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Cyclobenzaprine (Systemic)

Primary: MS200

Commonly used brand name(s): Flexeril.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).


Skeletal muscle relaxant—


Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.


Spasm, skeletal muscle (treatment)—Cyclobenzaprine is indicated as an adjunct to other measures, such as rest and physical therapy, for the relief of muscle spasm associated with acute, painful musculoskeletal conditions {03} {04} {11}. It is not effective in relieving muscle spasm or spasticity caused by central nervous system (CNS) disorders {03} {04} {11}.

[Fibromyalgia syndrome]1—Cyclobenzaprine is indicated in the treatment of fibromyalgia syndrome (fibrositis, fibrositis syndrome) {05} {13} {14} {15}. It has been shown to decrease pain, reduce muscle tightness and the number of tender points, and improve sleep in patients with this condition {05} {13} {14} {15}.

1 Not included in Canadian product labeling.


Physicochemical characteristics:
Molecular weight—
    311.86 {06}

    8.47 (25 °C) {03} {11}

Mechanism of action/Effect:

The precise mechanism of action has not been fully determined. Cyclobenzaprine acts primarily at the brain stem to reduce tonic somatic motor activity influencing both gamma and alpha motoneurons {03} {11}. Actions at spinal cord sites may also be involved {03} {05} {11}.

Other actions/effects:

Cyclobenzaprine is structurally related to, and may have actions similar to, the tricyclic antidepressants {03} {11}. These possible effects include central and peripheral anticholinergic actions, a sedative effect, and an increase in heart rate {03} {11}.


Well (but slowly) {05} absorbed following oral administration {03} {05} {11}.

Protein binding:

Very high (93%), with plasma concentrations ranging from 0.1 to 1 mcg per mL (0.32 to 3.21 micromoles per L) {05}.


Gastrointestinal and hepatic {04}.


1 to 3 days {03} {04} {05} {11}.

Onset of action:

Within 1 hour.

Time to peak concentration:

3 to 8 hours.

Peak serum concentration

15 to 25 nanograms per mL (0.048 to 0.08 micromoles per L) following a single 10-mg oral dose; subject to large interpatient variation {16}.

Therapeutic plasma concentration

20 to 30 nanograms per mL (0.064 to 0.096 micromoles per L).

Time to peak effect

1 to 2 weeks.

Duration of action:

Single dose—12 to 24 hours.

    Renal, primarily as conjugated metabolites {03} {04} {05} {11} (< 1% of a dose is excreted unchanged) {05}; 51% of a single 10-mg dose is excreted within 5 days {04} {05}. Cyclobenzaprine undergoes enterohepatic circulation {05}. Some unchanged cyclobenzaprine is also eliminated via the bile and feces {04} {05}.

Precautions to Consider


Cyclobenzaprine did not show evidence of carcinogenicity in an 81-week study in mice or a 105-week study in rats {03} {11}.


No evidence of mutagenicity occurred in male mice receiving up to 20 times the human dose of cyclobenzaprine {03} {11}.

No evidence of impaired fertility occurred in male or female rats receiving up to 10 times the human dose of cyclobenzaprine {03} {11}.

Adequate and well-controlled studies in humans have not been done {11}.

Studies in rats, mice, and rabbits have not shown that cyclobenzaprine has adverse effects in the fetus when given in doses up to 20 times the human dose {11}.

FDA Pregnancy Category B {03} {11}.


Problems in humans have not been documented. It is not known whether cyclobenzaprine is distributed into breast milk; however, it is known that some of the structurally related tricyclic antidepressants are distributed into breast milk {03} {11}.


No information is available on the relationship of age to the effects of cyclobenzaprine in pediatric patients {03} {04} {11}. Safety and efficacy have not been established {03} {04} {11}.


No information is available on the relationship of age to the effects of cyclobenzaprine in adolescents up to 15 years of age. Safety and efficacy have not been established {03} {04} {11}.


No information is available on the relationship of age to the effects of cyclobenzaprine in geriatric patients. However, it is known that geriatric patients exhibit increased sensitivity to other medications with anticholinergic activity and are more likely than younger adults to experience adverse reactions to the tricyclic antidepressants, which are structurally related to cyclobenzaprine.


