Skeletal Muscle Relaxants Classification Essay

Skeletal Muscle Relaxants (Systemic)

This monograph includes information on the following:

1) Carisoprodol
2) Chlorphenesin 
3) Chlorzoxazone 
4) Metaxalone 
5) Methocarbamol
6) Orphenadrine

VA CLASSIFICATION
Carisoprodol
Primary: MS200

Chlorphenesin
Primary: MS200

Chlorzoxazone
Primary: MS200

Metaxalone
Primary: MS200

Methocarbamol
Primary: MS200

Orphenadrine Citrate
Primary: MS200

Orphenadrine Hydrochloride
Primary: AU305


Commonly used brand name(s): Antiflex6; Banflex6; Carbacot5; Disipal6; EZE-DS3; Flexoject6; Maolate2; Mio-Rel6; Myolin6; Myotrol6; Norflex6; Orfro6; Orphenate6; Paraflex3; Parafon Forte DSC3; Relaxazone3; Remular3; Remular-S3; Robaxin5; Robaxin-7505; Skelaxin4; Skelex5; Soma1; Strifon Forte DSC3; Vanadom1.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Skeletal muscle relaxant—Carisoprodol; Chlorphenesin; Chlorzoxazone; Metaxalone; Methocarbamol; Orphenadrine Citrate;

Parkinsonism therapy adjunct—Orphenadrine Hydrochloride;

Indications

Accepted

Spasm, skeletal muscle (treatment)—Skeletal muscle relaxants are indicated as adjuncts to other measures, such as rest and physical therapy, for the relief of muscle spasm associated with acute, painful musculoskeletal conditions. {01}{02}{03}{04}{05}{06}{07}{09}{11}

Parkinsonism (treatment adjunct)—Orphenadrine hydrochloride is indicated (but is rarely used) as an adjunct to physical therapy and other medications in the treatment of postencephalic, arteriosclerotic, or idiopathic parkinsonism. {11} It produces symptomatic relief of tremor. The medication may be used concurrently with reduced dosages of more potent medications in treating patients who cannot tolerate effective doses of the other medications.

Unaccepted
Methocarbamol is also FDA-approved for control of the neuromuscular manifestations of tetanus. {05} However, it has largely been replaced in the treatment of tetanus by diazepam, or, in severe cases, a neuromuscular blocking agent such as pancuronium. Such therapy is used as an adjunct to other measures, such as debridement, tetanus antitoxin, penicillin, tracheotomy, fluid and electrolyte replacement, and supportive treatment. {05}


Pharmacology/Pharmacokinetics

Table 1. Pharmacology/Pharmacokinetics



* One of the metabolites is meprobamate. {13}
 Distributed into breast milk; concentration may reach 2 to 4 times the maternal plasma concentration. {01}{02} Also, may be removed from the circulation via hemodialysis and peritoneal dialysis. {01}{02}{14}
 At least partially metabolized. {14}
§ 85% of a dose excreted within 24 hours as the glucuronide metabolite.
# For the parent compound; half-life of metabolites may range from 2 to 25 hours. {17}

Table 2. Pharmacology/Pharmacokinetics



Drug
Onset of
Action
Time to
Peak Concentration
(hr)
(single dose)
Peak
Serum Concentration
(single dose)
Duration
of Action
(hr)
Carisoprodol
0.5 hr
{17}
4 (350 mg)
{17}
4–7 mcg/mL
{14}
4–6
{01}{02}{13}
Chlorphenesin
 1–3
{17}
3.8–17 mcg/mL (800 mg)
{17}
 
Chlorzoxazone
Within 1 hr
1–2
{03}{13}
10–30 mcg/mL (750 mg)
3–4
{17}
Metaxalone
1 hr
{17}
2 (800 mg)
{17}
295 mcg/mL (800 mg)
{17}
 
Methocarbamol
    
Oral
Within 0.5 hr
{14}
2 (2 grams)
{17}
16 mcg/mL (2 grams)
{14}
 
IV (300 mg/min)
Immediate
{14}
Almost immediate
{14}
19 mcg/mL (1 gram)
{14}
 
Orphenadrine citrate *
    
Oral (extended-release tablets)
Within 1 hr
6 to 8 (100 mg)
60–120 nanograms/mL (100 mg)
12
IM
5 min
0.5 (60 mg)
  
IV
Immediate
Immediate
  
Orphenadrine hydrochloride
Within 1 hr
3 (50 mg)
110–210 nanograms/mL (100 mg)
8
* Relief of muscle spasm.
 In parkinsonism.

