VA Class:MS200
Orphenadrine is a centrally acting skeletal muscle relaxant.110, 120, 121, 122, 125
Orphenadrine citrate is used alone or in combination with aspirin and caffeine as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute, painful musculoskeletal disorders.120, 121, 122
Evidence supporting the efficacy of skeletal muscle relaxants is generally low to moderate in quality; while these agents appear to be more effective than placebo in providing short-term relief of acute low back pain, they are associated with a high incidence of adverse effects (e.g., sedation).103, 104, 106, 109, 110, 111, 112 Although comparative studies are limited, available data suggest that various skeletal muscle relaxants generally have similar efficacy for such use.103, 104, 106, 108 Acute low back pain usually is a benign and self-limiting condition that improves spontaneously over time;105, 106, 108 therefore, nonpharmacologic treatment strategies (e.g., heat, massage) are recommended.109 If pharmacologic therapy is required, experts state that a nonsteroidal anti-inflammatory agent (NSAIA) or a skeletal muscle relaxant may be used; however, these drugs have been shown to result in only small improvements in pain relief and can increase the risk of adverse effects.104, 106, 107, 108, 109 In general, skeletal muscle relaxants should be used with caution after weighing the potential risks against the benefits in individual patients.104, 106, 107, 108 Although skeletal muscle relaxants are often used in combination with NSAIAs for the treatment of acute low back pain, randomized controlled studies generally have not demonstrated any additional improvement in pain or functional outcomes with such combination therapy compared with use of an NSAIA alone.110, 112, 113
Orphenadrine (as the hydrochloride salt) has been used in the adjunctive treatment of parkinsonian syndrome†;123 however, this formulation is no longer commercially available in the US.
Anticholinergic agents are used mainly to treat tremors in patients with parkinsonian syndrome; however, evidence supporting this use is based principally on anecdotal experience rather than on randomized controlled studies, and these drugs are associated with a high incidence of adverse effects.123, 124 If an anticholinergic agent is needed in the treatment of parkinsonian syndrome, trihexyphenidyl or benztropine generally is used.124
Orphenadrine is administered orally or by IM or IV injection.120, 121, 122 When orphenadrine is administered IV, the drug should be given over a period of about 5 minutes with the patient in a supine position; the patient should remain in this position for 5-10 minutes after the injection. To minimize adverse reactions after parenteral administration of the drug, the patient should be assisted from the recumbent position.
For the symptomatic relief of acute skeletal muscle conditions in adults, the usual oral dosage of orphenadrine citrate extended-release tablets is 100 mg twice daily.120 For acute relief in adults, the usual IM or IV dosage is 60 mg every 12 hours; for maintenance therapy, patients can usually be switched to oral therapy at a dosage of 100 mg twice daily.121
The recommended adult oral dosage of orphenadrine citrate in combination with aspirin and caffeine is 25-50 mg 3 or 4 times daily.122
Adverse reactions to orphenadrine are mainly extensions of its anticholinergic effects. (See Cautions: Adverse Effects, in the Antimuscarinics/Antispasmodics General Statement 12:08.08.) Adverse effects may include dryness of the mouth, urinary hesitancy or retention, blurred vision, mydriasis, drowsiness, headache, weakness, increased intraocular pressure, palpitation, and tachycardia. GI disturbances may also occur. CNS stimulation, usually manifested by restlessness, agitation, insomnia, or mental confusion (especially in geriatric patients) and occasionally by hallucinations, may occur with orphenadrine. Transient episodes of lightheadedness, dizziness, or syncope have occurred in some patients. Hypersensitivity reactions, pruritus, and, rarely, urticarial rash and other dermatoses have also been reported. In some instances, orphenadrine may appear to increase tremor as spasticity is relieved. Anaphylactic reactions have occurred rarely following IM injection of orphenadrine citrate.
Aplastic anemia has occurred rarely during therapy with orphenadrine citrate; however, a causal relationship to the drug has not been established.
Precautions and Contraindications
The usual precautions and contraindications associated with antimuscarinics should be observed with orphenadrine. For a complete discussion of the precautions and contraindications associated with antimuscarinics, see Cautions: Precautions and Contraindications, in the Antimuscarinics/Antispasmodics General Statement 12:08.08.
Orphenadrine should be used with caution or may be contraindicated in patients with conditions in which anticholinergic effects are undesirable.120, 121, 122 Patients should be warned that orphenadrine may impair their ability to perform hazardous activities requiring mental alertness or physical coordination, such as operating machinery or driving a motor vehicle.120, 121
Safety of continuous therapy with orphenadrine has not been established.120, 121, 122 The manufacturers state that periodic blood, urine, and liver function tests should be performed during prolonged therapy with the drug.120, 121, 122
Commercially available orphenadrine citrate injection may contain sodium bisulfite, a sulfite that can cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals.100, 121 The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.100, 121
When preparations containing orphenadrine in combination with other drugs (e.g., aspirin, caffeine) are used, the cautions, precautions, and contraindications applicable to each ingredient should be considered.122
Orphenadrine is contraindicated in patients with known hypersensitivity to the drug.120, 121, 122
Safety and efficacy of orphenadrine in pediatric patients have not been established.120, 121
Because of the risk of injury, skeletal muscle relaxants should generally be avoided in geriatric patients.111
Safe use of orphenadrine during pregnancy has not been established.120, 121 The drug has caused adverse effects in animals at high doses. In one reproduction study in rats receiving 5 times the human daily dose, degenerative changes in the urinary bladder occurred in 5% of the offspring; in a subsequent study using 12 times the human daily dose, this abnormality was not observed. Orphenadrine should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.
Since it is not known if orphenadrine is distributed into milk, the drug should be used with caution in nursing women.
