55

Skeletal Muscle Relaxants

RAVNEET BHULLAR, EVANGELINE P. KOUTALIANOS, CHARLES E. ARGOFF, ANDREW DUBIN

The term skeletal muscle relaxant can be confusing for patients formation in the brain. Interesting to note is that sedating agents
and clinicians alike as there are different classes of skeletal muscle also depress polysynaptic reflexes, making it difficult to determine
relaxants. Specifically, antispasticity, antispasmodic classes of skel- whether skeletal muscle relaxants produce their clinical activity via
etal muscle relaxants exist, and some medications overlap in both sedation or a change in the pain-spasm-pain cycle.
of these categories. (Table 55.1).1–4 The use of such agents with
or without nonsteroidal anti-inflammatory drugs (NSAIDs) can
be considered for acute low back pain.5 Medications commonly • BOX 55.1 Classification of Agents by Proposed
referred to as skeletal muscle relaxants include carisoprodol, chlor- Mechanism of Action
zoxazone, cyclobenzaprine, metaxalone, methocarbamol, and
orphenadrine.6 These agents are labeled by the United States Food Drug Mechanism of action Site of action
and Drug Administration (FDA) with an indication for the relief Baclofen Similar to GABA acts on Centrally acting-
of discomfort associated with an acute, painful, musculoskeletal the presynaptic GABAa site, spinal cord
condition. Baclofen and tizanidine have FDA indications for the decreasing synaptic transmission
treatment of spasticity caused by upper motor neuron syndromes, to the spinal cord
including multiple sclerosis and spinal cord disease or injury. Ben- Dantrolene Prevents the release of calcium Peripherally acting
zodiazepines, principally diazepam, are also used and indicated for from the sarcoplasmic reticulum
adjunctive relief of skeletal muscle spasms and are often consid- in skeletal muscle cells
ered in discussions regarding skeletal muscle relaxants.
Carisoprodol Causes altered neuronal output Centrally acting -
In discussing this broad class of skeletal muscle relaxants medi-
at the reticular formation and spinal cord and brain
cations, it becomes difficult to cull out the actual intended thera- spinal cord
peutic outcomes. These agents are typically prescribed during the
initial presentation of acute low back pain. The injury normally Chlorzoxazone Acts on the spinal cord and Centrally acting-
occurs to the muscles, ligaments, or tendons, structures around subcortical regions to inhibit spinal cord and brain
the lumbar spine. The presentations may include local pain and reflex arcs involved in causing
and maintaining muscle spasm
tenderness, muscle spasms, and limited range of motion. Muscle
spasm is often the most difficult to define and is the subject of con- Cyclobenzaprine α2 agonists at descending Centrally acting -
troversy among some clinicians.7 Muscle spasm can be described noradrenergic neurons on the brainstem
as a vicious pain-spasm-pain cycle that protects compromised tis- supraspinal area of the brain
sues and structures. Secondary to these pain impulses, an involun- stem, seratonergic antagonism at
tary reflex muscle contraction at the site of injury can occur, which 5HT2 receptor
in turn can lead to local ischemic injury. This can further facilitate Metalaxone CNS depressant Centrally acting
the pain-spasm-pain paradigm. Muscle spasm phenomena may be
Methocarbamol CNS depressant Centrally acting
considered a variation of a myofascial pain presentation.8
Orphenadrine Central atropine like structure Centrally acting
Mechanism of Action alleviates muscle spasm
Diazepam Benzodiazepine increases GABA Centrally acting -
In considering this discussion of muscle spasm pathophysiol- mediated presynaptic inhibition at spinal cord and brain
ogy, the problem with defining the activity of the skeletal muscle spinal and supraspinal sites
relaxants becomes manifest. The exact mechanism of action for
these various agents has not been fully elucidated. However, it is Tizanidine α2 adrenergic agonist, presynaptic Centrally acting
generally accepted that skeletal muscle relaxants can depress poly- inhibition of motor neurons