Physicochemical characteristics:
Molecular weight—
    Carisoprodol: 260.34 {12}
    Chlorphenesin carbamate: 245.66 {12}
    Chlorzoxazone: 169.57 {12}
    Metaxalone: 221.26 {12}
    Methocarbamol: 241.25 {12}
    Orphenadrine citrate: 461.51 {12}
    Orphenadrine hydrochloride: 305.85

Mechanism of action/Effect:

Skeletal muscle relaxant—Precise mechanism of action has not been determined. {01}{02}{03}{04}{05}{06}{09}{17}{18} These agents act in the central nervous system (CNS) {13}{17}{18} rather than directly on skeletal muscle. {01}{02}{03}{04}{05}{06}{09}{13}{18} Several of these medications have been shown to depress polysynaptic reflexes preferentially. {03}{13}{17}{18} The muscle relaxant effects of most of these agents may be related to their CNS depressant (sedative) effects. {01}{02}{03}{04}{05}{06}{17}{18} Carisoprodol blocks interneuronal activity in the descending reticular formation and in the spinal cord. {01}{02} Chlorzoxazone acts primarily at the spinal cord level and at subcortical areas of the brain. {13} Orphenadrine has analgesic activity, which may contribute to its skeletal muscle relaxant properties. {09}

Parkinsonism therapy adjunct—Orphenadrine has mild anticholinergic actions, which produce its beneficial effect in parkinsonism.


Other actions/effects:

Orphenadrine also has anticholinergic properties. {09}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other carbamate derivatives (for example, carbromal, meprobamate, mebutamate, or tybamate) may be sensitive to carisoprodol also. {01}

Pregnancy/Reproduction

Pregnancy—

Carisoprodol, chlorzoxazone, and methocarbamol

Problems in humans have not been documented.



Chlorphenesin

Studies have not been done in either animals or humans.



Metaxalone

Although studies in humans have not been done, studies in rats have not shown that metaxalone causes adverse effects in the fetus. {04}



Orphenadrine

Problems in humans have not been documented.

Studies in animals have not been done. {09}

Orphenadrine citrate—FDA Pregnancy Category C. {09}


Breast-feeding

Carisoprodol:

Carisoprodol is distributed into breast milk in concentrations that may reach 2 to 4 times the maternal plasma concentrations; {01}{02} use by nursing mothers may cause sedation and gastrointestinal upset in the infant.



Chlorphenesin, chlorzoxazone, metaxalone, methocarbamol, and orphenadrine:

It is not known whether these medications are distributed into breast milk. However, problems in humans have not been documented. {04}{05}{06}{07}{14}


Pediatrics


Carisoprodol:

Although appropriate studies with carisoprodol have not been performed in the pediatric population, {01} the medication has been used in children. {14} Pediatrics-specific problems that would limit the use of carisoprodol in these patients have not been documented.



Chlorphenesin, metaxalone, methocarbamol, and orphenadrine:

No information is available on the relationship of age to the effects of these medications in pediatric patients. Safety and efficacy have not been established. {04}{05}{06}{07}{09}{10}



Chlorzoxazone:

This medication has been used in children. Pediatrics-specific problems that would limit use of chlorzoxazone in these patients have not been documented.



Geriatrics


No information is available on the relationship of age to the effects of skeletal muscle relaxants in geriatric patients. However, elderly males are more likely to have age-related prostatic hypertrophy and may therefore be adversely affected by orphenadrine's anticholinergic activity. Also, elderly patients are more likely to have age-related renal function impairment, which may require that parenteral methocarbamol not be used at all and that other skeletal muscle relaxants be used with caution.


Dental


Orphenadrine:

The peripheral anticholinergic effects of orphenadrine may decrease or inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort.


Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.


