism
of action is unknown.
➔ Gabapentin has traditionally been used as an antiepileptic drug, but both gabapentin and
pregabalin have shown considerable promise as antispasticity agents in individuals with multiple
sclerosis.
➔ Both drugs are also recommended as first-line therapy in the pharmacological management of
neuropathic pain.
➔ Gabapentin has been added to the list of Schedule V controlled substances by several states due
to its potential abuse by individuals misusing opioids. Preliminary studies have shown that
progabide and glycine reduce spasticity.
➔ Progabide is a GABA A and GABA B agonist and has active metabolites, including GABA itself.
➔ Glycine, the principal inhibitory neurotransmitter in the spinal cord, appears to possess
pharmacologic activity when given orally and readily passes the blood-brain barrier.
➔ Idrocilamide and riluzole are newer drugs for the treatment of amyotrophic lateral sclerosis that
appear to have spasm-reducing effects, possibly through inhibition of glutamatergic transmission
in the CNS.
● PERIPHERALLY ACTING SPASMOLYTIC DRUGS
Botulinum Toxin
➔ When Clostridium botulinum bacteria are exposed to anaerobic conditions that allow the spores to
germinate, botulinum toxin (BoNT) is produced as an exotoxin. There are seven immunologically distinct
toxins, though only two strainsBoNT-A and BoNT-B-are used therapeutically.
➔ After injection into a muscle, BoNT blocks acetylcholine release at the neuromuscular junction (Figure
33-4), causing paralysis of muscles within the diffusion distance of the injected toxin (-1 inch).
➔ The localized paralysis is dose dependent and transient, with recovery occurring within 1-3 months.
Because muscle function returns in approximately 3 months, BoNT injections into affected muscles needs
to be ongoing.
➔ BoNT has been FDA-approved for at least nine indications, including blepharospasm, strabismus, cervical
dystonia, migraine prophylaxis, overactive bladder, upper limb spasticity, and improvement in the
appearance of wrinkles around the eyes and forehead.
➔ There has also been tremendous expansion of BoNT's off-label uses. These include many conditions
frequently treated by physical therapists such as focal dystonias, spastic conditions, and disorders of
localized muscle spasms.
➔ Several studies have evaluated the efficacy of combining physical and occupational therapy with BoNT
injection of carefully selected muscles to manage spasticity.
➔ Although these studies have shown benefits of regaining function and independence and reduced risk of
long-term complications like contractures, study heterogeneity limits the ability to demonstrate the overall
impact of adjunctive rehabilitative therapy to BoNT injections.
 Dantrolene
➔ Dantrolene is a drug related to phenytoin, an antiseizure medication. In contrast to the centrally active
muscle relaxants, dantrolene acts directly at the level of skeletal muscle cells. By binding to a specific
calcium channel in the sarcoplasmic reticulum, dantrolene decreases the release of calcium necessary for
excitation-contraction coupling.
➔ Cardiac and smooth muscle fibers are minimally affected because calcium release from their
sarcoplasmic reticulum involves a different calcium channel. Because there are more effective skeletal
muscle relaxants with better safety profiles,
➔ dantrolene is neither advocated for use in treating muscle injury spasms nor is it a first-line agent for
treating spasticity. For example, tizanidine, baclofen, and 390 PART VI Drugs Affecting the
Musculoskeletal System gabapentin are first-line options for pharmacologically managing spasticity due to
multiple sclerosis.
➔ Dantrolene is usually reserved to treat severe spasticity when no clinical improvement has been observed
with other agents. Dantrolene's most common adverse effects are drowsiness and generalized muscle
weakness.
➔ dantrolene may cause hepatotoxicity; dantrolene is recognized as a wellestablished cause of clinically
apparent liver injury. A special application of dantrolene is in the treatment of malignant hyperthermia — a
rare heritable disorder characterized by often-fatal hyperthermia due to a sudden and prolonged release
of calcium, with massive muscle contraction, lactic acid production, and increased body temperature.
➔ Dantrolene inhibits skeletal muscle contraction throughout the body, thus reducing excessive body
temperature generated by massive, repetitive muscle contractions.

ANTI SPASM DRUGS

Polysynaptic Inhibitors
➔ A large number of drugs (eg, carisoprodol, chlorzoxazone, cyclobenzaprine, metaxaJ.one, methocarbamol,
and orphenadrine) are promoted for the relief of acute muscle spasm caused by local tissue trauma or muscle
strains.
➔ All of these agents are centrally acting skeletal muscle relaxants that are thought to act primarily at the levels of
the brainstern and spinal cord. Although their mechanisms of action are not well understood, animal research
suggests that some of these drugs interfere with the polysynaptic transmission of neuronal impulses within the
spinal cord, thus reducing alpha motor neuron excitability and activity (Figure 33-3). Table 33-2 describes the
onset and duration of action of the polysynaptic inhibitors.
➔ Polysynaptic inhibitors are often used as adjuncts to rest and physical therapy for relief of painful muscle spasm
associated with musculoskeletal injuries. They are often prescribed in combination with nonsteroidal
anti-inflammatory agents or analgesics. These agents are ineffective in treating spasticity caused by cerebral
palsy, multiple sclerosis, or spinal cord injury. Major adverse effects of these drugs are generalized sedation,
confusion, headache, and nausea and vomiting.
➔ This drug class is also associated with abuse potential Cyclobenzaprine, the prototype agent in this class, also
has strong antimuscarinic actions, with manifestations of sedation that potentially increase fall risk.

REHABILITATION RELEVANCE
● Skeletal muscle relaxants are prescribed for many
patients involved in rehabilitation programs. These drugs are
used for both neurologic injury spasticity and for muscle
injury spasms; concurrent physical and occupational therapy
are important adjuncts to improve function.
- For example, the implementation of
therapeutic interventions may facilitate more normal
physiologic motor control and functioning to replace
previously used spastic tone.
- Localized injections of BoNT in spastic
muscles may be combined with stretching of these muscles
 and strengthening of antagonist muscle groups, which may improve self-care or nursing care and spastic
contractures.
- Similarly, skeletal muscle relaxants are frequently used in conjunction with nonpharmacologic
interventions (eg, modalities, manual therapy) to acutely reduce muscle spasm following strains or nerve
root impingement. While these medications are helpful to acutely interrupt the pain spasm-pain cycle, they
do not remove the inciting cause of the muscle spasm.
● Therapeutic programs to improve strength, flexibility, posture, relaxation, and body mechanics are often essential
to healing.
- One of the clinical challenges is encouraging patients to appreciate that such active therapy interventions
may be necessary to make lasting changes and ultimately decrease the need for skeletal muscle
relaxants.
➔ All but two skeletal muscle relaxants (dantrolene and BoNT) act centrally to decrease the activity
of alpha motor neurons. Thus, almost all drugs in this class have fairly predictable CNS effects
such as sedation, dizziness, and ataxia. If these adverse effects affect functional outcomes,
potential solutions include coordinating physical therapy sessions at a time of day when sedative
effects are less marked and alerting the prescribing practitioner to initiate discussion of other
therapeutic options.
➔ Many centrally acting skeletal muscle relaxants are associated with tolerance and risk of
physical dependence, abuse, and misuse. In addition, these agents should not be combined
with other CNS depressants (eg, alcohoL barbiturates, opioids), which can lead to profound
sedation, respiration depression, and death.
➔ Weakness is an inherent complication of all skeletal muscle relaxants. If muscle weakness
prevents attainment of therapeutic goals, therapists must assess patient performance with
functional or quality-of-life outcome measures and communicate these results to other team
providers and prescribers.