synaptic reflexes within the dorsal horn via various mechanisms Botulinum Toxin Neurotoxin- blocks the Centrally and
(Box 55.1), which may relax the skeletal muscle tissue in an indi- release of acetylcholine at the peripherally acting
rect manner.1–3 In animal studies, these agents exert their muscle- neuromuscular junction, causing
relaxing effects by inhibiting interneuronal activity and blocking muscle paralysis
polysynaptic neurons in the spinal cord and descending reticular

763
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764 PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues
Indications for Use
Despite the common use of skeletal muscle relaxants, relatively little
data exist to elucidate their role in the treatment of chronic low
back pain.9,10 None of the agents discussed in this chapter have an
indication for use in the setting of chronic back pain. In one survey
of skeletal muscle relaxant use in the United States, muscle relax-
ants, although indicated for short term treatment, are most often
prescribed on a long term basis.11 In general, skeletal muscle relax-
ants, excluding baclofen and tizanidine, maintain FDA labeling as
adjuncts for treatment of short term acute low back pain (LBP) and
are commonly used to treat muscle spasms and associated pain for
periods of one to three weeks as most patients with acute or sub-
acute low back pain improve with time.5 In this context, it may be
difficult to discern the role of these agents, other than the palliative
analgesic quality that they may provide for patients. Therefore skel-
etal muscle relaxant selection depends on an evaluation of adverse
effects, contraindications, patient tolerability, and clinical experi-
ence. This discussion will also include a brief review of the clinical
use of botulinum toxin as a treatment for musculoskeletal pain.
Specific Drugs By Class
Antispasmodic Agents
Carisoprodol (Soma)
Carisoprodol is a Schedule IV substance and is available as a
250 mg or 350 mg tablet and in combination with aspirin (soma
compound) and with aspirin and codeine (soma compound with
codeine). Carisoprodol dosing should not exceed four doses in a
24 h period (Table 55.1). In addition, it should not be prescribed
for longer than three weeks.12,13 Similar to other muscle relaxants,
carisoprodol has additive sedative effects when taken with alcohol
or other central nervous system (CNS) depressants. Its most com-
mon side effects are drowsiness, dizziness, and headache.12–14
Carisoprodol is converted in the liver to meprobamate, a
substance with a long half-life of 10 h.12,13 Meprobamate is well
known to produce phenomena that result in physical and psy-
chological dependence.13–15 After oral ingestion, carisoprodol has
a quick onset of action with time to maximum plasma concentra-
tion being 1.5 to 1.7 h.12 Within the United States since 2012,
carisoprodol has been listed as a Schedule IV controlled substance
by the Controlled Substance Act. Because of the risk of physical
and psychological dependence potential, carisoprodol use should
be avoided. It should also be cautiously tapered as opposed to
immediately discontinued following long-term use.
Chlorzoxazone (Paraflex, Parafon Forte DSC)
Chlorzoxazone is available as 250 and 500 mg tablets, taken up
to four times daily. It is a centrally acting muscle relaxant act-
ing primarily at the level of the subcortical regions of the brain
and spinal cord.16,17 It has been suggested that chlorzoxazone may
be less effective than the other skeletal muscle relaxants.9 It does
not have any significant drug-drug interactions, but it does have a
significant adverse effect profile that includes a rare idiosyncratic
hepatocellular reaction. The role of this agent is unclear, consider-
ing the potential lack of efficacy and significant toxicity profile.16,17
Cyclobenzaprine (Amrix, Flexeril)
Cyclobenzaprine is available as 5 and 10 mg tablets, with recom-
mended dosing of up to three times daily for up to three weeks
as longer therapy is not well supported. It is also available in an
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extended-release form. Cyclobenzaprine is structurally and phar-
macologically related to tricyclic anti-depressants. It is a centrally