The peripheral anticholinergic effects of cyclobenzaprine may inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort {12}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
In addition to the documented interactions listed below, the possibility should be considered that other interactions applying to tricyclic antidepressants may also apply to cyclobenzaprine because they are all chemically related.

» Alcohol or{11}
» Antidepressants, tricyclic or{03}
» CNS depression–producing medications, other (see Appendix II ){03}{04}{11}    (concurrent use with cyclobenzaprine may result in additive CNS depressant effects; caution is recommended, and dosage of one or both agents should be reduced)

    (concurrent use of a tricyclic antidepressant with cyclobenzaprine may also increase the risk of other side effects, such as anticholinergic effects and increased heart rate)

Antidyskinetics or
Anticholinergics or other medications with anticholinergic activity (see Appendix II ){03}{04}{07}{11}    (cyclobenzaprine may potentiate the anticholinergic actions of these medications; patients should be advised to report occurrence of gastrointestinal problems promptly, since paralytic ileus may occur)

Guanadrel or{03}{04}{11}
Guanethidine{03}{04}    (cyclobenzaprine may decrease or block the antihypertensive effects of these medications)

» Monoamine oxidase (MAO) inhibitors,{03}{04} including furazolidone, procarbazine, and selegiline    (concurrent use with cyclobenzaprine is not recommended on an outpatient basis, as hyperpyretic crises, severe seizures, and death have resulted when MAO inhibitors were used concurrently with tricyclic antidepressants; a minimum of 14 days should elapse between discontinuance of MAO inhibitors and initiation of cyclobenzaprine therapy, unless the patient is hospitalized; a minimum of 5 to 7 days should elapse between discontinuance of cyclobenzaprine and initiation of MAO inhibitor therapy)

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problems exist:
» Acute recovery phase of myocardial infarction or{03}{04}{11}
» Cardiac arrhythmias or{03}{04}{11}
» Congestive heart failure or{03}{04}{11}
» Heart block or other conduction disturbances{03}{04}{11}    (possible adverse cardiovascular effects)

» Hyperthyroidism{03}{04}{11}    (increased risk of cardiac arrhythmias; also, tachycardia associated with hyperthyroidism may be exacerbated {07})

Risk-benefit should be considered when the following medical problems exist
Glaucoma or predisposition to or{03}{04}
Urinary retention or history of{03}{04}    (cyclobenzaprine's anticholinergic effects may be detrimental to patients with these conditions)

Sensitivity to cyclobenzaprine{03}{04}{11}

Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
Anaphylaxis{11} (changes in facial skin color; skin rash, hives, and/or itching; fast or irregular breathing; puffiness or swelling of the eyelids or the area around the eyes; shortness of breath, troubled breathing, tightness in chest, and/or wheezing)
angioedema{11} (large, hive-like swellings on face, eyelids, mouth, lips, and/or tongue)
anticholinergic effect{03}{04}{11} (problems in urinating)
CNS toxicity{03}{04}{11} (abnormal thinking and dreaming; clumsiness or unsteadiness; severe confusion or disorientation; mental depression; ringing or buzzing in ears)
dermatitis, allergic{03}{04}{11} (skin rash, hives, or itching)
hepatitis/cholestasis{03}{04}{11} (yellow eyes or skin)
syncope{03}{04}{11} (fainting)

Note: Mania has also been reported in a few patients with pre-existing psychiatric illness {08}.

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Anticholinergic effects (dryness of mouth [7 to 27%]{11}; blurred vision [<3%]){03}{11}
dizziness or lightheadedness —3 to 11%{03}{11}
drowsiness —16 to 39%{11}

Note: Dizziness, lightheadedness, and drowsiness may be caused by cyclobenzaprine's anticholinergic, as well as its CNS, effects {17}.

