CHAPTER
36 Skeletal Muscle Relaxants
Kenneth C. Jackson II and Charles E. Argoff
The term skeletal muscle relaxant is often used to
describe a diverse group of medications commonly
used in the treatment of back pain (Table 36–1).1-4
Medications commonly referred to as skeletal muscle
relaxants include carisoprodol, chlorzoxazone, cyclo-
benzaprine, metaxalone, methocarbamol, and or-
phenadrine.5 All these agents are labeled by the U.S.
Food and Drug Administration (FDA) with an indica-
tion for the relief of discomfort associated with an
acute, painful, musculoskeletal condition. Oral
baclofen and tizanidine are also commonly used
to treat acute musculoskeletal conditions and are
considered by many clinicians as muscle relaxants,
despite the lack of an indication in this regard.
Baclofen and tizanidine do have FDA indications for
the treatment of spasticity caused by multiple sclero-
sis, spinal cord disease, or injury. Benzodiazepines,
principally diazepam, are also commonly used and
indicated for adjunctive relief of skeletal muscle
spasm and are often considered in discussions regard-
ing skeletal muscle relaxants.
In discussing this broad class of medications, it
becomes difficult to cull out the actual intended ther-
apeutic outcomes. These agents are typically pre-
scribed during the initial presentation of an acute low
back pain problem, often the result of a soft tissue
mechanical injury. The injury normally occurs in the
muscles, ligaments, and/or tendons, structures around
the lumbar spine. The presentations may include
local pain and tenderness, muscle spasm, and limited
range of motion. Muscle spasm is often the most dif-
ficult to define and is the subject of controversy
among some clinicians.6 Muscle spasm can be
described as a vicious pain-spasm-pain cycle that pro-
vides protection to compromised tissues and struc-
tures. Following the interpretation of pain impulses,
an involuntary reflex muscle contraction at the site
of injury can occur and can lead to local ischemic
injury. This can further facilitate the pain-spasm-pain
paradigm. Muscle spasm phenomena may be consid-
ered a variation of a myofascial pain presentation.7
MECHANISM OF ACTION
In considering the above discussion of muscle spasm
pathophysiology, one begins to discern the problem
with defining the activity of the skeletal muscle relax-
ants. In specific terms, the exact mechanism of action
for these various agents has not been fully elucidated.
ch036-A04184.indd 693
It is generally accepted that skeletal muscle relaxants
have the ability to depress polysynaptic reflexes
within the dorsal horn via a variety of mechanisms
(Box 36–1), which in turn may produce relaxation
of skeletal muscle tissue in an indirect manner.1-3
In animal studies, these agents exert their muscle-
relaxing effects by inhibiting interneuronal activity
and blocking polysynaptic neurons in the spinal cord
and descending reticular formation in the brain.1 It
is interesting to note that other sedating agents also
depress polysynaptic reflexes, making it difficult to
determine whether skeletal muscle relaxants produce
their clinical activity via sedation or a change in the
pain-spasm-pain cycle.
INDICATIONS FOR USE
Despite the common use of skeletal muscle relaxants,
relatively little data exist to elucidate their role in
the treatment of back pain, especially chronic back
pain.8,9 None of the agents discussed in this chapter
have an indication for use in the setting of chronic
back pain, but in one survey of the use of skeletal
muscle relaxant use in the United States, muscle
relaxants, although indicated for short-term treat-
ment, are most often prescribed on a long-term
basis.10 In general, skeletal muscle relaxants, exclud-
ing 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 1
to 3 weeks. This time frame coincides with how long
many patients may expect it will take to recover from
an initial acute low back insult. 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. Skeletal muscle relaxant
selection is dependent on an evaluation of adverse
effects, contraindications, patient tolerability, and
clinical experience. This discussion will also include
a brief review of the clinical use of botulinum toxin
as a treatment for musculoskeletal pain.