acting serotonin receptor antagonist as well as an α two agonist at
descending noradrenergic neurons rather than a CNS depressant
skeletal muscle relaxant.18–20 As with other skeletal muscle relax-
ants, cyclobenzaprine does not have activity directly on muscle
tissue, with animal data suggesting that this agent acts primarily in
the brainstem. The net result of this action is a reduction in tonic
somatic motor activity.21 Although no human evidence exists to
support this mechanism, the 5 mg dose has yielded similar clinical
efficacy with less sedation than the more sedating 10 mg dose.22
In the future, this may prove to be an important distinction with
other CNS depressant agents. In an open-label study of patients
with acute neck or LBP associated with muscle spasm who were
randomized to be treated for seven days with cyclobenzaprine 5 mg
PO three times daily alone or cyclobenzaprine 5 mg PO three
times daily in combination with ibuprofen, at doses of 400 mg
PO three times daily or 800 mg three times daily, no significant
treatment differences were found among these groups.23
Cyclobenzaprine shares a similar side effect profile, including
prominent anticholinergic effects, as it is structurally related to
tricyclic anti-depressants. The most common anticholinergic side
effects include drowsiness, dizziness, and dry mouth. Other side
effects also include urinary retention, hypotension, and constipa-
tion.23 Use of cyclobenzaprine is contraindicated in the setting of
arrhythmias, congestive heart failure, hyperthyroidism, acute glau-
coma, narrow angle glaucoma, or during the acute recovery phase
of a myocardial infarction. One report suggested that coadministra-
tion with pro-serotonergic agents such as selective serotonin reup-
take inhibitors may predispose patients to serotonin syndrome.24
Cyclobenzaprine can increase the risk of serotonin syndrome in
patients taking tramadol, increasing the risk of seizures. Attendant
use of cyclobenzaprine with monoamine oxidase inhibitors or use
within 14 days after their discontinuation is contraindicated. It
can also enhance the effects of agents with CNS depressant activ-
ity. Older adults appear to have a higher risk for CNS-related
adverse reactions, such as hallucinations and confusion when
using cyclobenzaprine. Withdrawal symptoms have been noted
with the discontinuation of chronic cyclobenzaprine use. Use of a
medication taper may be warranted for chronic-use patients.
Metaxalone (Skelaxin)
Metaxalone is available as a 400 and 800 mg tablet and has a rec-
ommended maximal dose of 800 mg three or four times daily.
Its exact mechanism of action is not well understood, but it does
cause general depression of the CNS.25 Metaxalone does not have
any significant drug-drug interactions and appears to have a mini-
mal risk side effect profile. However, fatalities attributed to the use
of metaxalone have been reported.25,26 Hemolytic anemia, leuko-
penia, and impaired liver function have been seen with the use of
metaxalone, but they are uncommon. Metaxalone is contraindi-
cated in patients who have severe renal or hepatic impairment. It
is known to cause an elevation in the cephalin flocculation test,
necessitating serial liver function assessments. Metaxalone can also
produce a false-positive result for Benedict’s test. In this scenario,
alternatives to urine glucose testing may be necessary.27,28
Methocarbamol (Robaxin, Robaxisal)
Methocarbamol is available in oral and parenteral forms. How-
ever, many complications have arisen with the injectable form,
including pain, sloughing of the skin, and thrombophlebitis. The
exact mechanism of action is unknown. However, it causes general
 CHAPTER 55  Skeletal Muscle Relaxants 765

TABLE
55.1
Skeletal Muscle Relaxant Profiles

Dosing (can be
Onset of taken as needed Important Drug
Drug Action Duration (h) or standing) Side Effects Interactions
Dantrolene >7 days (PO) Variable (PO) 25–100 mg PO Muscle weakness, Chronic therapy can cause
Antispacticity agent peak plasma four times daily phlebitis, hepatic dysfunction. Ace-
concentration respiratory failure, Inhibitors, paralytics, i.e.
