mainline pro 12-13-06

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Mainline
Volume 3	December 13, 2006	Number 12
An Exclusive Continuing Education Publication of Acadiana Consultant Pharmacy Service Author, Publisher, Editor-in Chief, Typesetter & Printer, Charles S. Feucht,PD,FASCP PharmD candidate

Medication News & Update

Oral Muscle Relaxants

There are differences between muscle relaxants currently available on the market. Use of these products in any geriatric patient should always be with extreme caution for obvious reasons which can increase the risk of falls. Some of these agents are intended for use for problems associated with muscle spasticity problems resulting from conditions such as multiple sclerosis or spinal cord injuries not for musculoskeletal problems. These agents include baclofen ((Lioresal®) and tizanidine (Zanaflex®) or dantrolene (Dantrium®). Baclofen has been the mainstay for this type of problem as it is effective and inexpensive. Tizanidine works as effectively as baclofen and does cause less weakness but also causes hypotension. It can reduce blood pressure approximately 20/%. This is a concern in the elderly population and may increase fall risk more than baclofen. Additional concerns seen with tazanidine is to avoid combination with CYP1A2 inhibitors such as fluvoxamin(Luvox ®) and ciprofloxacin. CYP1A2 inhibitors can significantly increase tizanidine levels increasing hypotensive effects. Dantrolene while indicated for spasticity problems should be avoided in geriatric patients because of its serious hepatotoxicity potential and use in younger patients should be reserved as a third line agent.

The other agents such as cyclobenzaprine (Flexeril®) carisoprodol(Soma®) and metaxolone (Skelaxin®) are indicated for musculoskeletal problems. Remember that these agents are sedating and increase risk of falls in the elderly. Additionally, cyclobenzaprine has a higher risk for falls due to its high anticholinergic properties. Likewise due to these properties it will interfere with the minimal beneficial activity of cholinesterase inhibitors. Carisoprodol causes more dizziness than cyclobenzaprine and has higher abuse potential as it is metabolized to meprobamate which should be avoided in geriatric patients. It will enhance and prolong the effects of opiods as well. Meaxolone causes less drowsiness than cyclobenzaprine but requires qid dosing and cost twenty times more. Use of any of these agents should be reserved in the elderly to only short term when absolutely necessary.

Adverse effects common to all muscle relaxants include drowsiness, dizziness, and GI effects. CNS depression additive with other CNS depressants (e.g., opioids). The table below is provided for comparisons courtesy of The Pharmacist Letter and RxPERTUSA.com

