Introduction
Flexeril (cyclobenzaprine hydrochloride) is a centrally-acting skeletal muscle relaxant marketed by Merck & Co. It is FDA-approved as an adjunct to rest and physical therapy for the short-term management of acute, painful musculoskeletal conditions. Unlike other muscle relaxants, cyclobenzaprine is structurally related to tricyclic antidepressants and shares some of their pharmacological properties.
Mechanism of Action
Cyclobenzaprine primarily acts at the brainstem level by reducing tonic somatic motor activity. While its exact mechanism remains incompletely understood, it appears to work through central nervous system depression rather than direct peripheral action on muscles. The drug likely inhibits polysynaptic reflexes in the spinal cord without significantly affecting monosynaptic reflexes. Its structural similarity to tricyclic antidepressants suggests it may also affect norepinephrine and serotonin reuptake, though this is not its primary therapeutic mechanism for muscle relaxation.
Indications
FDA-approved for short-term (up to 2-3 weeks) management of acute, painful musculoskeletal conditions as an adjunct to rest and physical therapy. Common indications include:
- Muscle spasms associated with acute musculoskeletal conditions
- Back pain with muscle spasm
- Post-traumatic and post-surgical muscle spasm
Dosage and Administration
Adults: 5 mg three times daily. May increase to 7.5 mg or 10 mg three times daily based on response and tolerance Maximum dose: 30 mg daily in divided doses Duration: Generally not to exceed 2-3 weeks Special populations:- Geriatric patients: Use lower doses (5 mg) due to increased sensitivity
- Hepatic impairment: Use contraindicated in patients with hepatic impairment
- Renal impairment: Use with caution; consider dose reduction
- Pediatric patients: Safety and effectiveness not established
Pharmacokinetics
Absorption: Well absorbed orally; bioavailability approximately 55% Distribution: Extensive tissue binding; volume of distribution approximately 7 L/kg Protein binding: 93% Metabolism: Extensive hepatic metabolism via CYP3A4, CYP1A2, and CYP2D6 to inactive metabolites Elimination: Primarily renal excretion (64%) with some fecal elimination (16%) Half-life: 18 hours (range 8-37 hours)Contraindications
- Hypersensitivity to cyclobenzaprine or any component of the formulation
- Concomitant use of monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI therapy
- Hyperthyroidism
- Recent myocardial infarction
- Cardiac arrhythmias, including heart block
- Congestive heart failure
Warnings and Precautions
Boxed Warning: None Important precautions:- May impair mental or physical abilities required for hazardous tasks
- Use with caution in patients with urinary retention, angle-closure glaucoma, increased intraocular pressure
- Anticholinergic effects may be problematic in elderly patients
- Risk of serotonin syndrome when used with other serotonergic drugs
- Not recommended during acute recovery phase of myocardial infarction
- Use with caution in patients with history of seizures
Drug Interactions
Major interactions:- MAO inhibitors: Risk of hypertensive crisis, hyperpyrexia, seizures
- Other CNS depressants (alcohol, benzodiazepines, opioids): Additive CNS depression
- Tramadol: Increased seizure risk
- Serotonergic drugs (SSRIs, SNRIs, triptans): Increased risk of serotonin syndrome
- Anticholinergic drugs: Additive anticholinergic effects
- CYP3A4 inhibitors (ketoconazole, clarithromycin): Increased cyclobenzaprine levels
Adverse Effects
Common (≥1%):- Drowsiness (29-39%)
- Dry mouth (21-27%)
- Dizziness (11%)
- Fatigue (6%)
- Constipation (5%)
- Nausea (3%)
- Dyspepsia (3%)
- Serotonin syndrome
- Seizures
- Tachycardia
- Arrhythmias
- Hepatitis
- Anaphylaxis
- Neuroleptic malignant syndrome (rare)
Monitoring Parameters
- Therapeutic response and pain control
- Sedation and CNS effects
- Anticholinergic effects (dry mouth, constipation, urinary retention)
- Signs of serotonin syndrome (agitation, hyperthermia, autonomic instability)
- Hepatic function (with prolonged use)
- Fall risk in elderly patients
Patient Education
- Take only as prescribed for short-term use (2-3 weeks maximum)
- Avoid alcohol and other CNS depressants
- May cause drowsiness - avoid driving or operating machinery
- Rise slowly from sitting/lying position to prevent dizziness
- Maintain adequate hydration to manage dry mouth
- Report any signs of allergic reaction, chest pain, rapid heartbeat, or severe dizziness
- Do not stop abruptly if taking for more than few weeks
- Inform all healthcare providers about Flexeril use
References
1. FDA Prescribing Information: Flexeril (cyclobenzaprine HCl) 2. Toth PP, Urtis J. Commonly used muscle relaxant therapies for acute low back pain: a review of carisoprodol, cyclobenzaprine, and metaxalone. Clin Ther. 2004;26(9):1355-1367. 3. Browning R, Jackson JL, O'Malley PG. Cyclobenzaprine and back pain: a meta-analysis. Arch Intern Med. 2001;161(13):1613-1620. 4. Chou R, Peterson K, Helfand M. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions. J Pain Symptom Manage. 2004;28(2):140-175. 5. Micromedex Solutions: Cyclobenzaprine Drug Monograph 6. Lexicomp Online: Cyclobenzaprine Drug Information 7. American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694.