Incidence less frequent or rare (< 3%)
CNS effects{03}{11} (headache; confusion; excitement or nervousness; general feeling of discomfort or illness; numbness, tingling, pain, or weakness in hands or feet; muscle twitching; trembling; trouble in sleeping; unusual tiredness)
frequent urination{03}{11}
gastrointestinal irritation{03}{11} (stomach cramps or pain; bloated feeling or gas; diarrhea; indigestion; nausea; vomiting)
pounding heartbeat{03}{11}
problems in speaking{03}{11}
unpleasant taste or other taste changes{03}{11}
unusual muscle weakness{03}{11}

For specific information on the agents used in the management of cyclobenzaprine overdose, see:

Benzodiazepines (Systemic) monograph;

Charcoal, Activated (Oral-Local) monograph;

Neostigmine in Antimyasthenics (Systemic) monograph;

Physostigmine (Systemic) monograph;

Propranolol in Beta-adrenergic Blocking Agents (Systemic) monograph; and/or

Pyridostigmine in Antimyasthenics (Systemic) monograph.

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic
Cardiotoxicity{03} (fast or irregular heartbeat; troubled breathing)—may include bundle branch block or other arrhythmias and congestive heart failure
CNS toxicity (severe confusion{05}{09}{10}; delirium{09}; convulsions{03}; severe drowsiness{03}; hallucinations{03}; severe nervousness or restlessness{03})
dry, hot, flushed skin{05}{10} —a few cases of paradoxical diaphoresis have also been reported{10}
increase or decrease in body temperature{03}
unexplained muscle stiffness

Treatment of overdose
To decrease absorption—Emptying the stomach via induction of emesis, gastric lavage, or activated charcoal {03} {04} {11}.

Monitoring—Taking an electrocardiogram (ECG) and monitoring cardiac function if any signs of dysrhythmia are evident {03} {04} {11}.

Careful monitoring of the patient {03} {04} {11}.

Specific treatment—

Use of physostigmine salicylate for severe or life-threatening anticholinergic effects. Repeating dose as required if life-threatening symptoms (e.g., arrhythmias, convulsions, coma) persist or recur. Because of its toxicity, physostigmine is recommended only in severe cases {03} {04} {11}. See the package insert or Physostigmine (Systemic) monograph for specific dosing guidelines for use of this product.

Use of neostigmine, pyridostigmine, or propranolol for cardiac arrhythmias {03} {04} {11}. See the package insert or Neostigmine or Pyridostigmine in Antimyasthenics (Systemic) monograph or Propranolol in Beta-adrenergic Blocking Agents (Systemic) monograph for specific dosing guidelines for use of this product.

Use of a short-acting digitalis preparation for cardiac failure should be considered. Close monitoring of cardiac function for at least 5 days is recommended {03} {04} {11}. See the package insert or Digitalis Glycosides (Systemic) monograph for specific dosing guidelines for use of this product.

Use of an appropriate anticonvulsant {11} for convulsions. Benzodiazepines are most often used {16}. However, because intravenously administered benzodiazepines may cause respiratory {20} and circulatory {21} depression, especially when administered rapidly {21} {22}, medications and equipment needed for support of respiration and for resuscitation must be immediately available {23}. See the package insert or Benzodiazepines (Systemic) monograph for specific dosing guidelines for use of this product.

Supportive—May include maintaining an open airway, maintaining adequate fluid intake, regulating body temperature, and treating circulatory shock, convulsions, and metabolic acidosis, if necessary {03} {04} {11}. Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation.

Note:  Dialysis is probably of no value in removing cyclobenzaprine from the body {03} {04} {11}.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Cyclobenzaprine (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to cyclobenzaprine
Other medications, especially other CNS depression–producing medications, monoamine oxidase inhibitors, and tricyclic antidepressants
Other medical problems, especially cardiac arrhythmias, congestive heart failure, heart block or other conduction disturbances, hyperthyroidism, and myocardial infarction (acute recovery phase)

Proper use of this medication
Not taking more medication than the amount prescribed, to minimize possibility of side effects

» Proper dosing
Missed dose: Taking if remembered within an hour; not taking if not remembered until later; not doubling doses

» Proper storage

Precautions while using this medication
» Avoiding alcohol or other CNS depressants unless prescribed or otherwise approved by physician

» Caution if blurred vision, drowsiness, or dizziness occurs

Possible dryness of mouth; using sugarless gum or candy, ice, or saliva substitute for relief; checking with physician or dentist if dry mouth continues for more than 2 weeks

Side/adverse effects
Signs and symptoms of potential side effects, especially anaphylaxis, angioedema, anticholinergic effects, CNS toxicity, allergic dermatitis, hepatitis, cholestasis, and syncope

General Dosing Information
It is recommended that cyclobenzaprine therapy for acute, painful musculoskeletal conditions be discontinued after 2 to 3 weeks, because evidence of its effectiveness for longer periods is not available {03} {11}. However, studies of the usefulness of cyclobenzaprine in fibromyalgia syndrome have indicated that the medication remains effective for at least 12 weeks {05} {19}.