-Canadian product information given if differs from U.S.-

Drug	Indication	Mechanism of Action	Dose	Unusual or significant adverse effects or interactions	Approx. Cost 30-day supplya	Comments
baclofen (Lioresal) [Generic available]	Spasticity associated with multiple sclerosis or spinal cord injury2	Inhibits spinal reflexes; structural analog of gamma-aminobutyric acid (GABA)2	• Starting dose: 5 mg three times daily • Titration: increase by 5 mg three times daily every three days2 • Max dose: 20 mg four times daily2	Withdrawal syndrome (e.g., hallucinations, psychosis, seizures)1,2	U.S.: $54.91 (30 mg/day) Canada: $20.80 (30 mg/day)	• Dose cautiously in renal impairment or seizure disorders1 • Intrathecal formulation available
carisoprodol (Soma) [Generic available]	Discomfort due to acute painful musculoskeletal conditions3	Unknown; may work as sedative3	350 mg four times daily3	• Hypomania at higher than recommended doses1 • Withdrawal syndrome1 • Hypersensitivity (skin reaction, hypotension, bronchospasm, angioedema, weakness, dizziness, burning eyes, fever, shock)3 • Idiosyncratic reaction: weakness, visual or motor disturbances, confusion, euphoria3 • Allergic or idiosyncratic reactions occur within first four doses.3	U.S.: $71.53 (1400 mg/day)	• Abuse potential1 • Metabolized to meprobamate (e.g., Equanil)1 • Used to enhance opiate or tramadol effects, or lessen cocaine's stimulant effects1 • Dose cautiously in renal or liver impairment1
chlorzoxazone (Parafon Forte) [Generic available]	Discomfort due to acute painful musculoskeletal conditions4	Unknown; may work as sedative4	• Starting dose: 250 mg or 500 mg three or four times daily4,13 • Max dose: 750 mg three or four times daily4	• Rare hepatotoxicity1 • Hypersensitivity (e.g., urticaria, itching, angioedema)1 • Urine discoloration (orange, red, or purple)1	U.S.: $44.53 (1500 mg/day) Canada: $55.10 (1500 mg/day of chlorzoxazone/acetaminophen product)	None
cyclobenzaprine (Flexeril) [Generic available]	• Muscle spasm, pain, tenderness, and movement restriction due to acute musculoskeletal conditions5 • Canada: fibromyalgia; muscle spasm due to acute musculoskele-tal conditions12	Acts in brain stem and spinal cord5	• Starting dose: 5 mg or 10 mg three times daily5,14 • Max dose: 20 mg three times daily5	• Anticholinergic effects • Compared to carisoprodol, dry mouth is more frequent, but dizziness is less frequent14 • Quinidine-like effects on heart (e.g., QT prolongation) • Caution with CYP3A4/1A2, 2D6 inhibitors	U.S.: $92.74 (30 mg/day) Canada: $36.26 (30 mg/day)	• Long half-life; caution in elderly1 • Structurally related to amitriptyline • Has the most evidence for efficacy14 • Dose of 5 mg three times daily seems as effective as higher doses, with less side effects14
dantrolene (Dantrium) [Generic available]	• Spasticity due to upper motor neuron disorders (e.g., spinal cord injury, cerebral palsy, multiple sclerosis)6 • Malignant hyperthermia prevention or management6	Interferes with calcium release from the sarcoplasmic reticulum6	For spasticity: • Recommended titration:6 • Week 1: 25 mg daily for a week • Week 2: 25 mg three times daily • Week 3: 50 mg three times daily • Week 4 and thereafter: 100 mg three times daily • Max dose: 100 mg four times daily6	Dose dependent hepatotoxicy6 • most common between 3 and 12 months of therapy • most common in women over 35 • severe, sometimes fatal Diarrhea • dose-dependent • may be severe and require discontinuation	U.S.: $179.34 (300 mg/day) Canada: $67.14 (300 mg/day)	• Contraindicated in hepatic disease6 • Periodic liver function tests recommended6 • IV formulation indicated for malignant hyperthermia management15
diazepam (Valium) [Generic available]	• Reflex spasm due to muscle or joint trauma or inflammation7 • Spasticity due to upper motor neuron disorders (e.g., spinal cord injury, cerebral palsy)7	Neuronal inhibition through GABA receptors1	Usual dose: 2 mg to 10 mg three or four times daily7	None	U.S.: $17.96 (15 mg/day) Canada: $0.55 (15 mg/day)	Abuse potential
metaxalone (Skelaxin)	Relief of acute, painful musculoskeletal conditions.8	Unknown; may work as sedative8	800 mg three or four times daily8	• Relatively low risk of drowsiness or cognitive effects1 • Paradoxical muscle cramps1 • Mild withdrawal syndrome1	U.S.: $276.55 (2400 mg/day)	• Contraindicated in serious liver or renal impairment8 • Periodic liver function testing recommended in patients with liver impairment8 • Costly
methocarbamol (Robaxin) [Generic available]	Discomfort due to acute painful musculoskeletal conditions9	Unknown; may work as a sedative9	• Initial dose: 1500 mg four times daily • Maintenance dose: 1000 mg four times daily	• Urine discoloration (brown, brown-black, green)1 • Less drowsiness than cyclo-benzaprine14	U.S.: $81 (4 g/day) Canada: $105.46 (4 g/day)	IV/IM formulation available
orphenadrine (Norflex) [Generic available]	• Discomfort due to acute painful musculoskele-tal conditions10 • Canada: acute muscle spasm12	Unknown; may work as an analgesic10	100 mg twice daily10	• Anticholinergic (e.g., dry mouth, urinary retention)1 • Rare aplastic anemia1 • Some products contain sulfites13	U.S: $130.37 (200 mg/day) Canada: $29.22 (200 mg/day)	• Relatively costly • Twice daily dosing may be advantageous • Long half-life may be problematic if intolerable side effects occur1 • Structurally similar to diphenhydra-mine (e.g., Benadryl) • IM/IV formulation available
tizanidine (Zanaflex) [Generic available (tablets only)]	Spasticity11	Inhibits motor neurons by stimulating alpha-2 receptors; structurally related to clonidine11	• Initial dose: 4 mg every six to eight hours (max three doses daily)11 • Titration: increase dose by 2 mg or 4 mg as needed/tolerated,11 • Max dose: 36 mg, but limited info on doses greater than 24 mg	• Hypotension (20% decrease in blood pressure)11 • Hepatotoxicity11 (usually reversible, rarely fatal) • Ciprofloxacin and fluvoxamine (Luvox) contraindicated due to increased tizanidine levels11 • Avoid use with other CYP1A2 inhibitors (e.g., cimetidine, oral contraceptives)11 • Withdrawal syndrome: hypertension, tachycardia, hypertonia	U.S.: tablets $263.74 capsules $389.33 (24 mg/day) Canada: tablets $131.10 (24 mg/day)	• Effect is short-lived (3 to 6 hours); reserve for time relief most important • Food affects absorption, and affects tablets and capsules differently11 • Monitor liver function at baseline, 3 months, and 6 months, then periodically or as clinically indicated11 • Avoid in hepatic disease11 • Dose cautiously if creatinine clearance <25 mL/min)11

a. U.S. cost is average wholesale price (AWP). Price is for generic, if available.

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