Orphenadrine may reduce skeletal muscle spasm, possibly through an atropine-like central action on cerebral motor centers or on the medulla. The drug does not have direct skeletal muscle relaxant activity. It has been suggested that the drug may have analgesic activity that contributes to its effect in patients with skeletal muscle spasm. Orphenadrine also exhibits postganglionic anticholinergic effects and some antihistaminic and local anesthetic action. The antihistaminic activity of orphenadrine is less than that of diphenhydramine; in contrast to the sedative effect of diphenhydramine, orphenadrine produces slight CNS stimulation.
Orphenadrine is readily absorbed from the GI tract.
Distribution of orphenadrine into human body tissues and fluids has not been fully characterized. In animals, the drug and/or its metabolites may be detected in all organs, but particularly in those with greatest perfusion (e.g., lungs). It is not known if orphenadrine is distributed into human milk. The drug may cross the placenta.
Orphenadrine reportedly has a half-life of about 14 hours. The metabolic fate of orphenadrine has not been fully determined. The drug is almost completely metabolized to at least 8 metabolites. Orphenadrine is excreted principally in urine as metabolites and, in small amounts, as unchanged drug.
Orphenadrine is a centrally acting skeletal muscle relaxant.110, 120, 121, 122, 125 Structurally, orphenadrine is the o -methyl analog of diphenhydramine. Orphenadrine is available as the citrate salt, which occurs as a bitter, white, and crystalline powder. Orphenadrine citrate is sparingly soluble in water and slightly soluble in alcohol.
Orphenadrine citrate injection is a solution of the drug in water for injection, prepared with the aid of sodium hydroxide; sodium chloride may be added to make the solution isotonic. The injection has a pH of 5-6.
Orphenadrine citrate extended-release tablets should be stored in tight, light-resistant containers at 20-25°C.120 Orphenadrine citrate injection should be stored at 20-25°C and protected from light; the injection should not be used if precipitation occurs.121
Additional Information
For further information on pharmacology, cautions, acute toxicity, and drug interactions of orphenadrine, see the Antimuscarinics/Antispasmodics General Statement 12:08.08.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, extended-release | 100 mg* | Orphenadrine Citrate Extended-release Tablets | |
Parenteral | Injection | 30 mg/mL* | Orphenadrine Citrate Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 25 mg with Aspirin 385 mg and Caffeine 30 mg* | Orphenadrine Citrate, Aspirin, and Caffeine Tablets | |
50 mg with Aspirin 770 mg and Caffeine 60 mg* | Orphenadrine Citrate, Aspirin, and Caffeine Tablets | |||
Orphengesic® Forte |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
100. Food and Drug Administration. Sulfiting agents; labeling in drugs for human use; warning statements. [21 CFR Part 201] Fed Regist . 1986; 51:43900-5.
103. See S, Ginzburg R. Skeletal muscle relaxants. Pharmacotherapy . 2008; 28:207-13. [PubMed 18225966]
104. van Tulder MW, Touray T, Furlan AD et al. Muscle relaxants for non-specific low back pain. Cochrane Database Syst Rev . 2003; :CD004252. [PubMed 12804507]
105. Roelofs PD, Deyo RA, Koes BW et al. Non-steroidal anti-inflammatory drugs for low back pain. Cochrane Database Syst Rev . 2008; :CD000396. [PubMed 18253976]
106. Chou R, Qaseem A, Snow V et al. 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. [PubMed 17909209]
107. Institute for Clinical Systems Improvement. Health care guideline: adult acute and subacute low back pain. 15th ed. Bloomington, MN; 2012 Jan. From the ICSI website [Web]
108. 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. [PubMed 15530999]
109. Qaseem A, Wilt TJ, McLean RM et al. Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med . 2017; 166:514-530. [PubMed 28192789]
110. Friedman BW, Cisewski D, Irizarry E et al. A Randomized, Double-Blind, Placebo-Controlled Trial of Naproxen With or Without Orphenadrine or Methocarbamol for Acute Low Back Pain. Ann Emerg Med . 2018; 71:348-356.e5. [PubMed 29089169]
111. Spence MM, Shin PJ, Lee EA et al. Risk of injury associated with skeletal muscle relaxant use in older adults. Ann Pharmacother . 2013 Jul-Aug; 47:993-8. [PubMed 23821610]
112. Friedman BW, Irizarry E, Solorzano C et al. A Randomized, Placebo-Controlled Trial of Ibuprofen Plus Metaxalone, Tizanidine, or Baclofen for Acute Low Back Pain. Ann Emerg Med . 2019; [PubMed 30955985]
113. Friedman BW, Dym AA, Davitt M et al. Naproxen With Cyclobenzaprine, Oxycodone/Acetaminophen, or Placebo for Treating Acute Low Back Pain: A Randomized Clinical Trial. JAMA . 2015; 314:1572-80. [PubMed 26501533]
120. Sandoz. Orphenadrine citrate extended-release tablets prescribing information. Princeton, NJ: 2017 July.
121. Actavis. Orphenadrine citrate injection prescribing information. Parsipanny, NJ: 2016 July.
122. Galt. Orphengesic® Forte (orphenadrine citrate, aspirin, and caffeine tablets 50 mg/770 mg/60 mg) prescribing information. Atlanta, GA: 2018 Sept.
123. Katzenschlager R, Sampaio C, Costa J et al. Anticholinergics for symptomatic management of Parkinson's disease. Cochrane Database Syst Rev . 2003; :CD003735. [PubMed 12804486]
124. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA . 2014 Apr 23-30; 311:1670-83. [PubMed 24756517]
125. Hunskaar S, Donnell D. Clinical and pharmacological review of the efficacy of orphenadrine and its combination with paracetamol in painful conditions. J Int Med Res 1991 Mar-Apr;19(2):71-87.