in 6 h gastrointestinal Vecuronium
failure
Baclofen Three to four Variable (PO) 5–10 mg PO three Drowsiness, Anti-depressants (short-term
Antispasticity agent days (PO) times daily slurred speech, memory loss); additive
4–6 h (IT) hypotension, effects with imipramine
30 min (IT) constipation,
urinary retention
Carisoprodol 30 min 4–6 250–350 mg PO Drowsiness, CYP2C19 inhibitors and
Antispasmodic three times daily dizziness, inducers
headache
Chlorzoxazone ∼1 h 3–4 250–750 mg PO N/V, headache, Additive effects when taken
Antispasmodic four times daily drowsiness, with alcohol or other CNS
agent dizziness depressants
Cyclobenzaprine ∼1 h 12–24 5–10 mg PO three Drowsiness, Additive effects with
Antispasmodic times daily dizziness, dry barbiturates, alcohol, other
agent mouth CNS depressants; seizures
with tramadol and MAOIs;
additive effects with TCAs
Metaxalone 1h 4–6 800 mg PO four Dizziness, Additive effects when taken
Antispasmodic times daily headache, with alcohol or other CNS
agent drowsiness, N/V, depressants
rash
Methocarbamol 30 min (PO) 4–6 750–1500 mg PO Dizziness, blurred Additive effects when taken
Antispasmodic four times daily vision, with with alcohol or other CNS
drowsiness depressants
Orphenadrine 1 h (PO) 4–6 100 mg PO twice Tachycardia, Propoxyphene (confusion,
Antispasmodic daily lightheadedness, N/V, dry mouth, tremors)
anxiety
Diazepam 30 min (PO) Variable, 2–10 mg PO four Sedation, fatigue, Potentiation of effects when
Antispasmodic and depending on times daily hypotension taken with phenothiazines,
antispasticity agent elimination ataxia, respiratory opioids, barbiturates, MAOIs
depression
Tizanidine Two weeks Variable 2–8 mg PO four Drowsiness, dry Additive effects with alcohol
Antispasmodic and times daily mouth, dizziness, and other CNS depressants;
antispasticity agent hypotension, reduced clearance with oral
increased spasm, contraceptives
or muscle tone

CNS, Central nervous system; IT, intrathecal; MAOIs, monoamine oxidase inhibitors; N/V, nausea and vomiting; TCA, tricyclic anti-depressant.

CNS depression. If combined with benzodiazepines, barbiturates,
codeine, or its derivatives, methocarbamol can cause respiratory
depression.29 The injectable form should be used cautiously in
patients with known latex hypersensitivity. The oral dosage form of
the medication is marketed as a 500 and 750 mg tablet, with a rec-
ommended daily dosage range of 4000 to 4500 mg as three or four
divided doses daily. For difficult situations, the dose for the first 24
to 48 h can be up to 6 to 8 g/day. Methocarbamol is also combined
with aspirin and marketed as Robaxisal. In a randomized, dou-
ble blinded placebo-controlled trial of naproxen with or without
orphenadrine or methocarbamol for acute LBP in the emergency
department population, no functional improvement was demon-
strated in either group compared to placebo with naproxen.30
Orphenadrine Citrate (Norflex, Norgesic, Norgesic Forte)
Orphenadrine is structurally related to diphenhydramine and thus
exhibits antihistaminic and anticholinergic properties. Orphen-
adrine appears to block muscarinic acetylcholine receptors and

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766 PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues
N-methyl-d-aspartate receptors in the CNS.31 Like methocarba-
mol, orphenadrine is available in a parenteral dosage formulation.
However, there have been reports of severe adverse reactions with
parenteral use (e.g. anaphylactoid reaction), making this formula-
tion difficult to use. Orphenadrine is available as a 100 mg tablet
(Norflex) and in combination with aspirin (Norgesic) and caffeine
(Norgesic Forte).
Orphenadrine’s anticholinergic actions have been noted to
produce significant adverse effects at high dosages such as tachy-
cardia, palpitations, urinary retention, and blurred vision.32 Given
its significant anticholinergic profile, orphenadrine use is contra-
indicated in patients with underlying neuromuscular junction
defects such as myasthenia gravis and Lambert Eaton syndrome.