For all skeletal muscle relaxants
» Alcohol or
» CNS depression–producing medications, other (See Appendix II )    (concurrent use with a skeletal muscle relaxant may result in additive CNS depressant effects; caution is recommended and dosage of one or both agents should be reduced {01}{02}{03}{05}{06}{07})


For orphenadrine (in addition to the interaction listed above)
Anticholinergics or other medications with anticholinergic action (See Appendix II )    (anticholinergic effects may be intensified when these medications are used concurrently with orphenadrine because of orphenadrine"s secondary anticholinergic activity)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results

For metaxalone:
Copper sulfate urine sugar tests    (false-positive test results may occur, possibly because of the presence of an unknown reducing substance; results of tests using glucose oxidase are not affected {04})


For methocarbamol:
5-Hydroxyindoleacetic acid (5-HIAA), in urine, determinations     (values may be falsely increased when the nitrosonaphthol reagent is used )


Vanillylmandelic acid (VMA), in urine, determinations    (values may be falsely increased when the Gitlow screening method is used; no error occurs when the quantitative procedure of Sunderman is used)

With physiology/laboratory test values

For metaxalone
Cephalin flocculation tests    (elevations may occur without concurrent changes in other liver function tests {04})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Table 3. Medical considerations/Contraindications



The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance).
Legend:
I=Carisoprodol
II=Chlorphenesin
III =Chlorzoxazone


IV=Metaxalone
V =Methocarbamol
VI=Orphenadrine

I
 
II
 
III
 
IV
 
V
 
VI
 
Except under special circumstances, these medications should not be used when the following medical problems exist:
 
      
» Achalasia or
     
» Bladder neck obstruction or
     
» Glaucoma, or predisposition to, or
     
» Myasthenia gravis or
     
» Peptic ulcer, stenosing, or
     
» Prostatic hypertrophy or
     
» Pyloric or duodenal obstruction
     
(anticholinergic actions detrimental in these conditions)
      
» Hemolytic anemia, or history of, especially if drug-induced
(may be induced by metaxalone)
   
  
» Porphyria, acute intermittent, known or suspected

    
 
» Renal function impairment or disease
(for parenteral dosage form only—polyethylene glycol 300 vehicle is nephrotoxic and may cause increased urea retention and acidosis in these patients)
    

 
Risk-benefit should be considered when the following medical problems exist:
 
      
Allergic reaction to the medication considered for use, history of






Allergies or history of
  
   
Cardiac disease or arrhythmias or
     
tachycardia
     
(orphenadrine may cause tachycardia)
      
CNS depression
(may be exacerbated)






Drug abuse or dependence, history of
(psychological dependence and abuse reported rarely)

     
Epilepsy
(for parenteral dosage form only—may increase risk of seizures)
    

 
Hepatic function impairment
(metabolized in liver)


  

» Hepatic function impairment or disease
(metabolized in liver; also, potentially hepatotoxic)
  

  
Renal function impairment
(excreted via kidneys)






» Renal function impairment, severe
(excreted via kidneys)
   
  

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):


For metaxalone
Liver function tests    (recommended periodically during prolonged metaxalone therapy, especially if the patient has pre-existing hepatic function impairment or disease {04})


For methocarbamol
Renal function determinations    (recommended if parenteral therapy lasts 3 days or more because the polyethylene glycol 300 vehicle may be nephrotoxic)


For orphenadrine
Blood count and
Liver function tests and
Renal function tests    (recommended during prolonged therapy since the safety of continuous long-term use has not been established {09}{10})




Side/Adverse Effects

Table 4. Side/Adverse Effects *



The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Legend:
I=Carisoprodol
II=Chlorphenesin
III=Chlorzoxazone


IV=Metaxalone
V=Methocarbamol
VI=Orphenadrine

I
 
II
 
III
 
IV
 
V
 
VI
 
Medical attention needed
 
      
Anticholinergic effects, specifically:
Decreased urination
 





L
Increased intraocular pressure (eye pain)





L
Cardiovascular effects, specifically:
Fast heartbeat —with orphenadrine, anticholinergic activity may contribute to this effect
L
U
U
U
U
L
Pounding heartbeat
 
U
U
U
U
U
L
Slow heartbeat—with parenteral dosage form only




L
U
Thrombophlebitis (local pain, tenderness, heat, redness, swelling at site of affected vein)—with parenteral administration only




R
U
Central nervous system effects, specifically:
Convulsions
 
U
U
U
U
R
U
Fainting—with carisoprodol, may also be caused by orthostatic hypotension
L
U
U
U
R
L
Hallucinations —orphenadrine's anticholinergic activity may contribute to this effect
U
U
U
U
U
R
Mental depression
 
