Jeffrey Fudin
Jeffrey Fudin
Dr. Jeff Fudin graduated from Albany College of Pharmacy & Health Sciences with a bachelor's degree and PharmD. He is a Diplomate to the American Academy of Pain Management, a Fellow to ACCP, a Fellow to ASHP, and a member of several other professional organizations. He is founder and CEO of Remitigate, LLC (remitigate.com), a software platform for interpreting urine drug screens (Urintel) and pharmacogenetics(Phenotel). Dr. Fudin is a section editor for Pain Medicine and serves on the editorial board for Practical Pain Management. He is founder/chairman of Professionals for Rational Opioid Monitoring & Pharmacotherapy (PROMPT), an advocacy group in favor of safe opioid prescribing. He practices as a clinical pharmacy specialist (WOC) and director of PGY-2 pharmacy pain residency programs at the Stratton Veterans Administration Medical Center in Albany, New York. He is an adjunct associate professor of pharmacy practice at Western New England University College of Pharmacy and Albany C

Reassessing Routine Refills for Cyclobenzaprine

JUNE 28, 2016
Pharmacists in all health care settings commonly see what seems like lifelong refills for cyclobenzaprine for musculoskeletal conditions.

Cyclobenzaprine is recommended along with other skeletal muscle relaxants for short-term use in the relief of spasms and pain associated with acute musculoskeletal conditions. Although these agents aren’t recommended for long-term use, approximately 44.5% of patients who receive them remain on them for more than a year.1
 
The manufacturer doesn’t recommend use of cyclobenzaprine beyond 2 to 3 weeks due to lack of data on efficacy with prolonged use.Nevertheless, we tend to see cyclobenzaprine prescribed to patients with multiple refills. Worse yet, the prescriptions are generally refilled and renewed without question. Plus, combining cyclobenzaprine with opioids isn’t a pretty picture, considering the sedation associated with this drug class.

Efficacy, safety, and cost are the cornerstones of pharmacotherapy and important factors to consider when evaluating medication use and contemplating best therapeutic options. These factors must be considered at therapy initiation and reassessment should be ongoing throughout the course of treatment. 

If a medication isn’t effective and is causing side effects, it’s common sense to recommend against its use. If a medication is effective but poses safety concerns, then clinical judgment comes into play to weigh risks and benefits when deliberating chronic use.   

Cyclobenzaprine’s main role is for adjunct treatment for short-term use in acute musculoskeletal conditions, and evidence on benefit with long-term use is sorely lacking. Non-specific low back pain without identifiable cause is typically acute and resolves within 4 weeks.3 In this case, patients may attribute the prolonged relief beyond to the medication, even though it’s really due to a naturally resolving acute musculoskeletal flare-up.4-7 
 
This phenomenon has been demonstrated in multiple placebo-controlled studies that showed no improvement in pain beyond 4 weeks with cyclobenzaprine compared with placebo. Nevertheless, it’s commonplace for providers to prescribe cyclobenzaprine and for pharmacists to fill the prescription without question.

Cyclobenzaprine has no direct activity on skeletal muscles, and its muscle relaxant effects are thought to be secondary to its sedative effects that may be desirable in some situations to aid with sleep.However, the drug’s half-life is 18 hours in patients with normal hepatic function, which, like its antidepressant cousins, often leads to a hangover effect. Cyclobenzaprine undergoes extensive hepatic metabolism through CYP1A2, CYP3A4, and CYP2D6, which is a setup for drug interactions and also additional accumulation in the elderly.

Cyclobenzaprine is structurally similar to amitriptyline, differing only by 1 bond in the central ring. Since cyclobenzaprine is a tricyclic, however, it shares a similar adverse effect profile to tricyclic antidepressants, including anticholinergic effects (dry mouth, urinary retention, confusion), fatigue, tachycardia, and cardiac conduction disturbances, and it isn’t recommended in patients with arrhythmias or cardiac conduction abnormalities.3 
 
Cyclobenzaprine and other skeletal muscle relaxants are listed on the Beers Criteria due to central nervous system (CNS) depression. Furthermore, when used in patients receiving opioid therapy, cyclobenzaprine and other CNS depressants potentiate the risk for opioid-induced respiratory depression.Therefore, it’s important to counsel patients on opioids who present a prescription for cyclobenzaprine, or better yet, call the prescriber and share your knowledge.   

It’s important to note that not all skeletal muscle relaxants are created equal. For instance, methocarbamol and metaxalone are associated with less sedation compared with other members of this therapeutic class, whereas cyclobenzaprine and orphenadrine are associated with higher sedation risk.4,9 Physiological changes in elderly patients and altered renal and hepatic function also play a role in exposure to such agents.
 
Metaxalone undergoes extensive hepatic metabolism, yielding active metabolites that are renally cleared, and it’s therefore contraindicated in patients with renal or hepatic impairment.10 Since cyclobenzaprine undergoes extensive hepatic metabolism, its half-life may be prolonged from 18 hours to 222 hours in patients with hepatic impairment.4

Pharmacists are well-positioned to play a major role to mitigate risks and improve safety. We have the opportunity to educate prescribers and patients on the role of skeletal muscle relaxants and expectations regarding duration of use.
 
When patients request refills, it’s important to follow up on the safety and efficacy of the medication to determine if continued use is warranted. Patients on opioids should be informed about the increased potential for respiratory depression with skeletal muscle relaxants and reminded not to add other sedating agents, like OTC cough and cold products containing diphenydramine, antivertigo agents like dimenhydrinate, alcohol, or any number of prescription medications.

This article was collaboratively written with Mena Raouf, PhamD. Dr. Raouf received his PharmD from Albany College of Pharmacy and Health Sciences, with a concentration in nephrology. He is currently pursuing a PGY-1 pharmacy practice residency at the VA Tennessee Valley Healthcare System.

References
1. Dillon C, Paulose-Ram R, Hirsch R, Gu Q. Skeletal muscle relaxant use in the United States: Data from the third National Health and Nutrition Examination Survey (NHANES III). Spine. 2004;29(8):892-896.
2. Amrix (cyclobenzaprine hydrochloride) capsule, extended release [package insert]. North Wales, PA: Teva Pharmaceuticals USA, Inc.; 2013 Jun.
3. Carragee EJ. Clinical practice. Persistent low back pain. N Engl J Med. 2005 May 5;352(18):1891-1898.
4. Beebe FA, Barkin RL, Barkin S. A clinical and pharmacologic review of skeletal muscle relaxants for musculoskeletal conditions: review. Am J Ther. 2005;12(2):151-171.
5. Chou R, Peterson K. Drug class review on skeletal muscle relaxants. ncbi.nlm.nih​.gov/pubmedhealth/PMH0005346/pdf/TOC​.pdf. Published May 2005. Accessed January 29, 2015.
6. Van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the Cochrane Collaboration. Spine. 2003 Sep 1;28(17):1978-1992.
7. Browning R, Jackson JL, O'Malley PG. Cyclobenzaprine and back pain: a meta-analysis. Arch Intern Med. 2001 Jul 9;161(13):1613-1620.
8. Carette S, Bell MJ, Reynolds WJ et al. Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia. A randomized, double-blind clinical trial. Arthritis Rheum. 1994 Jan;37(1):32-40.
9. Preston EJ, Miller CB, Herbertson RK. A double-blind, multicenter trial of methocarbamol (Robaxin) and cyclobenzaprine (Flexeril) in acute musculoskeletal conditions. Today’s Ther Trends. 1984;1(4):1-11.
10. Metaxalone [package insert]. Bristol, Tennessee: King Pharmaceuticals, Inc.; Apr, 2008.


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