Antispasticity and Antispasmodic Agents
Diazepam (Valium)
Diazepam is approved for the management of anxiety, acute alco-
hol withdrawal, skeletal muscle spasm, and convulsive disorders.33
With respect to muscle relaxation, g-aminobutyric acid (GABA)-
mediated presynaptic inhibition at the spinal level is thought to
be the main mechanism of action for diazepam.34 This medication
is a Schedule IV controlled substance with serious adverse effects
such as sedation and abuse potential and should not be considered
as a first-line muscle relaxant agent.35 It is important to taper this
agent slowly after long-term use to avoid any withdrawal symp-
toms. Withdrawal symptoms can range from mild headaches and
pain to psychosis, hallucinations, seizures, mania, and death from
convulsions if high dose chronic treatment is stopped abruptly.36
Diazepam is available in a wide range of dosages, and each patient
should be treated on an individual basis. For example, the rec-
ommended dosage range for musculoskeletal pain is 2 to 10 mg
orally, administered two to four times daily.34 There are serious
medication interactions in patients taking both benzodiazepines
and opioids, increasing the risk of respiratory depression and mor-
tality from respiratory failure.
Tizanidine (Zanaflex)
Tizanidine is a centrally acting a-2 noradrenergic receptor ago-
nist and inhibits excitatory neurotransmitters at the spinal and
supraspinal levels. Through its inhibition of neurotransmit-
ter release and the spinal pathways that enhance muscle move-
ment, tizanidine has been found to be effective in reducing
muscle spasticity in patients with spinal cord injury.37 The main
adverse effects are sedation, dizziness, hypotension, hepatotoxic-
ity, and dry mouth.38 Liver function tests should be monitored
periodically while on this medication. Currently, tizanidine is
FDA approved for the management of spasticity, which may be
caused by multiple sclerosis, acquired brain injury, or a spinal
cord injury. A meta-analysis that compared tizanidine, baclofen,
and diazepam found that they were equally effective in decreasing
excessive muscle tone in patients with multiple sclerosis or cere-
brovascular lesions, and muscular strength improved in all three
treatment groups, but the improvement was greatest with tizani-
dine.39 There are published studies on tizanidine’s effectiveness
in cervical and lumbar spine myofascial pain.40 A double-blind,
multicenter study evaluated 105 patients with acute LBP given
tizanidine 4 mg PO three times daily with ibuprofen 400 mg
PO three times daily, or ibuprofen 400 mg PO three times daily
with placebo. The study results suggested that the tizanidine-
ibuprofen combination is more effective for treating moderate or
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severe acute lower back pain than placebo and ibuprofen alone.41
Dosing for tizanidine begins at 2 to 4 mg tablets daily, usually
given at bedtime, and may gradually be increased to a maximum
of 36 mg per day, divided three to four times daily, depending on
patient tolerance.42
Tizanidine should be used with caution in the setting of renal
impairment. Tizanidine clearance decreases by 50% in patients
with creatinine clearance lower than 25 mL/min. Therefore it is
recommended to start patients with renal insufficiency at 2 mg/
day rather than at 4 mg/day for this reason.43 Liver function tests
should be monitored regularly while on this medication, as this
medication has been found to cause hepatotoxicity. In addition,
coadministration with alcohol increases the maximum concentra-
tion by approximately 15%, and concomitant use of oral contra-
ceptives decreases the clearance of tizanidine, which can enhance
its sedating effects.