Cyclobenzaprine is closely related to the tricyclic antidepressants and shares many of their adverse reactions and drug interactions {03} {11}.

Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.


Usual adult dose
Acute musculoskeletal conditions—Oral, 20 to 40 mg a day in two to four divided doses, usually 10 mg three times a day {03} {04} {11}.

[Fibromyalgia syndrome]1—Oral, 5 {18} {20} to 40 {05} {13} {14} {15} mg at bedtime.

Usual adult prescribing limits
Not to exceed 60 mg daily {03} {04}.

Usual pediatric and adolescent dose
Children up to 15 years of age—Dosage has not been established {03}.

Patients 15 years of age and older—See Usual adult dose .

Strength(s) usually available

10 mg (Rx) [Flexeril{03}][Generic]


10 mg (Rx) [Flexeril{03}]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F). Store in a well-closed container.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.

Revised: 06/03/1999


Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

  1. HOLD
  1. Flexeril (MSD). In: PDR Physicians' desk reference. 52nd ed. Oradell, NJ: Medical Economics Company, 1998; p.1656-7.
  1. Flexeril (Frosst). In: Gillis MC, editor. CPS Compendium of pharmaceuticals and specialties. 33rd ed. Ottawa: Canadian Pharmacists Association, 1998; p. 619.
  1. Katz WA, Dube J. Cyclobenzaprine in the treatment of acute muscle spasm: review of a decade of clinical experience. Clin Ther 1988; 10: 216-28.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1998. p. 201.
  1. Reviewers' consensus on Anticholinergics/antispasmodics Monograph, 1991 revision.
  1. Harsch HH. Mania in two patients following cyclobenzaprine. Psychosomatics 1984 Oct; 25: 791-3.
  1. Linden CH, Mitchiner JC, Lindzon RD, et al. Cyclobenzaprine overdosage. Clin Toxicol 1983; 20: 281-8.
  1. Heckerling PS, Bartow TJ. Paradoxical diaphoresis in cyclobenzaprine poisoning [letters]. Ann Intern Med 1984 Dec; 101: 881.
  1. Cyclobenzaprine Hydrochloride Tablets package insert (Watson—US), Rev 12/91, Rec 4/99.
  1. Standard statement for drugs with significant anticholinergic activity, per Dentistry Practice Advisory Panel.
  1. Bennett RM, Gatter RA, Campbell SM, et al. A double blind study of cyclobenzaprine versus placebo in patients with fibrositis. Arthritis Rheum 1984; 27: S76.
  1. Gatter RA. Pharmacotherapeutics in fibrositis. Am J Med 1986; 81 Suppl 3A: 63-6.
  1. Bennett RM, Gatter RA, Campbell SM, et al. A comparison of cyclobenzaprine and placebo in the management of fibrositis: a double-blind controlled study. Arthritis Rheum 1988 Dec; 31: 1535-42.
  1. Panel comments, Lidocaine and Prilocaine (Topical) monograph revision 6/93.
  1. Panel comment, draft 1991.
  1. Panel comment, draft 1991.
  1. Panel comment, draft 1991.
  1. Ellenhorn MJ, Barceloux DG. Medical toxicology: diagnosis and treatment of human poisoning. New York: Elsevier; 1988. p. 1263-5, 1317-24.
  1. Comment, Lidocaine and Prilocaine (Topical) ballot 6/93.
  1. Comment, Lidocaine and Prilocaine (Topical) ballot 6/93.
  1. Comments, Lidocaine and Prilocaine (Topical) monograph draft 6/93 and ballot 6/93.