SPECIFIC DRUGS
Carisoprodol (Soma)
Carisoprodol is available as a 350-mg tablet and in
combination with aspirin (Soma Compound) and
693
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 694 Pharmacologic, Psychological, and Physical Modalities

Table 36–1. Skeletal Muscle Relaxant Profiles

IMPORTANT DRUG
DRUG ONSET OF ACTION DURATION (hr) SIDE EFFECTS INTERACTIONS
Carisoprodol 30 min 4-6 Drowsiness, N/V, dizziness, Additive effects with alcohol and
ataxia; withdrawal other CNS depressants
potential
Chlorzoxazone ∼1 hr 3-4 N/V, headache, drowsiness, Additive effects when taken with
dizziness alcohol or other CNS
depressants
Cyclobenzaprine ∼1 hr 12-24 Drowsiness, dizziness, dry Additive effects with
mouth barbiturates, alcohol, other
CNS depressants; seizures with
tramadol and MAOIs; additive
effects with TCAs
Metaxalone 1 hr 4-6 Dizziness, headache, Additive effects when taken with
drowsiness, N/V, rash alcohol or other CNS
depressants
Methocarbamol 30 min (PO) N/A Dizziness, blurred vision, Additive effects when taken with
drowsiness alcohol or other CNS
depressants
Orphenadrine 1 hr (PO) 4-6 Tachycardia, Propoxyphene (confusion,
lightheadedness, N/V, dry anxiety, tremors)
mouth
Diazepam 30 min (PO) Variable, depending Sedation, fatigue, Potentiation of effects when
on elimination hypotension, ataxia, taken with phenothiazines,
respiratory depression opioids, barbiturates, MAOIs
Baclofen 3-4 days (PO) Variable (PO); Drowsiness, slurred speech, Antidepressants (short-term
30 min (IT) 4-6 hr (IT) hypotension, constipation, memory loss); additive effects
urinary retention with imipramine
Tizanidine 2 weeks Variable Drowsiness, dry mouth, Additive effects with alcohol and
dizziness, hypotension, other CNS depressants;
increased spasm, or muscle reduced clearance with oral
tone contraceptives

CNS, central nervous system; IT, intrathecal; N/V, nausea and vomiting; TCA, tricyclic antidepressant.

BOX 36–1. CLASSIFICATION OF AGENTS BY Table 36–2. Comparative Dosing of Commonly Used
PROPOSED MECHANISM OF ACTION Muscle Relaxants
AGENT DOSAGE
CNS Depressants
Antihistamine—orphenadrine Baclofen Initially, 5-10 mg PO qid
Sedatives—carisoprodol, chlorzoxazone, metaxa- Carisoprodol 350 mg PO qid
Chlorzoxazone 250-750 mg PO qid
lone, methocarbamol Cyclobenzaprine 5-10 PO tid
TCA-like—cyclobenzaprine Diazepam 2-10 mg PO qid
Metaxalone 800 mg PO qid
Central α2 Agonists Methocarbamol 750-1500 mg PO qid
Tizanidine Orphenadrine 100 mg PO bid
Tizanidine 4-8 mg PO qid
GABA Agonists
Baclofen, benzodiazepines
CNS, central nervous system; GABA, gamma-aminobutyric acid; TCA,
as a controlled substance in their state formularies.
tricyclic antidepressant. However, carisoprodol is not considered a controlled
substance at the federal level. Because of the depen-
dence potential, carisoprodol should be cautiously
with aspirin and codeine (Soma Compound with tapered as opposed to immediately discontinued fol-
Codeine). Carisoprodol dosing should not exceed lowing long-term use.
four doses in a 24-hour period (Table 36–2). Similar
to other muscle relaxants, carisoprodol has additive Chlorzoxazone (Paraflex, Parafon Forte DSC)
effects when taken with alcohol or other central
nervous system (CNS) depressants. Chlorzoxazone is available as 250- and 500-mg
Carisoprodol is converted in the liver to mepro- tablets, taken up to four times daily. It has been sug-
bamate (Miltown), a schedule intravenous (IV) con- gested that chlorzoxazone may be less effective than
trolled substance. Meprobamate is well known to the other skeletal muscle relaxants.8 It does not have
produce phenomena that result in physical and psy- any significant drug-drug interactions, but does have
chological dependence.11-16 Substance abuse appears a significant adverse effect profile that includes a rare
to be problematic with carisoprodol, probably as a idiosyncratic hepatocellular reaction.17 The role of
consequence of meprobamate formation. In recent this agent is unclear, considering the potential lack
years, several states have begun listing carisoprodol of efficacy and significant toxicity profile.18

ch036-A04184.indd 694 12/5/2007 9:35:52 AM


Cyclobenzaprine (Flexeril)
Cyclobenzaprine is available as 5- and 10-mg tablets,
with recommended dosing of up to three times daily.