L
U
U
U
U
U
Gastrointestinal bleeding (bloody or black, tarry stools; vomiting of blood or material that looks like coffee grounds)
U
R
R
U
U
U
Hematologic effects, specifically:
Agranulocytosis (fever with or without chills; sores, ulcers, or white spots on lips or in mouth; sore throat)
U
R
R
U
U
U
Anemia (unusual tiredness or weakness)
U
U
R
U
U
U
Anemia, aplastic [pancytopenia] (shortness of breath, troubled breathing, tightness in chest, and/or wheezing; sores, ulcers, or white spots on lips or in mouth; swollen and/or painful glands; unusual bleeding or bruising; unusual tiredness or weakness)
R
U
U
U
U
R
Anemia, hemolytic (troubled breathing, exertional; unusual tiredness or weakness)
U
U
U
R
U
U
Leukopenia (usually asymptomatic; rarely, fever or chills, cough or hoarseness, lower back or side pain, painful or difficult urination)
R
R
U
R
R
U
Thrombocytopenia (usually asymptomatic; rarely, unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)
U
R
U
U
U
U
Hepatotoxicity (yellow eyes or skin)
U
U
R
R
U
U
Hypersensitivity reactions, specifically:
Anaphylactic or anaphylactoid reaction (changes in facial skin color; skin rash, hives, and/or itching; fast or irregular breathing; puffiness or swelling of the eyelids or around the eyes; shortness of breath, troubled breathing, tightness in chest, and/or wheezing)—with carisoprodol, anaphylactic shock with sudden, severe decrease in blood pressure and collapse has also occurred
R
R
R
R
U
U
Angioedema (hive-like swellings, large, on face, eyelids, mouth, lips, and/or tongue)
L
U
R
U
U
U
Bronchospastic allergic reaction (shortness of breath, troubled breathing, tightness in chest, and/or wheezing)
L
U
U
U
U
U
Conjunctivitis and nasal congestion (stuffy nose and red or bloodshot eyes)
U
U
U
U
L
U
Dermatitis, allergic (skin rash, hives, itching, and/or redness)—with carisoprodol, fixed drug eruptions with cross-sensitivity to meprobamate have also been reported; with chlorzoxazone, petechial rashes and ecchymoses have also been reported
L
R
R
R
L
U
Eosinophilia
 
R
U
U
U
U
U
Erythema multiforme (fever with or without chills; muscle cramps or pain; skin rash; sores, ulcers, or white spots on lips or in mouth)
R
U
U
U
U
U
Fever, allergic
 
L
R
U
U
L
U
Stinging or burning of eyes
 
L
U
U
U
U
U
Medical attention needed only if continuing or bothersome
 
      
Anticholinergic effects (dryness of mouth [more frequent], confusion, difficult urination, constipation, unusually large pupils, blurred or double vision, weakness)





L
Central nervous system effects, specifically:
Blurred or double vision or any change in vision —with orphenadrine, anticholinergic activity may also contribute to this effect
R
U
U
U
M
L
Clumsiness or unsteadiness
 
R
U
U
U
U
U
Confusion—with orphenadrine, anticholinergic activity may also contribute to this effect, especially in elderly patients
U
L
U
U
U
L
Dizziness or lightheadedness—with carisoprodol, orthostatic hypotension may also contribute to this effect
L
L
M
M
M
L
Drowsiness
 
M
L
M
M
M
L
Headache
 
L
R
L
M
L
L
Muscle weakness
 
U
R
U
U
L
R
Nystagmus (uncontrolled movements of eyes)
U
U
U
U
L
U
Stimulation, paradoxical (excitement, nervousness, restlessness, irritability, trouble in sleeping)
L
R
L
M
U
L
Trembling
 
L
U
U
U
U
L
Flushing or redness of face
 
L
U
U
U
L
U
Gastrointestinal irritation, specifically:
Abdominal or stomach cramps or pain
 
L
R
L
M
U
L
Constipation—with orphenadrine, anticholinergic activity may contribute to this effect
U
U
L
U
U
L
Diarrhea
 
U
U
L
U
U
U
Heartburn
 
U
U
L
U
U
U
Hiccups
 
L
U
U
U
U
U
Nausea or vomiting
 
L
R
L
M
L
L
Pain or peeling at place of injection
 




L
U
* Differences in frequency of occurrence may reflect either lack of clinical-use data or actual pharmacologic distinctions among agents (although their pharmacologic similarity suggests that side effects occurring with one may occur with the others, except for those caused by anticholinergic activity, which is specific for orphenadrine). M = more frequent; L = less frequent; R = rare; U = unknown.
 A causal association has not been established.
 Usually reported with too-rapid intravenous administration.