Antispasticity Agents
Baclofen (Lioresal)
Baclofen functions as a GABAB receptor agonist and produces its
effects by inhibiting monosynaptic and polysynaptic transmission
along the spinal cord. This drug is FDA approved for the manage-
ment of reversible spasticity, particularly for the relief of flexor
spasms, clonus, and associated pain, which commonly occurs in
patients with spinal cord lesions and multiple sclerosis.44 Studies
have shown baclofen to have superior efficacy and tolerance when
compared with tizanidine.45 Baclofen can be administered intra-
thecally in cases of severe spasticity and for patients who do not
tolerate or have failed oral therapy. Intrathecal baclofen therapy
allows a patient to receive a high concentration of the medication
directly to the spinal cord while reducing the CNS side effects,
such as sedation, that develop with high oral doses of baclofen.46
Oral administration of baclofen is initially 5 mg three times per
day with a dose increase every three days until optimal response is
achieved. However, the dose should not exceed 80 mg daily. The
usual therapeutic range of baclofen is 40 to 80 mg daily.44 Com-
mon adverse effects of baclofen are muscle weakness, somnolence,
paresthesia, vertigo, and nausea.47 A gradual dose reduction is rec-
ommended to prevent withdrawal symptoms. Abrupt discontinu-
ation of oral baclofen can cause seizures and hallucinations, while
discontinuation of intrathecal baclofen may result in hyperpy-
rexia, impaired mental status, muscle rigidity, and severe rebound
spasticity. As baclofen use can lead to adverse effects in several
organ systems, it should be used with caution in older patients and
patients with renal impairment.48
Dantrolene
Dantrolene is a direct acting skeletal muscle relaxant that interferes
with the release of calcium ions from the sarcoplasmic reticulum
in skeletal muscle cells. It binds to the ryanodine receptor 1 and
decreases intracellular calcium. This, in turn, slows the contrac-
tion cycles of muscle cells. It is FDA approved to treat malignant
hyperthermia in both adults and children, neuroleptic malignant
syndrome, as well as upper motor neuron disorders involving the
brain and spinal cord. It is not recommended to be used as an
agent for acute musculoskeletal pain.
It is available in both oral and intravenous forms. Common
adverse effects include skeletal muscle weakness, hepatotoxicity.
Therefore it is contraindicated in patients who have preexisting
underlying liver disease.31,49

Botulinum Toxins (Botox-onabotulinumtoxin A, Dysport-
abobotulinumtoxin A, Xeomin-incobotulinumtoxin A, and
Myobloc-rimabotulinumtoxin B)
Botulinum toxin is a potent neurotoxin protein produced by the
gram-positive anaerobic bacterium Clostridium botulinum.50 Botuli-
num toxin types A and B have been developed for routine commer-
cial use. The toxin’s primary mechanism of action has been linked
to its ability to inhibit the release of acetylcholine from cholinergic
nerve terminals. However, it also inhibits the release of glutamate,
substance P, and calcitonin gene-related peptide, as well as inhibit-
ing the expression of the transient receptor potential vanilloid type 1
(TRPV1) and Purinergic (P2X3 receptor) in the dorsal root ganglion
(DRG) ganglion.51 These effects likely contribute to the analgesic
properties of botulinum toxin. Botulinum toxin has been studied
in several chronic pain conditions associated with painful muscle
spasms, including head and neck myofascial pain, temporomandib-
ular joint disorders, cervical dystonia syndromes, and chronic LBP.
The potential benefit of botulinum toxin for the treatment of
chronic myofascial pain in the head and neck has been noted. A
2016 meta-analysis reviewed 13 randomized controlled trials evalu-
ating the efficacy of botulinum toxin type A injections for head and
neck myofascial pain compared to placebo.52 This review included a
total of 656 total participants, with 366 receiving botulinum toxin
type A injections to myofascial trigger points and 290 participants in
the control group receiving saline injections. This review concluded
no significant improvement in pain intensity at four to six weeks
posttreatment with botulinum toxin injections. However, there was
a significant improvement in pain intensity with botulinum toxin
injections at two to six months compared to placebo (p = 0.008).52 A
2017 retrospective review evaluated the efficacy of botulinum toxin
(onabotulinumtoxin A, Botox) for patients with chronic temporo-
mandibular disorders with injections into the temporalis and mas-
seter muscles. Fifty-five of the 71 subjects (77%) reported beneficial
effects with Botox. In addition, patients reported a greater pain
improvement after Botox injections at five to ten weeks post-injec-
tion compared to less than five weeks (p = 0.009).53 This is consistent
with the above meta-analysis, showing pain improvement several
weeks after botulinum toxin injections. More recently, a random-
ized clinical trial evaluated onabotulinum toxin A injections for the
treatment of masseter and anterior temporalis myofascial pain.54 This
study concluded that botulinum toxin injections reduced pain inten-
sity (p < 0.0001) and increased pressure pain threshold (p < 0.0001)
for up to 24 weeks compared to placebo. However, dose-related
adverse effects were seen, such as a transient decline in mastica-
tory performance (p < 0.05), muscle contraction (p < 0.0001), and
decrease in muscle thickness (p < 0.05) and coronoid and condylar
Conclusion
Clinical data has shown that skeletal muscle relaxants are more
effective than placebo in relieving acute LBP.58 It is important
to recognize the different classes of muscle relaxants and the
intended effect when selecting an agent for a patient. Most clin-
ical guidelines list skeletal muscle relaxants as optional agents
for use individually or in combination with an NSAID. An
open-label, prospective, multicenter study evaluated patients
with acute LBP and provided either a fixed dose combination
of chlorzoxazone 500 mg and ibuprofen 400 mg or ibuprofen
400 mg alone for three times daily for a total of seven days.59
This study revealed that the fixed dose combination of chlor-
zoxazone and ibuprofen demonstrated a superior efficacy than
ibuprofen monotherapy in acute LBP patients. Most clinicians
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CHAPTER 55  Skeletal Muscle Relaxants 767
process bone volume (p < 0.05).54 As a result of these findings, low
doses of botulinum toxin are recommended for persistent myofascial
pain that does not improve with conservative treatments.