Cyclobenzaprine is more structurally and pharmaco-
logically related to the tricyclic antidepressants than
to the CNS depressant skeletal muscle relaxants. As
with other skeletal muscle relaxants, 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.19 Although
no human evidence exists to support this mecha-
nism, it is interesting to note that the newer 5-mg
dose has yielded similar clinical efficacy with less
sedation than the more sedating 10-mg dose.20 In the
future, this may prove to be an important distinction
with the CNS depressant agents. In an open-label
study of patients with acute neck or low back pain
associated with muscle spasm who were randomized
to be treated for 7 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.21
Because of the structural relationship to tricyclic
antidepressants (TCAs), clinicians must be cognizant
of the anticholinergic side effects, such as dry mouth,
urinary retention, and constipation, seen with cyclo-
benzaprine. Use of cyclobenzaprine is contraindi-
cated in the setting of arrhythmias, congestive heart
failure, hyperthyroidism, or during the acute recov-
ery phase of a myocardial infarction. A recent report
has suggested that coadministration with proseroto-
nergic agents such as selective serotonin reuptake
inhibitors (SSRIs) may predispose patients to life-
threatening serotonin syndrome.22
Cyclobenzaprine labeling suggests that concomi-
tant use with tramadol may place patients at higher
risk for developing seizures.19 Concomitant use of
cyclobenzaprine with monoamine oxidase inhibitors
or use within 14 days after their discontinuation is
contraindicated. It can enhance the effects of agents
with CNS depressant activity. 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 cycloben-
zaprine use. Use of a medication taper may be war-
ranted for patients with chronic use.
Metaxalone (Skelaxin)
Metaxalone is available as a 400- and 800-mg tablet
and has a recommended dose of 800 mg three or four
times daily. Metaxalone does not have any signifi-
cant drug-drug interactions and appears to have a
fairly benign side effect profile, although fatalities
attributed to the use of metaxalone have been
reported..23,24 Hemolytic anemia and impaired liver
function have been seen with the use of metaxalone,
ch036-A04184.indd 695
Skeletal Muscle Relaxants 695
but both 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 sce-
nario, alternatives to urine glucose testing may be
necessary.25 Although FDA-approved over 30 years
ago, there are few published placebo-controlled
studies comparing metaxalone with placebo for the
treatment of musculoskeletal pain.26
Methocarbamol (Robaxin, Robaxisal)
Methocarbamol is available in oral and parenteral
forms for IV or intramuscular use. However, many
complications have arisen with the injectable form,
including pain, sloughing of the skin, and thrombo-
phlebitis. The oral dosage form of the medication is
marketed as a 500- and 750-mg tablet, with a recom-
mended daily dosage range of 4000 to 4500 mg as
three or four divided doses daily. For difficult situa-
tions, the dose for the first 24 to 48 hours can be up
to 6 to 8 g/day. Methocarbamol is also combined
with aspirin and marketed as Robaxisal. Similar to
metaxalone, although FDA-approved over 30 years
ago, there are few published placebo-controlled
studies comparing methocarbamol with placebo for
the treatment of musculoskeletal pain.27
Orphenadrine Citrate (Norflex, Norgesic,
Norgesic Forte)
Orphenadrine is a direct descendant of diphen-
hydramine, and thus exhibits antihistaminic and
anticholinergic properties. Like methocarbamol,
orphenadrine is available in a parenteral dosage for-
mulation. There have been reports of severe adverse
reactions with parenteral use (e.g., anaphylactoid
reaction), making this formulation difficult to use.
Orphenadrine is available as a 100-mg tablet (Norflex)
and in combination with aspirin (Norgesic) and
caffeine (Norgesic Forte).