Note: Rarely, an idiosyncratic reaction to carisoprodol may occur within minutes or hours following the first dose of the medication. Reported symptoms include agitation, ataxia, confusion, disorientation, dizziness, euphoria, extreme weakness, speech disturbances, temporary loss of vision or other vision disturbances, and transient quadriplegia. Symptoms usually subside within several hours, but in some cases, supportive and symptomatic therapy, including hospitalization, may be necessary. {01}{02}
Psychological dependence and abuse have occurred very rarely with carisoprodol. Signs of abstinence have not been reported with clinical usage; however, in one study abrupt withdrawal of 100 mg per kg of body weight (mg/kg) per day of carisoprodol (5 times the recommended daily dose) produced withdrawal symptoms including abdominal cramps, insomnia, chills, headache, and nausea. {01}{02}




Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Carisoprodol {01}
To decrease absorption—Emptying the stomach via induction of emesis or gastric lavage.

Specific treatment—Administering respiratory assistance, CNS stimulants, and pressor agents cautiously, if necessary.

To enhance elimination—Removing carisoprodol from the body via induction of diuresis, osmotic (mannitol) diuresis, peritoneal dialysis, or hemodialysis.

Monitoring—Monitoring urinary output.

Taking care to prevent overhydration.

Monitoring the patient for relapse due to incomplete gastric emptying and delayed absorption, and administering additional treatment as required.

Supportive care—Administering supportive treatment of observed symptoms.


Chlorphenesin:
To decrease absorption—Emptying the stomach via institution of saline catharsis or gastric lavage.

Supportive care—Administering supportive therapy of observed symptoms.



Chlorzoxazone {03}:
To decrease absorption—Emptying the stomach via induction of emesis or gastric lavage.

Specific treatment—Administering oxygen and artificial respiration for respiratory depression and plasma volume expanders or vasopressors for hypotension.

Supportive care—Administering supportive treatment of observed symptoms.

Note: Cholinergic medications and analeptic medications are of no value in chlorzoxazone overdose and should not be used.




Metaxalone:
Experience with overdose causing major toxicity is extremely limited {04}.

To decrease absorption—Emptying the stomach via induction of emesis or gastric lavage {04}.

Supportive care—Administering supportive treatment of observed symptoms {04}.



Methocarbamol:
To decrease absorption—Emptying the stomach via induction of emesis or gastric lavage (if administered orally).

To enhance elimination—The usefulness of forced diuresis or hemodialysis in treating overdose has not been determined.

Supportive care—Administering supportive treatment of observed symptoms.



Orphenadrine:
To decrease absorption—Emptying the stomach via induction of emesis or gastric lavage (if administered orally).

To enhance elimination—Maintaining a high-volume urinary output.

Institution of hemodialysis or peritoneal dialysis may be of some benefit if the serum concentration exceeds 4 mcg per mL.

Supportive care—Administering intravenous fluids and circulatory support as required. Administering supportive treatment of observed symptoms.


Note: Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.



Patient Consultation

Table 5. Patient Consultation



As an aid to patient consultation, refer to Advice for the Patient, Skeletal Muscle Relaxants (Systemic) or Orphenadrine (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Legend:
I=Carisoprodol
II=Chlorphenesin
III=Chlorzoxazone


IV=Metaxalone
V=Methocarbamol
VI=Orphenadrine

I
 
II
 
III
 
IV
 
V
 
VI
 
Before using this medication
 
      
»Conditions affecting use, especially:
Sensitivity to the muscle relaxant considered for use, history of, and, for carisoprodol, sensitivity to other carbamate derivatives






Breast-feeding—Carisoprodol distributed into breast milk and may cause sedation and gastrointestinal upset in the infant; problems in nursing infants have not been reported with other skeletal muscle relaxants

     
Other medications, especially other CNS depression–producing medications






Other medical problems, especially:
Acute intermittent porphyria (known or suspected)