Botulinum toxins are considered first line therapy for the
treatment of cervical dystonia, and a systematic review and
meta-analysis were published in 2014 evaluating the efficacy of
onabotulinumtoxin A in these patients.55 A total of 18 studies
were reviewed in the meta-analysis showing a mean duration of
93.2 days after injections with onabotulinum toxin A and doses
greater than 180 units were associated with longer durations of
effect (107–109 days) compared to less than 180 units (86–88
days, p < 0.01).55 Based on the published literature and duration of
effect, patients with cervical dystonia treated with onabotulinum-
toxin A should require approximately four treatments annually.
Botulinum toxin injections have also been studied in the treat-
ment of chronic LBP. In one study, 31 patients with chronic LBP
were randomized, 15 patients received 200 units of botulinum toxin
A (onabotulinumtoxinA) injected into five sites (40 units injected
per site at five lumbar paravertebral levels), and 16 patients received
placebo injections.56 Pain and disability were measured at three and
eight weeks after injection using both the visual analog scale (VAS)
and the Oswestry LBP and disability questionnaire. At three weeks,
73.3% of the patients receiving botulinum toxin A had >50% pain
relief vs. 25% of patients receiving placebo (p = 0.012). At eight
weeks, 60% of patients receiving botulinum toxin A and 12.5%
of patients receiving placebo injections experienced pain relief
(p = 0.009).56 None of these patients experienced adverse effects.
This study concluded that botulinum toxin A injections within
the paravertebral muscles could improve chronic LBP and physical
functioning at three and eight weeks posttreatment. An open-label
pilot study also evaluated the efficacy of botulinum neurotoxin A
on patients with chronic LBP.57 The effect of botulinum toxin A on
chronic LBP was prospectively studied in 75 patients with repeated
treatments over the course of 14 months. Injections were placed
into the paraspinal muscles at four to five levels between L1 and
S1, with dosing ranging between 40 and 50 units per site. Pain
intensity using the VAS pain frequency, functional status using the
Oswestry scale were assessed at baseline, three weeks, and at two,
four, six, eight, ten, 12, and 14 months. At three weeks, 40 patients
(53%) and at two months, 39 patients (52%) reported significant
pain relief. The change in VAS, Oswestry score, and the number of
pain days were significant compared with baseline at two months
after each injection period (p<0.005) and continued to remain sig-
nificant over subsequent treatments. The majority, 91%, responded
well to the injections throughout the length of the study, with 4%
of the patients experiencing transient mild flu-like symptoms.57
and researchers agree that skeletal muscle relaxants may be ben-
eficial to patients with acute LBP by reducing the duration of
discomfort and accelerating functional recovery. It is recom-
mended to consider the use of skeletal muscle relaxants as an
adjunct or alternative to NSAIDs, especially in cases in which
NSAID toxicity is a concern or when NSAID monotherapy
proves suboptimal.