Orphenadrine use with propoxyphene may cause
confusion, anxiety, and tremors, perhaps because
of additive effects. Orphenadrine’s anticholinergic
actions have been noted to produce significant
adverse effects at high dosages, such as tachycardia,
palpitations, urinary retention, and blurred vision.28
Diazepam (Valium)
This is the most commonly prescribed and refer-
enced benzodiazepine for the treatment of muscle
spasms.29 Diazepam demonstrates hypnotic, anxio-
lytic, antiepileptic, and antispasmodic properties.
With respect to muscle relaxation, gamma-aminobu-
tyric acid (GABA)–mediated presynaptic inhibition at
the spinal level is thought to be the main mechanism
of action for diazepam. Sedation and abuse potential
are the main concerns with this agent and class. It is
important to taper this agent slowly after long-term
12/5/2007 9:35:52 AM
 696 Pharmacologic, Psychological, and Physical Modalities
use, as opposed to abrupt removal, to avoid any with-
drawal symptoms. Diazepam is available in a wide
range of dosages and each patient should be treated
on an individual basis. The recommended dosage
range for musculoskeletal pain is 2 to 10 mg four
times daily.
Baclofen (Lioresal)
Baclofen is chemically related to GABA, and produces
its effects by inhibiting monosynaptic and polysyn-
aptic transmission along the spinal cord. This drug
is mainly used for spasticity associated with CNS
disorders (multiple sclerosis [MS], spinal cord lesions).
Studies have shown baclofen to be superior with
respect to efficacy when compared with diazepam.2
Baclofen is unique in that it can be administered
intrathecally in cases of severe spasticity and for
patients who do not tolerate or have failed oral
therapy. It has also found a niche in the treatment
of trigeminal neuralgia because of a more favorable
side effect profile. Baclofen is available in 10- and
20-mg tablets, with a therapeutic range of 40 to
80 mg daily. However, the dose should be started at
5 mg three times daily and tapered up to a therapeu-
tic level of 5 mg every 3 to 5 days. It should be
tapered slowly after long-term use to avoid a with-
drawal reaction and rebound phenomena, and should
be used with caution in older patients and patients
with renal impairment.
Tizanidine (Zanaflex)
Tizanidine (Zanaflex) is a short-acting inhibitor of
excitatory (presynaptic) motor neurons at the spinal
and supraspinal levels, producing agonistic activity
at the noradrenergic α2 receptors. This activity results
in the inhibition of neurotransmitter release from
spinal interneurons and the concomitant inhibition
of facilitatory spinal pathways that enhance muscle
movement. Tizanidine is related chemically to cloni-
dine, but has significantly lower antihypertensive
effects.30 The main adverse effect for most patients
is profound sedation.31 Currently, tizanidine is FDA-
approved for the management of increased muscle
tone associated with spasticity resulting from CNS
disorders, such as multiple sclerosis or spinal cord
injury. There are currently two published studies on
the use of tizanidine in the setting of back pain or
muscle spasm, either alone or in combination with
ibuprofen, as well as one report of effective use for
myofascial pain.32-34 In a multicenter placebo-
controlled study evaluating the efficacy and safety of
tizanidine for the treatment of low back pain, tizani-
dine was found to provide more pain relief and less
restriction of movement compared with placebo.
Drowsiness was the most common side effect but, as
the authors pointed out, for patients with acute low
back pain, especially at night, this adverse effect may
actually be desired.32 In a separate study, 105 patients
with acute low back pain were given tizanidine 4 mg
PO three times daily in conjunction with ibuprofen
ch036-A04184.indd 696
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 the treatment of moderate or
severe acute low back pain than ibuprofen only.33
Tizanidine is available as 2- and 4-mg tablets; treat-
ment should be instituted with a 4-mg single dose,
increasing by 2- to 40-mg increments up to a thera-
peutic dose. The maximum daily dose should not
exceed 36 mg.