     
Conditions that may be adversely affected by anticholinergic activity
     
Hemolytic anemia, or history of
   
  
Hepatic function impairment or disease

Skeletal muscle relaxants are a heterogeneous group of medications commonly used to treat two different types of underlying conditions: spasticity from upper motor neuron syndromes and muscular pain or spasms from peripheral musculoskeletal conditions. Although they have by convention been classified into one group, the Food and Drug Administration (FDA) has approved only a few medications in this class for treatment of spasticity; the remainder are approved for treatment of musculoskeletal conditions. Data from the Third National Health and Nutrition Examination (NHANES III) survey (1988–1994) estimated that 1% of American adults are taking muscle relaxants, often on a chronic basis.1

Spasticity, although difficult to define precisely, is a clinical condition that has been described as "a motor disorder characterized by velocity dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyper-excitability of the stretch reflex, as one component of the upper motor neuron syndrome."2 The upper motor neuron syndrome is a complex of signs and symptoms that, in addition to spasticity, can be associated with exaggerated cutaneous reflexes, autonomic hyperreflexia, dystonia, contractures, paresis, lack of dexterity, and fatigability.3 Spasticity from the upper motor neuron syndrome can result from a variety of conditions affecting the cortex or spinal cord. Some of the more common conditions associated with spasticity and requiring treatment include multiple sclerosis,4 spinal cord injury,5 traumatic brain injury, cerebral palsy, and post-stroke syndrome.6 In many patients with these conditions, spasticity can be disabling and painful with a marked effect on functional ability and quality of life.7

Common musculoskeletal conditions causing tenderness and muscle spasms include fibromyalgia,8 tension headaches,9 myofascial pain syndrome, and mechanical low back or neck pain. If muscle spasm is present in these conditions, it is related to local factors involving the affected muscle groups. There is no hypertonicity or hyperreflexia, and the other symptoms associated with the upper motor neuron syndrome are not present. These conditions are commonly encountered in clinical practice and can cause significant disability and pain in some patients. Skeletal muscle relaxants are one of several classes of medications (including antidepressants, neuroleptics, anti-inflammatory agents, and opioids) frequently used to treat these conditions.10–12

Skeletal muscle relaxants have been approved for either treatment of spasticity or for treatment of musculoskeletal conditions. Drugs classified as skeletal muscle relaxants are baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxalone, methocarbamol, orphenadrine, and tizanidine. Only baclofen, dantrolene, and tizanidine are approved for the treatment of spasticity. These three antispasticity medications act by different mechanisms: baclofen blocks pre- and post-synaptic GABAB receptors,13, 14 tizanidine is a centrally acting agonist of α2 receptors,15, 16 and dantrolene directly inhibits muscle contraction by decreasing the release of calcium from skeletal muscle sarcoplasmic reticulum.17 Medications from other classes have also been used to treat spasticity. Diazepam, a benzodiazepine, was the first medication thought to be effective for spasticity. It acts by central blockade of GABAA receptors.18, 19 Other medications used to treat spasticity but not formally approved for this indication include other benzodiazepines, clonidine, gabapentin, and botulinum toxin.17

The skeletal muscle relaxants carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine have been approved for treatment of musculoskeletal disorders, but not for spasticity. They constitute a heterogeneous group of medications. Cyclobenzaprine is closely related to the tricyclic antidepressants,20 carisoprodol is metabolized to meprobamate,21 methocarbamol is structurally related to mephenesin,20 chlorzoxazone is a benzoxazolone derivative,22 and orphenadrine is derived from diphenhydramine.23 The mechanism of action for most of these agents is unclear, but may be related in part to sedative effects. These drugs are often used for treatment of musculoskeletal conditions whether muscle spasm is present or not.12 Although there is some overlap between clinical usage (tizanidine in particular has been studied for use in patients with musculoskeletal complaints),24 in clinical practice each skeletal muscle relaxant is used primarily for either spasticity or for musculoskeletal conditions.

The purpose of this report is to determine whether there is evidence that one or more skeletal muscle relaxant is superior to others in terms of efficacy or safety. This report was originally submitted in February 2003 and updated annually. Update #1 was completed in January 2004 from searches performed in October 2003. Update #2 is based on searches performed in November 2004. New data for Update #2 are highlighted in the text and tables of this report. Since the last update, the Food and Drug Administration (FDA) has not approved any new skeletal muscle relaxants.

Scope and Key Questions

The scope of the review and key questions were originally developed and refined by the Oregon Evidence-based Practice Center with input from a statewide panel of experts (pharmacists, primary care clinicians, pain care specialists, and representatives of the public). Subsequently, the key questions were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project (DERP). The participating organizations of DERP are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to both clinicians and patients. The participating organizations approved the following key questions to guide this review:

  1. What is the comparative efficacy of different muscle relaxants in reducing symptoms and improving functional outcomes in patients with a chronic neurologic condition associated with spasticity, or a chronic or acute musculoskeletal condition with or without muscle spasms?

