1

Statewide Pharmacy and Therapeutics Committee Medication Review: Skeletal Muscle Relaxants May 17, 2002
Commonly Used Muscle Relaxants: Generic Drug Name Brand Drug Name

Carisoprodol Soma Chlorphenesin Maloate Chlorzoxazone Paraflex/Parafon Forte DSC Cyclobenzaprine Flexeril Metaxalone Skelaxin Methocarbamol Robaxin Orphenadrine Norflex Associated Drugs used in the Treatment of Muscle Spasm and Spasticity Baclofen Lioresal Dantrolene Dantrium Diazepam Valium Tizanidine Zanaflex Purpose of Review: To review the necessity of the addition of a skeletal muscle relaxant to the State P&T Formulary. The agents currently on the Formulary include baclofen and dantrolene. These agents are not commonly used for the treatment of acute musculoskeletal pain and muscle spasm. The addition of a Formulary agent may aid in choice of prescribing of these agents as there is not an established superiority for one agent over another. Indications: Used as adjuncts to rest, physical therapy, and other measures for relief of discomfort related to acute, painful musculoskeletal conditions. Mechanism of Action/Clinical Pharmacology: The exact mechanism of action of the skeletal muscle relaxants is not known. The centrally acting skeletal muscle relaxants, unlike some of the associated agents, appear to preferentially depress polysynaptic reflexes and may influence monosynaptic reflexes at higher doses. In animal studies, these drugs seem to produce muscle relaxation through the inhibition of interneuronal activity and blocking postsynaptic neurons in the spinal cord and descending reticular formation in the brain. In man, however, the skeletal muscle relaxants do not appear to directly relax skeletal muscle. They may produce their effects through sedation, with resultant depression of neuronal activity. Efficacy and Clinical Trials: Numerous clinical trials have been conducted. Deficiencies in study design have made interpretations and comparisons across agents difficult. However, most studies have shown the skeletal muscle relaxants to be more effective than placebo in the treatment of acute painful musculoskeletal disorders and muscle spasm, while efficacy was less consistent when treating chronic disorders. When 1

2 used as monotherapy, the skeletal muscle relaxants were not consistently superior to simple analgesics in relieving pain. When the skeletal muscle relaxants were used in combination with analgesics, pain relief was superior to either agent used alone. Studies have suggested that these drugs are effective, have tolerable side effects, and can be an adjunct in the treatment of painful musculoskeletal conditions with associated muscle spasm. No studies have documented superior efficacy of one skeletal muscle relaxant over another. Dosage and Administration: Agents are primarily dosed orally when used for acute musculoskeletal conditions. Although some parenteral formulations are available, frequent usages of these are not anticipated within our hospital system. See table for dosing recommendations for individual agents. Pharmacokinetics: See table Adverse Effects: The most commonly reported adverse effect is drowsiness. Patients are cautioned to avoid activities requiring mental alertness while taking these medications. Skeletal muscle relaxants should be used cautiously when combined with other CNS depressants and alcohol. Central nervous system adverse effects include drowsiness, dizziness, blurred vision, confusion, hallucinations, agitation, and headache. Gastrointestinal side effects have been reported. Allergic reactions (skin rash, pruritus, edema, anaphylaxis) have been reported with some agents. The skeletal muscle relaxants are generally not recommended for use in children or in pregnant or lactating women. These agents are hepatically and/or renally excreted, so caution must be used when treating patients with hepatic or renal function. Toxicity is possible upon overdose. Upon abrupt cessation with some agents, withdrawal symptoms may occur. Drug Interactions: See table Cost: Medication Carisoprodol Chlorphenesin Chlorzoxazone Cyclobenzaprine Metaxalone Methocarbamol Orphenadrine Cost/Day of Treatment (Dollars) 1.98-2.64 pricing not available Approx. 0.20-0.60 0.27-0.54 4.62-6.19 0.56-2.28 0.28

Conclusions: The centrally acting skeletal muscle relaxants have been shown to be efficacious in the treatment of painful musculoskeletal disorders. Studies have indicated they may be more effective in combination with analgesics. The skeletal muscle relaxants may potentiate the effects of other CNS depressants.

3 References:
AHFS Drug Information, 2001. Browning, Robert MD; Jackson, Jeffrey L. MD, MPH; O'Malley, Patrick G. MD, MPH. Arch Intern Med, Volume 161(13).July 9, 2001.1613-1620 Drug Facts and Comparisons, 2002. Waldman HJ. Centrally Acting Skeletal Muscle Relaxants and Associated Drugs. Journal of Pain and Symptom Management 1994; 9(7): 434-441.

4 Medication
Carisoprodol

Onset/ Duration
Onset: 30 min Duration: 4-6 hours Onset: 30 min Duration: not reported

Adult Oral Dosage

350 mg TID or QID

Available Forms
350 mg tablets

Precautions/ Comments
Congener of meprobamate, Potential for dependence and withdrawal symptoms. Caution in hepatic/renal impairment. Contraindicated in patients with acute intermittent porphyria Caution in hepatic impairment, contains tartrazine, rare hematologic adverse effects, anaphylactoid reactions and drug fever

Chlorphenesin

Chlorzoxazone

Onset: 1 hour Duration: 34 hours Onset: 1 hour Duration: 12-24 hours

800 mg TID until desired effect, may reduce to 400 mg QID or less Start at 250 mg TID or QID; max 750 mg QID 10 mg TID, do not exceed 60 mg QD, use only for short periods (<3 wk)

400 mg tablets

250 and 500 mg tablets

May produce urine discoloration (orange or purple-red), very rare hypersensitivity, reported cases of hepatotoxicity

Cyclobenzaprine

10 mg tablets

Diazepam

2-10 mg TID or QID; individualize dosage for maximum benefit Onset: 30 min- 1 hour Duration: 46 hours Onset: 1 hour Duration: 45 hours 800 mg TID or QID

2, 5, 10 mg tablets

Metaxalone

400 mg tablets

Similar to tricyclic antidepressants Not effective for spasticity assoc with spinal cord disease or cerebral palsy Contraindicated with MAOIs or within 14 days of MAOI, hyperthyroidism, heart block, arrhythmias, conduction disturbances, recent MI or CHF. Anticholinergic action may exacerbate urinary retention or glaucoma. Not effective for spasticity associated with cerebral palsy or spinal cord disease Adjunct for relief of skeletal muscle spasm due to reflex spasm; spasticity caused by upper motor neuron disorders Muscle relaxant actions occur in two proposed sites, at spinal level resulting in GABA-mediated presynaptic inhibition and at supraspinal sites, probably in brain stem reticular formation Use with caution in patients with hepatic or renal impairment Contraindicated in patients with known tendencies for hemolytic anemia Use injectible form cautiously in patients with seizure disorder

Methocarbamol

Orphenadrine citrate

Duration of action: 4-6 to 12-24 hours

1.5 gram QID for first 48-72 hours, then 1 gram QID; or 750 mg Q4H; or 1.5 gram TID 100 mg BID

500, 750 mg tablets

100 mg tablets

Contraindication in glaucoma, pyloric/duodenal obstruction, stenosing peptic ulcers, prostatic hypertrophy, Caution in cardiac disease, some products may contain sulfite, hypersensitivity, Drug interactions: effect of phenothiazines may be decreased, decreased haloperidol levels may occur, increased antichol effects may be seen when used with amantadine