Tizanidine should be used with caution in the
setting of renal impairment. Tizanidine clearance is
decreased by 50% in patients with creatinine clear-
ance lower than 25 mL/min. Coadministration with
alcohol can increase the area under the curve (AUC)
of tizanidine by approximately 20% and increase the
maximum concentration (Cmax) by approximately
15%. Use with oral contraceptives can decrease the
clearance of tizanidine and place patients at higher
risk for sedating adverse effects.
Botulinum Toxin (Botox, Myobloc)
Botulinum toxin is a potent neurotoxin produced by
the gram-positive anaerobic bacterium Clostridium
botulinum. Of the seven known immunologically dis-
tinct serotypes of botulinum toxin (A to G), only
types A and B have been developed for routine com-
mercial use. Historically, the toxin’s primary mecha-
nism of action has been linked to its ability to inhibit
the release of acetylcholine from cholinergic nerve
terminals. However, it is now appreciated that
these neurotoxins may also inhibit the release of
glutamate, substance P, and calcitonin gene-related
peptide. These effects may strongly contribute to the
analgesic effects of these toxins.35-37 Botulinum toxin
has been studied in a number of chronic pain condi-
tions associated with painful muscle spasm, includ-
ing cervicogenic headache, temporomandibular joint
disorders, craniocervical dystonia syndromes, chronic
myofascial pain, and chronic low back pain.
The potential benefit of the use of botulinum toxin
for the treatment of cervicogenic headache asso-
ciated with “whiplash” injuries has been studied
over the last decade. In 1997, Hobson and Gladish38
reported that botulinum toxin type A injections
could be effective in reducing cervicogenic headache
resulting from cervical whiplash type injuries. In a
randomized, double-blind, placebo-controlled study,
Freund and Schwartz39 have found that the botuli-
num toxin type A–treated patients demonstrate
significant greater improvement from baseline
with respect to pain reduction and cervical range of
motion. Mixed results have been observed in evaluat-
ing the effect of botulinum toxin injection on tem-
poromandibular joint and other orofacial-related
pain. In an open-label study completed by Freund
and Schwartz,40 patients with temporomandibular
joint dysfunction believed to be related to myofascial
dysfunction were treated with a total of 200 units of
botulinum toxin A (masseter and temporalis muscles
injected), with most patients experiencing pain
12/5/2007 9:35:52 AM

reduction as well as improvements in jaw function.
Von Lindern and colleagues’41 study of patients with
chronic facial pain associated with muscular hyper-
activity also demonstrated improvement in botuli-
num toxin type A–treated patients. However, in a
placebo-controlled crossover trial evaluating botuli-
num toxin type A inpatients with chronic moderate
to severe orofacial pain of muscular origin, no statis-
tically significant differences were seen between
placebo and active treatment.42
There have been several published evaluations of
the use of botulinum toxin for the treatment of myo-
fascial pain in the cervicothoracic regions. In a small
crossover trial (N = 6), patients whose cervical myo-
fascial trigger points were injected with botulinum
toxin type A had an average of 30% pain reduction.43
In a separate study, Wheeler and associates44 com-
pleted a randomized, double-blind, prospective,
placebo-controlled study in 33 patients with chronic
cervical myofascial pain who were injected with
either 50 or 100 units of botulinum toxin type A or
normal saline. No clear benefit was found in the
botulinum toxin–treated patients. Porta,45 in a single-
blinded study, evaluated the potential difference
between “conventional” lidocaine-methylpredniso-
lone trigger point injections and botulinum toxin
type A injections for myofascial pain treatment and
concluded that although each group received benefit,
the duration of benefit was longer in the botulinum
toxin–treated group.
Botulinum toxin injections have also been studied
in the treatment of chronic low back pain. In one
study, 31 patients with chronic low back pain were
randomized to be treated with 200 units of botuli-
num toxin A into five sites (L1-5 or L2-S1, 40 units/
site) or placebo injections. Pain and disability were
measured at 3 and 8 weeks following injection using
the visual analogue scale and the Oswestry Low Back
Pain and Disability Questionnaire. At 3 and 8 weeks,
the pain reduction experienced by the botulinum
toxin–treated group was greater than that experi-
enced by the placebo group and, at 8 weeks, there
was less disability in the botulinum toxin–treated
group compared with placebo.46 The precise role of
botulinum toxin injection therapy in the manage-
ment of conditions associated with chronic muscle
spasm remains to be determined.