  2. What are the comparative incidence and nature of adverse effects (including addiction and abuse) of different muscle relaxants in patients with a chronic neurologic condition associated with spasticity, or a chronic or acute musculoskeletal condition with or without muscle spasms?

  3. Are there subpopulations of patients for which one muscle relaxant is more effective or associated with fewer adverse effects?

Several aspects of the key questions deserve comment:

Population

The population included in this review is adult or pediatric patients with spasticity or a musculoskeletal condition. We defined spasticity as muscle spasms associated with an upper motor neuron syndrome. Musculoskeletal conditions were defined as peripheral conditions resulting in muscle or soft tissue pain or spasms. We included patients with nocturnal leg cramps. We excluded obstetric and dialysis patients. We also excluded patients with restless legs syndrome or nocturnal myoclonus.

Drugs

We included the following oral drugs classified as skeletal muscle relaxants: baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, metaxalone, methocarbamol, orphenadrine, and tizanidine. Benzodiazepenes were not considered primary drugs in this report. However, diazepam, clonazepam, and clorazepate were reviewed when they were compared in head-to-head studies with any of the skeletal muscle relaxants listed above. Other medications used for spasticity but considered to be in another drug class, such as gabapentin (a neuroleptic) and clonidine (an antihypertensive), were also only reviewed when they were directly compared to an included skeletal muscle relaxant. Quinine was only included if it was compared to a skeletal muscle relaxant.

The dose of skeletal muscle relaxants used in trials may affect either the efficacy or adverse event profile. One clinical trial25 of cyclobenzaprine, for example, found equivalent efficacy at 10 and 20 mg tid, but increased adverse events with the higher dose. A study on dantrolene also found a `ceiling' effect at doses of 200 mg daily, with no increased efficacy but more side effects above that dose.26 Most trials titrated skeletal muscle relaxants to the maximum tolerated dose or a pre-specified ceiling dose, but there are no standardized methods of titration and determining target doses.

Outcomes

The main efficacy measures were relief of muscle spasms or pain, functional status, quality of life, withdrawal rates, and adverse effects (including sedation, addiction, and abuse). We excluded non-clinical outcomes such as electromyogram measurements or spring tension measurements. There is no single accepted standard on how to measure the included outcomes. Clinical trials of skeletal muscle relaxants have often used different scales to measure important clinical outcomes such as spasticity, pain, or muscle strength.27 Many trials have used unvalidated or poorly described methods of outcome assessment. Studies that use the same scale often report results differently (for example, mean raw scores after treatment, mean improvement from baseline, or number of patients "improved"). All of these factors make comparisons across trials difficult.

Spasticity is an especially difficult outcome to measure objectively. The most widely used standardized scales to measure spasticity in patients with upper motor neuron syndromes are the Ashworth28 and modified Ashworth29 scales. In these scales, the assessor tests the resistance to passive movement around a joint and grades it on a scale of 0 (no increase in tone) to 4 (limb rigid in flexion or extension). The modified Ashworth scale adds a "1+" rating between the 1 and 2 ratings of the Ashworth scale. For both of these scales, the scores are usually added for four lower and four upper limb joints, for a total possible score of 0–32, though scoring methods can vary. Some experts have pointed out that resistance to passive movement may measure tone better than it does spasticity and that the Ashworth scale and other `objective' measures of spasticity may not correlate well with patient symptoms or functional ability.30 Other areas of uncertainty regard the significance of the 1+ rating in the modified Ashworth scale and how a non-continuous ordinal variable should be statistically analyzed.31 An important advantage of the Ashworth scale is that it is a consistent way to measure spasticity or tone across studies, and has been found to have moderate reproducibility.31 Other measures of spasticity include the pendulum test, muscle spasm counts, and patient assessment of spasticity severity on a variety of numerical (e.g., 1–3, 1–4, 0–4) or categorical (e.g., none, mild, moderate, severe) scales. The best technique may be to perform both objective and subjective assessments of spasticity, but validated subjective assessment techniques of spasticity are lacking.