Skeletal muscle relaxants have CNS depressant effects and
should be used with caution, particularly for the elderly and in
patients with concomitant use of alcohol, anxiolytics, opioid
analgesics, and/or other sedating medications. Skeletal muscle
relaxants are associated with higher risks for total adverse effects,
especially those involving the CNS. The most common and
768 PA RT 5 Pharmacologic, Psychologic, and Physical Medicine Treatments and Associated Issues
consistent adverse effects noted with the CNS were drowsiness
and dizziness.60 The benzodiazepines-muscle relaxants such as
diazepam and sedative-muscle relaxants such as carisoprodol are
highly addictive and should never be used as first line agents.61
Key Points
• There are three broad classes of muscle relaxants: antispas-
modic, antispasticity, and combination agents.
• Muscle relaxants may treat muscle spasticity in two manners.
First, they can modify the stretch reflex arc, either by reducing
the excitatory signals or by augmenting the inhibitory inter-
neurons. This decreases activation of the alpha motor neuron.
Second, they can disrupt the excitation-contraction coupling
that produces muscle contraction.
• Cyclobenzaprine is a centrally acting skeletal muscle relaxant
that is structurally related to tricyclic anti-depressants; it acts
primarily at the level of the brainstem.
• As a GABAB agonist, baclofen causes hyperpolarization and
thus decreases the release of excitatory neurotransmitters in the
brain and spinal cord. It causes less sedation than benzodiaz-
epines and may reduce pain by decreasing substance P release.
• Skeletal muscle relaxants have been shown to be more effec-
tive than placebo for patients with acute LBP with respect to
Suggested Readings
Bailey DN, Briggs JR. Carisoprodol: An unrecognized drug of abuse. Am
J Clin Pathol. 2002;117:396–400.
Kamen L, Henney HR, Runyan JD. A practical overview of tizanidine
use for spasticity secondary to multiple sclerosis, stroke, and spinal
cord injury. Curr Med Res Opin. 2008:425–439.
Borenstein DG, Korn S. Efficacy of a low-dose regimen of cyclobenza-
prine hydrochloride in acute skeletal muscle spasm: Results of two
placebo-controlled trials. Clin Ther. 2003;25:1056–1073.
Descargado para Lucia Soler Torres (lucysol_1994@gmail.com) en Mexico National Cancer Institute de ClinicalKey.es por Elsevier en abril 25, 2023.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.
Considering many medications are found to be ineffective or
not tolerable by some patients (e.g. adverse effects of NSAIDs),
it is important to consider the use of skeletal muscle relaxants in
patients with persistent and intractable myofascial pain.
outcomes, such as short term pain relief, global efficacy, and
improvement of physical outcomes.
• Botulinum toxin not only inhibits the release of acetylcholine
from cholinergic nerve terminals but has also been found to
inhibit the release of glutamate, substance P, and calcitonin
gene-related peptide, as well as inhibiting the expression of
the transient receptor potential vanilloid type 1 (TRPV1) and
P2X3 receptors in the DRG ganglion. These effects contribute
to its analgesic properties.
• Botulinum toxin type A (onabotulinumtoxinA) injections are
found to be effective for head and neck myofascial pain, tem-
poromandibular joint disorders, cervical dystonia, and chronic
LBP.
• Carisoprodol is converted in the liver to meprobamate, an
intravenous controlled substance. Meprobamate is well known
to produce phenomena that result in physical and psychological
dependence.
Qaseem A, Wilt T, McLean RM, et al. Noninvasive treatments for acute, sub-
acute, and chronic low back pain: A clinical practice guideline from the
American College of Physicians. Ann Intern Med. 2017;166:514–530.
Reeves RR, Carter OS, Pinkofsky HB, et al. Carisoprodol (soma): Abuse
potential and physician unawareness. J Addict Dis. 1999;18:51–56.
Soprano SE, Hennessy S, Bilker WB, et al. Assessment of physician pre-
scribing of muscle relaxants in the United States, 2005–2016. JAMA
Netw Open. 2020;3(6):e207664.
The references for this chapter can be found at ExpertConsult.com.
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