CONCLUSION
Available clinical data indicate that skeletal muscle
relaxants are more effective than placebo with respect
to relieving acute low back pain.8 Most of this infor-
mation is dated, however, with study designs and
analyses that would not be acceptable if this research
were conducted today. In general terms, no data
support any one agent being more efficacious than
another. Some reports have suggested that chlor-
zoxazone may be less effective than other agents,
which puts into question the viability of using this
agent.8,47
ch036-A04184.indd 697
Skeletal Muscle Relaxants 697
Most clinical guidelines list skeletal muscle relax-
ants as optional agents for use individually or in
combination with an NSAID. The Agency for Health
Care Policy and Research (AHCPR) guidelines, pub-
lished in 1995, specifically noted that skeletal muscle
relaxants alone or in combination with an NSAID are
no more effective than using an NSAID alone.48 This
conclusion has been supported in systematic reviews
by van Tulder and colleagues.8,47 Skeletal muscle
relaxants have been shown to more effective than
placebo for patients with acute LBP with respect to
outcomes such as short-term pain relief, global effi-
cacy, and improvement of physical outcomes,49-52 but
there remains no quality evidence that allows for a
direct comparison of skeletal muscle relaxants with
NSAIDs. Most clinicians and researchers agree that
skeletal muscle relaxants may be of benefit to patients
with acute low back pain by reducing the duration
of their discomfort and accelerating recovery. A meta-
analysis of cyclobenzaprine use in acute low back
pain by Browning and associates53 has concluded
that despite limitations in the available evidence,
the combination of an NSAID with cyclobenzaprine
appears to be warranted. It is probably best to con-
sider 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 mono-
therapy proves suboptimal.
Skeletal muscle relaxants have CNS depressant
effects and should be used with caution, particularly
for patients with concomitant use of alcohol, anxio-
lytics, opioid analgesics, or other sedating medica-
tions. There is strong evidence that skeletal muscle
relaxants are associated with higher risks for total
adverse effects, especially those related to the central
nervous system.8,9,47 The most common and consis-
tent adverse effects noted with the central nervous
system were drowsiness and dizziness.25
Thus, skeletal muscle relaxants remain an enig-
matic collection of agents with an ill-defined role in
the treatment of acute and chronic back pain. This
is partly because of the nature of their discovery and
early clinical applications that predate more modern
research approaches. Considering the many issues
currently facing clinicians (e.g., adverse effects of
NSAIDs), it will become necessary to reevaluate the
role and use of skeletal muscle relaxants in the
future.
References
1. Elenbaas JK: Centrally acting oral skeletal muscle relaxants.
Am J Hosp Pharm 1980;37:1313-1323.
2. Waldman HJ: Centrally acting skeletal muscle relaxants and
associated drugs. J Pain Symptom Manage 1980;9:434-441.
3. Balano KB: Anti-inflammatory drugs and myorelaxants: Phar-
macology and clinical use in musculoskeletal disease. Prim
Care 1996;23:329-334.
4. Patel AT, Ogle AA: Diagnosis and management of acute
low back pain. Am Fam Physician 2000;61:1779-1786,
1789-1790.
5. Jackson KC: Evaluation of skeletal muscle relaxant use for
acute musculoskeletal pain and injury in ambulatory care.
J Pain 2003;4(Suppl 1):84.
12/5/2007 9:35:52 AM
 698 Pharmacologic, Psychological, and Physical Modalities
6. Johnson EW: The myth of skeletal muscle spasm. Am J Phys
Med Rehabil 1989;68:1.
7. Rivner MH: The neurophysiology of myofascial pain syn-
drome. Curr Pain Headache Rep 2001;5:432-440.
8. van Tulder MW, Touray T, Furlan AD, et al: Muscle relaxants
for non-specific low back pain. Cochrane Database Syst Rev
2003(3):CD004252.
9. Chou R, Peterson K, Helfand M: Comparative efficacy and
safety of skeletal muscle relaxants for spasticity and musculo-
skeletal conditions: A systematic review. J Pain Symptom
Manage 2004;28:140-175.