Muscle strength is usually assessed with the time-honored British Medical Research Council Scale, which is based on the observation of resistance provided by voluntary muscle activity and used in everyday clinical practice.16 An assessor grades each muscle or muscle group independently on a scale of 0 (no observed muscle activation) to 5 (full strength). This scale was originally devised to test the strength of polio survivors. Data are not available regarding its reliability and validity in assessing spastic and weak patients.

Most studies measure pain using either visual analogue or categorical pain scales. Visual analogue scales (VAS) consist of a line on a piece of paper labeled 0 at one end, indicating no pain, and a maximum number (commonly 100) at the other, indicating excruciating pain. Patients designate their current pain level on the line. An advantage of VAS is that they provide a continuous range of values for relative severity. A disadvantage is that the meaning of a pain score for any individual patient depends on the patient's subjective experience of pain. This poses a challenge in objectively comparing different patients' scores, or even different scores from the same patient. Categorical pain scales, on the other hand, consist of several pain category options from which a patient must choose (e.g., no pain, mild, moderate, or severe). A disadvantage of categorical scales is that patients must choose between categories that may not accurately describe their pain. The best approach may be to utilize both methods.32 Pain control (improvement in pain) and pain relief (resolution of pain) are also measured using visual analogue and categorical scales.

Studies can evaluate functional status using either disease-specific or non-specific scales. These scales measure how well an individual functions physically, socially, cognitively, and psychologically. Disease-specific scales tend to be more sensitive to changes in status for that particular condition, but non-specific scales allow for some comparisons of functional status between conditions. The most commonly used disease-specific measure of functional and disability status in patients with multiple sclerosis, for example, is the Kurtzke Extended Disability Status Scale (EDSS).33 The EDSS measures both disability and impairment, combining the results of a neurological examination and functional assessments of eight domains into an overall score of 0–10 (in increments of 0.5). The overall score of the EDSS is heavily weighted toward ambulation and the inter-rater reliability has been found to be moderate.33 Disease-specific scales are also available for fibromyalgia,34, 35 low back pain, cerebral palsy, and other musculoskeletal and spastic conditions.

Scales that are not disease-specific include the Medical Outcomes Study Short Form-36 (SF-36), Short Form-12 (SF-12), or another multi-question assessment. Another approach to measuring function is to focus on how well the medication helps resolve problems in daily living that patients with spasticity or musculoskeletal conditions commonly face, such as getting enough sleep or staying focused on the job. Some studies also report effects on mood and the preference for one medication over another.

The following adverse events were specifically reviewed: somnolence or fatigue, dizziness, dry mouth, weakness, abuse, and addiction. We also paid special attention to reports of serious hepatic injury.36 The subcommittee considered these the most common and potentially troubling adverse events in clinical practice. We recorded rates of these adverse events as well as rates of discontinuation of treatment due to a particular adverse effect. In some studies, only "serious" adverse events or adverse events "thought related to treatment medication" are reported. Many studies do not define these terms. We recorded any information about abuse and addiction, and rates of death and hospitalization when available.

Withdrawal rates

Because of inconsistent reporting of outcomes, withdrawal rates may be a more reliable surrogate measure for either clinical efficacy or adverse events in studies of skeletal muscle relaxants. High withdrawal rates probably indicate some combination of poor tolerability and ineffectiveness. An important subset is withdrawal due to any adverse event (those who discontinue specifically because of adverse effects).

Study types

We included controlled clinical trials to evaluate efficacy. The validity of controlled trials depends on how they are designed. Randomized, properly blinded clinical trials are considered the highest level of evidence for assessing efficacy.37–39 Clinical trials that are not randomized or blinded or that have other methodologic flaws are less reliable. These are also discussed in our report with references to specific flaws in study design and data analysis.

Trials comparing one skeletal muscle relaxant to another provided direct evidence of comparative efficacy and adverse event rates. Trials comparing skeletal muscle relaxants to other active medications or placebos provided indirect comparative data.

To evaluate adverse event rates, we included clinical trials and large, high-quality observational cohort studies. Clinical trials are often not designed to assess adverse events, and may select patients at low risk for adverse events (in order to minimize dropout rates) or utilize methodology inadequate for assessing adverse events. Observational studies designed to assess adverse event rates may include broader populations, carry out observations over a longer time, utilize higher quality methodologic techniques for assessing adverse events, or examine larger sample sizes. We did not systematically review case reports and case series in which the proportion of patients suffering an adverse event could not be calculated.

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