Criteria for Outpatient Use Guidelines
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Skeletal Muscle Relaxants
[Developed, October 2008; Revised, March 2011]
Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].
1.* Dosage
Adults
The skeletal muscle relaxants (SMRs), carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol, metaxalone, and orphenadrine, are FDA-approved for short-term use to manage discomfort associated with acute, painful musculoskeletal conditions such as strains, sprains, and other muscle injuries. These gents should be used as an adjunct to non-pharmacologic treatments, including rest and physical herapy. The SMRs, baclofen, dantrolene, and tizanidine, are FDA-approved for managing spasticity due to upper motor neuron disorders (e.g., spinal cord injury, cerebral palsy, multiple sclerosis, stroke). Maximum recommended dosages for SMRs are summarized in Table 1. Dosages exceeding these recommendations will be reviewed.
| DRUG | MAXIMUM RECOMMENDED DOSE |
|---|---|
| Muscle Spasm: Monotherapy - carisoprodol tablet (Soma®, generic) | 1400 mg/day, in divided doses |
| Muscle Spasm: Monotherapy - chlorzoxazone (Parafon Forte®, generic) | 3000 mg/day, in divided doses |
| Muscle Spasm: Monotherapy - cyclobenzaprine tablet (Flexeril®, Fexmid®, generic) | 30 mg/day, in divided doses |
| Muscle Spasm: Monotherapy - cyclobenzaprine capsule, extended-release (Amrix®) | 30 mg/day |
| Muscle Spasm: Monotherapy - metaxalone (Skelaxin®) | 3200 mg/day, in divided doses |
| Muscle Spasm: Monotherapy - methocarbamol tablet (Robaxin®, generic) | 8 g/day, in divided doses |
| Muscle Spasm: Monotherapy - orphenadrine (generic) | 200 mg/day, in divided doses |
| Spasticity: Monotherapy - baclofen (Kemstro®, generic) | 80 mg/day |
| Spasticity: Monotherapy - dantrolene (Dantrium®, generic) | 400 mg/day |
| Spasticity: Monotherapy - tizanidine (Zanaflex®, generic) | 36 mg/day |
| Moderate Pain*: Combination therapy: carisoprodol/ASA/codeine (generic) | 400 mg/650 mg/32 mg (2 tablets) four times daily |
| Moderate Pain*: Combination therapy: carisoprodol/ASA [carisoprodol compound] (generic) | 400 mg/650 mg (2 tablets) four times daily |
| Moderate Pain*: Combination therapy: orphenadrine/ASA/caffeine [orphenadrine compound] (generic) | 50 mg/770 mg/60 mg (2 tablets) four times daily |
| Moderate Pain*: Combination therapy: orphenadrine/ASA/caffeine-DS [orphenadrine compound- DS] (generic) | 50 mg/770 mg/60 mg (1 tablet) four times daily |
*associated with musculoskeletal conditions, muscle spasm
Dosing in Kidney and Liver Disease
Carisoprodol dosing adjustments should be considered for patients with severe hepatic insufficiency, as carisoprodol is extensively metabolized by the liver. Carisoprodol is also renally eliminated and should be dosed cautiously in patients with severe renal impairment
Chlorzoxazone should be administered cautiously, if at all, in patients with a history of hepatic disease as hepatotoxicity has been reported with chlorzoxazone use. Chlorzoxazone should not be prescribed to patients with active hepatic disease, including hepatitis.
Cyclobenzaprine is extensively metabolized by liver and is not recommended for use in patients with moderate to severe hepatic impairment. Cyclobenzaprine dosage adjustments are necessary in patients with mild hepatic impairment.
Administer baclofen cautiously in patients with renal impairment as the drug is primarily renally excreted.
Orphenadrine should be administered cautiously to patients with renal and hepatic disease, as the drug is extensively metabolized in the liver, with metabolites and unchanged drug eliminated by the kidneys.
Dosage adjustments for methocarbamol may be necessary for patients with hepatic impairment, as the drug is extensively metabolized in the liver.
Metaxalone is contraindicated for use in patients with significantly impaired renal and/or hepatic function.
Dantrolene should not be prescribed to patients with hepatic disease due to risk of hepatic injury associated with this drug.
Tizanidine is extensively metabolized by the liver and eliminated by the kidneys; therefore, tizanidine should be prescribed cautiously to patients with hepatic and renal impairment.