10. Dillon C, Paulose-Ram R, Hirsch R, et al: Skeletal muscle relax-
ant use in the United States: Data from the Third National
Health and Nutrition Examination Survey (NHANES III). Spine
2004;29:892-896.
11. Littrell RA, Hayes LR, Stillner V: Carisoprodol (Soma): A new
and cautious perspective on an old agent. South Med J
1993;86:753-756.
12. Bailey DN, Briggs JR: Carisoprodol: An unrecognized drug of
abuse. Am J Clin Pathol 2002;117:396-400.
13. Reeves RR, Carter OS, Pinkofsky HB, et al: Carisoprodol (soma):
Abuse potential and physician unawareness. J Addict Dis
1999;18:51-56.
14. Reeves RR, Carter OS, Pinkofsky HB: Use of carisoprodol by
substance abusers to modify the effects of illicit drugs. South
Med J 1999;92:441.
15. Rust GS, Hatch R, Gums JG: Carisoprodol as a drug of abuse.
Arch Fam Med 1993;2:429-432.
16. Elder NC: Abuse of skeletal muscle relaxants. Am Fam Physi-
cian 1991;44:1223-1226.
17. Powers BJ, Cattau EL Jr, Zimmerman HJ: Chlorzoxazone hepa-
totoxic reactions: An analysis of 21 identified or presumed
cases. Arch Intern Med 1986;146:1183-1186.
18. Jackson KC: Low back pain pharmacotherapy. Drugs Today
(Barc) 2004;40:765-772.
19. Flexeril prescribing information. Fort Washington, Pa, McNeil
Consumer & Specialty Pharmaceuticals, April 2003.
20. Borenstein DG, Korn S: Efficacy of a low-dose regimen of
cyclobenzaprine hydrochloride in acute skeletal muscle spasm:
Results of two placebo-controlled trials. Clin Ther 2003;25:
1056-1073.
21. Childers MK, Borenstein D, Brown RL, et al: Low-dose cyclo-
benzaprine versus combination therapy with ibuprofen for
acute neck or back pain with muscle spasm: A randomized
trial. Curr Med Res Opin 2005;21:1485-1493.
22. Keegan MT, Brown DR, Rabinstein AA: Serotonin syndrome
from the interaction of cyclobenzaprine with other serotonin-
ergic drugs. Anesth Analg 2006;103:1466-1468.
23. Moore KA, Levine B, Fowler D: A fatality involving meta-
xalone. Forens Sci Int 2005;149:49-51.
24. Poklis JL, Ropero Miller JD, Garside D, et al: Metaxalone
(Skelaxin)-related death. J Anal Toxicol 2004;28:537-541.
25. Toth PP, Urtis J: Commonly used muscle relaxant therapies
for acute low back pain: A review of carisoprodol, cyclobenza-
prine hydrochloride, and metaxalone. Clin Ther 2004;26:
1355-67.
26. Dent RW, Ervin DK: A study of metaxalone (Skelaxin) vs.
placebo in acute musculoskeletal disorders: A cooperative
study. Curr Ther Res Clin Exp 1975;18:433-440.
27. Tisdale SA, Ervin DK: A controlled study of methocarbamol
(Robaxin) in acute painful musculoskeletal conditions. Curr
Ther Res Clin Exp 1975;17:525-530.
28. Gareri P, De Fazio P, Cotroneo A, et al: Anticholinergic drug-
induced delirium in an elderly Alzheimer’s dementia patient.
Arch Gerontol Geriatr 2007;44(Suppl 1):199-206.
29. Cherkin DC, Wheeler KJ, Barlow W, et al: Medication use for
low back pain in primary care. Spine 1998;23:607-614.
30. Coward DM: Tizanidine: Neuropharmacology and mechanism
of action. Neurology 1994;44(Suppl 9):S6-S10.
31. Smith HS, Barton AE: Tizanidine in the management of spas-
ticity and musculoskeletal complaints in the palliative care
population. Am J Hospice Palliat Care 2000;17:50-58.
ch036-A04184.indd 698
32. Berry H, Hutchinson DR: A multicentre placebo-controlled
study in general practice to evaluate the efficacy and safety of
tizanidine in acute low back pain. J Int Med Res 1988;16:
75-82.
33. Berry H, Hutchinson DR: Tizanidine and ibuprofen in acute
low back pain: Results of a double-blind multicentre study in
general practice. J Int Med Res 1988;16:83-91.
34. Malanga GA, Gwynn MW, Smith R, et al: Tizanidine is effec-
tive in the treatment of myofascial pain syndrome. Pain Physi-
cian 2002;5:422-432.
35. Guyer BM: Mechanism of botulinum toxin in the relief of
chronic pain. Curr Rev Pain 1999;3:427-431.
36. Gobel H, Heinze A, Heinze-Kuhn K, et al: Botulinum toxin A
in the treatment of headache syndromes and pericranial pain
syndromes. Pain 2001;91:195-199.
37. Hallet M: How does botulinum toxin work? Ann Neurol 2000;
48:7-8.
38. Hobson DE, Gladish DF: Botulinum toxin injection for cervi-
cogenic headache. Headache 1997;37:253-255.
39. Freund BJ, Schwartz M: Treatment of chronic cervical-
associated headache with botulinum toxin A: A pilot study.
Headache 2000;40:231-236.
40. Freund B, Schwartz M, Symington J: Botulinum toxin: New
treatment for temporomandibular disorders. Br J Oral Maxil-
lofac Surg 2000;38:466-471.
41. von Lindern JJ, Niederhagen B, Berge S, et al: Type A botuli-
num toxin in the treatment of chronic facial pain after neck
dissection. Head Neck 2004;26:39-45.
42. Nixdorf DR, Heo G, Major PW: Randomized controlled trial
of botulinum toxin A for chronic myogenous orofacial pain.
Pain 2002;99:465-473.
43. Cheshire WP, Abashian SW, Mann JD: Botulinum toxin in the
treatment of myofascial pain syndrome. Pain 1994;59:65-69.
44. Wheeler AH, Goolkasian P, Gretz SS: A randomized, double-
blind, prospective pilot study of botulinum toxin for refrac-
tory, unilateral, cervicothoracic, paraspinal, myofascial pain
syndrome. Spine 1998;23:1662-1666.
45. Porta M: A comparative trial of botulinum toxin type A and
methylprednisolone for the treatment of myofascial pain syn-
drome and pain from chronic muscle spasm. Pain 2000;67:
101-105.
46. Foster L, Clapp L, Erickson M, et al: Botulinum toxin and
chronic low back pain: A randomized, double-blind study.
Neurology 2001;56:1290-1293.
47. van Tulder MW, Koes BW, Bouter LM: Conservative treatment
of acute and chronic nonspecific low back pain: A systematic
review of randomized controlled trials of the most common
interventions. Spine 1997;22:2128-2156.
48. Bigos SJ, Bowyer OR, Braen GR, et al: Clinical Practice Guide-
line No. 14: Acute Low Back Problems in Adults (Publ. No.
95-0642). Rockville, Md, U.S. Department of Health and
Human Services, Agency for Health Care Policy and Research,
1994.
49. Barrata R: A double-blind study of cyclobenzaprine and
placebo in the treatment of acute musculoskeletal conditions
of the low back. Curr Ther Res 1982;32:646-652.
50. Berry H, Hutchinson D: A multicentre placebo-controlled
study in general practice to evaluate the efficacy and safety of
tizanidine in acute low-back pain. J Int Med Res 1988;16:
75-82.
51. Lepisto P: A comparative trial of dS 103-282 and placebo in
the treatment of acute skeletal muscle spasms caused by dis-
orders of the back. Ther Res 1979;26:454-459.
52. Gold R: Orphenadrine citrate: Sedative or muscle relaxant?
Clin Ther 1978;1:451-453.
53. Browning R, Jackson JL, O’Malley PG: Cyclobenzaprine and
back pain: A meta-analysis. Arch Intern Med 2001;161:1613-
1620.
12/5/2007 9:35:52 AM