Pediatrics
With the exception of dantrolene, skeletal muscle relaxants are not FDA-approved for use in children. Safety and efficacy of cyclobenzaprine extended-release capsules (Amrix®) have not been evaluated in pediatric patients, including adolescents. Select skeletal muscle relaxants are FDA-approved for use in adolescents. Recommended pediatric dosages and age limitations for skeletal muscle relaxants are summarized in Table 2.
| DRUG | MAXIMUM RECOMMENDED DOSE |
|---|---|
| Muscle Spasm: carisoprodol | > 16 years of age: 1400 mg/day, in divided doses |
| Muscle Spasm: cyclobenzaprine tablets | > 15 years of age: 30 mg/day, in divided doses |
| Muscle Spasm: methocarbamol | > 16 years of age: 8 g/day |
| Muscle Spasm: metaxalone | >12 years of age: 3200 mg/day, in divided doses |
| Spasticity: baclofen | > 12 years of age: 80 mg/day, in divided doses |
| Spasticity:dantrolene | > 5 years of age: 400 mg/day, in divided doses |
2. Duration of Therapy
For muscle spasm, centrally acting skeletal muscle relaxants have been evaluated for short-term use in managing acute pain associated with musculoskeletal conditions. Therefore, with the exception of carisoprodol and cyclobenzaprine, patient profiles documenting prolonged skeletal muscle relaxant use for greater than three months will be reviewed.
Cyclobenzaprine therapy for muscle spasm should not last longer than three weeks as efficacy beyond this time period has not been demonstrated.
Limited information exists regarding carisoprodol therapy duration for muscle spasm. As carisoprodol has been evaluated only for use in the treatment of acute painful musculoskeletal conditions, patient profiles documenting prolonged carisoprodol or carisoprodol combination therapy use (greater than 21 days) will be reviewed. Cases of psychological dependence have been reported following carisoprodol administration. Therefore, carisoprodol should be administered cautiously, if at all, to patients with a history of drug or alcohol abuse and/or dependence.
There is no basis for limiting therapy duration for skeletal muscle relaxants prescribed for spasticity (e.g., baclofen, dantrolene, tizanidine) as spasticity due to upper motor neuron disorders (e.g., spinal cord injury, cerebral palsy, multiple sclerosis, stroke) is a chronic disorder.
3. Duplicative Therapy
Concurrent administration of two or more skeletal muscle relaxants is not justified as additional therapeutic benefit is not realized and patients may be subjected to enhanced pharmacologic and/or adverse effects. Adjunctive prescriptions for two or more skeletal muscle relaxants will be reviewed.
4. * Drug-Drug Interactions
Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions.
Drug-drug interactions considered clinically significant for skeletal muscle relaxants are summarized in Table 3. Only those drug-drug interactions identified as major severity or those considered life-threatening which have not been classified will be reviewed:
| TARGET DRUG | INTERACTING DRUG | INTERACTION | RECOMMENDATION | CLINICAL SIGNIFICANCE*+ |
|---|---|---|---|---|
| cyclobenzaprine | monoamine oxidase inhibitors (MAOIs) | combined administration may increase risk of hypertensive crises, convulsions, and death; mechanism not determined but may be due to additive norepinephrine effects or serotonin syndrome |
combined use contraindicated; do not use cyclobenzaprine within 14 days of MAOI discontinuation | contraindicated (DrugReax) 1-severe (CP) 1 (DIF) |
| cyclobenzaprine | QT interval-prolonging medications | cyclobenzaprine is structurally related to tricyclic antidepressants (TCAs), which have been associated with QT interval prolongation; combined administration of cyclobenzaprine with QT interval-prolonging medications may increase risk of QT interval prolongation |
administer combination cautiously and monitor for QT interval prolongation | moderate (DrugReax) 1-severe (CP) |
| cyclobenzaprine | selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors |
combined administration may increase risk of serotonin syndrome(e.g., tremor, fever, agitation, seizures, coma) due to additive serotonergic effects |
administer drug combination cautiously and monitor closely for signs/symptoms of serotonin syndrome | major (DrugReax) 2-major (CP) 4 (DIF) |
| cyclobenzaprine | tramadol | combined administration may increase seizure risk as cyclobenzaprine is structurally related to TCAs and TCAs may decrease seizure threshold |
avoid combination, if possible, especially in patients predisposed to seizures; if combination necessary, monitor closely for seizure activity | major (DrugReax) 3-moderate (CP) |
| orphenadrine | phenothiazines | combined administration may result in decreased phenothiazine serum levels/decreased phenothiazine effectiveness due to orphenadrine anticholinergic effects, which delay phenothiazine gastric emptying and absorption; combined therapy may also produce additive anticholinergic effects |
avoid combination, if possible; if combined therapy necessary, adjust phenothiazine doses to effect | moderate (DrugReax) 3-moderate (CP) 2 (DIF) |
| skeletal muscle relaxants | central nervous system (CNS) depressants | increased risk of additive CNS depressant effects (e.g., sedation, dizziness, respiratory depression) |
administer combined therapy cautiously; adjust doses as necessary | major (DrugReax) 3-moderate (CP) |
| tizanidine | potent CYP1A2 inhibitors (e.g., ciprofloxacin, fluvoxamine) | tizanidine is primarily metabolized by CYP1A2; adjunctive administration may result in increased tizanidine levels and enhanced pharmacologic/adverse effects (e.g., hypotension, excessive sedation) due to substantial inhibition of CYP1A2 by potent inhibitors |
combined use contraindicated | contraindicated (DrugReax) 1-severe (CP) 1 (DIF) |
| tizanidine | other CYP1A2 inhibitors (e.g., acyclovir, verapamil) | tizanidine is primarily metabolized by CYP1A2; adjunctive administration may result in increased tizanidine levels and enhanced pharmacologic/adverse effects (e.g., hypotension, excessive sedation) due to substantial inhibition of CYP1A2 by CYP1A2 inhibitors |
avoid combination, if possible; if adjunctive therapy necessary, administer cautiously and observe for increased adverse effects | major (DrugReax) 2-major (CP) |
References
- DRUGDEX® System (electronic version). Thomson Reuters (Healthcare) Inc., Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com.libproxy.uthscsa.edu. Accessed March 11th, 2011.
- Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2011. Available at: http://www.clinicalpharmacology.com. Accessed March 11th, 2011.
- Drug Facts and Comparisons. Clin-eguide [database online]. St. Louis, MO: Wolters Kluwer Health, Inc; 2011. Available at: http://clineguide.com. Accessed March 11th, 2011.
- Chlorzoxazone tablets package insert. Watson Pharma, Inc., November 2010.
- Methocarbamol (Robaxin®, Robaxin®-750) package insert. Schwarz Pharma, LLC, September 2009.
- Drug interaction facts. Clin-eguide [database online]. St. Louis, MO: Wolters Kluwer Health, Inc; 2011. Available at: http://clineguide.com. Accessed March 7th, 2011.
- DRUG-REAX® System (electronic version). Thomson Reuters (Healthcare) Inc., Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com.libproxy.uthscsa.edu. Accessed March11th, 2011.
- Reeves RR. Beddingfield JJ. Mack JE. Carisoprodol withdrawal syndrome. Pharmacotherapy. 2004; 24:1804-6.
- Toth PP, Urtis J. Commonly used muscle relaxant therapies for acute low back pain: a review of carisoprodol, cyclobenzaprine hydrochloride, and metaxalone. Clin Ther. 2004; 26:1355-67.
- Beebe FA, Barkin RL, Barkin S. A clinical and pharmacologic review of skeletal muscle relaxants for musculoskeletal conditions. Am J Ther. 2005;12:151-71.
- Chou R, Qaseem A, Snow V, et al, for the Clinical Efficacy Assessment Subcommittee of the American College of Physicians and the American College of Physicians/American Pain Society Low Back Pain Guidelines Panel. Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society. Ann Intern Med. 2007;147:478-91.
- van Tulder MW, Touray T, Furlan AD, et al. Muscle relaxants for non-specific low-back pain. Cochrane Database Syst Rev.2003, Issue 4. Art. No.: CD004252. DOI: 10.1002/14651858.CD004252.
- American Society of Anesthesiologists Task Force on Chronic Pain Management, American Society of Regional Anesthesia and Pain Medicine. Practice guidelines for chronic pain management: an updated report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology. 2010;112(4):810-33.
- See S, Ginzburg R. Skeletal muscle relaxants. Pharmacotherapy. 2008;28(2):207-13.
Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.