Baclofen, a γ-aminobutyric acid (GABA) derivative, is a skeletal muscle relaxant and antispastic agent.113, 128
Baclofen is used orally in the management of spasticity and its sequelae secondary to severe chronic disorders such as multiple sclerosis and other types of spinal cord lesions.112, 128 For the drug to be beneficial, patients must have presumably reversible spasticity where relief of spasticity will aid in restoring residual function.128 In these patients, baclofen decreases the number and severity of spasms (particularly flexor spasms); alleviates associated pain, clonus, and muscle rigidity; and improves mobility to a greater extent than does placebo. In patients with multiple sclerosis, the drug produces little improvement in residual muscle function, but patient comfort is improved when the painful spasms are reversible. In one uncontrolled study, less than one-third of multiple sclerosis patients with urinary retention caused by bladder spasm showed decrease in urinary retention.
Although few controlled studies have been conducted comparing efficacy and tolerability of the various antispastic agents, available data suggest that oral baclofen appears to have similar efficacy to other commonly used oral agents (e.g., diazepam, tizanidine).129, 130, 131, 132 In studies comparing doses of about 60 mg of baclofen daily to 30 mg of diazepam daily in patients with multiple sclerosis or spinal cord lesions, the drugs were equally effective in reducing the number and severity of muscle spasms; however, baclofen produced a lower incidence of sedation than did diazepam. In comparative studies in patients with spasticity associated with cerebral or spinal disorders, improvement in muscle tone occurred in a similar proportion of patients receiving baclofen, diazepam, or tizanidine.133, 134, 135 When spasticity cannot be adequately managed with oral antispastic agents,132 other interventions such as botulinum toxin injection,132 intrathecal baclofen,132 intrathecal injection of sclerosing agents (e.g., phenol), or surgery (e.g., rhizotomy, chordotomy) may be necessary.
Baclofen crosses the blood-brain barrier in only small amounts following oral administration.8, 16, 109 It has been suggested that administration of the drug at the spinal cord level (i.e., intrathecally) would increase drug efficacy while decreasing the dosage required and possibly the toxicity profile in patients with spasticity of spinal cord origin.110, 114 While baclofen may be effective at relatively high oral dosages in some patients with spasticity of spinal cord origin,16, 109, 110, 114 many other patients, particularly those with severe spasticity, do not respond adequately to and/or do not tolerate such therapy.16, 109, 110, 114 Therefore, intrathecal baclofen may be a suitable alternative to ablative surgical or chemical procedures in patients who do not tolerate or respond adequately to oral therapy with the drug.109, 110, 113, 114, 115 (See Uses: Severe Spasticity.)
Baclofen usually is used intrathecally in the management of severe spasticity of spinal cord origin in patients who do not tolerate or respond adequately to oral therapy with the drug.109, 110, 113, 114, 115, 116, 117, 118, 119, 120 Baclofen also is used intrathecally in the management of intractable spasticity secondary to severe chronic disorders such as multiple sclerosis and other types of spinal diseases such as spinal ischemia, spinal tumor, transverse myelitis, cervical spondylosis, and degenerative myelopathy.112 Baclofen is designated an orphan drug by the FDA for use in these conditions.112 The clinical goal of such therapy is to maintain muscle tone as close to normal as possible and to minimize the frequency and severity of spasms without inducing intolerable adverse effects.113, 115 In controlled studies in patients with severe spasticity and spasms secondary to spinal cord injury or multiple sclerosis, single doses or 3-day continuous infusions of intrathecal baclofen were more effective than placebo in improving the Ashworth (rigidity) rating of spasticity and in reducing the frequency of spasms.110, 113 During chronic intrathecal baclofen therapy, many patients experience improvement in activities associated with daily living, especially in self-care, transferring, bowel function, and urinary continence.110, 114, 115, 116, 117, 118, 119
Baclofen also is used intrathecally in patients with spasticity of cerebral origin , including those with cerebral palsy and acquired brain injury.113, 121, 122, 123, 124, 125, 126, 127 Baclofen injection is designated an orphan drug by the FDA for the management of spasticity in patients with cerebral palsy.112 The clinical goal of such therapy is to maintain muscle tone as close to normal as possible and to minimize the frequency and severity of spasms without inducing intolerable adverse effects or to titrate dosage of baclofen to the desired degree of muscle tone for optimal function.113 Results of one randomized, controlled, crossover study in patients with cerebral palsy indicate that intrathecal baclofen was more effective than placebo in reducing spasticity as measured by the Ashworth scale.113 In addition, results of a small (11 patients) controlled study in patients with brain injury indicate that intrathecal baclofen was more effective than placebo in reducing spasticity.113
Patients with spasticity secondary to brain injury should wait at least one year after the injury before considering long-term intrathecal baclofen therapy.113
Baclofen has been used orally to reduce choreiform movements in patients with Huntington's chorea†, to reduce rigidity in patients with parkinsonian syndrome†, and to reduce spasticity in patients with cerebral lesions†, cerebral palsy†, or rheumatic disorders†; however, the drug has not been shown to produce a substantial degree of improvement in these patients. Oral baclofen also has been used to reduce spasticity in patients with cerebrovascular stroke†; however, therapy with the drug generally did not provide substantial improvement and was poorly tolerated.128 The manufacturer states oral baclofen is not indicated for use in patients with rheumatic disorders; use of oral baclofen also is not recommended in patients with stroke, cerebral palsy, or Parkinson's disease.128
Although in one study oral baclofen reportedly improved behavior in patients with schizophrenic disorder† receiving other drugs concomitantly (e.g., phenothiazines), schizophrenic behavior worsened in other patients when baclofen was used alone. Preliminary data indicate that oral baclofen has beneficial effects in the treatment of trigeminal neuralgia† and may be synergistic with carbamazepine and phenytoin.
Baclofen is administered orally or intrathecally.113, 127, 128 Abrupt discontinuance of the drug, including inadvertent discontinuance of the intrathecal infusion, should be avoided because of the risk of precipitating withdrawal.113, 127, 128
For intrathecal use, baclofen is administered as an additive-free injection by direct intrathecal injection (via lumbar puncture or catheter) over a period of at least 1 minute employing barbotage or by continuous intrathecal infusion into a lumbar intrathecal space via an implantable controlled-infusion device (pump).110, 113, 114, 115 The manufacturer's labeling should be consulted for specialized administration techniques.113
In the preparation of test doses of the drug for the purposes of drug-response screening prior to initiation of chronic intrathecal baclofen therapy, 1-mL ampuls containing 50 mcg of baclofen should be used without further dilution.113 For maintenance therapy in patients receiving concentrations of the drug other than the commercially available strengths (i.e., 0.5 or 2 mg/mL), baclofen for injection concentrate for intrathecal administration must be diluted.113 The concentrate must only be diluted with sterile, preservative-free 0.9% sodium chloride injection.113 The specific concentration that should be used depends on the total daily dosage required and the delivery rate of the pump.113 The manufacturer's manual should be consulted for specific recommendations.113
As with other parenteral drug products, baclofen for injection concentrate and diluted solutions of the drug should be inspected visually for particulate matter and/or discoloration prior to administration, whenever solution and container permit.113
Patients receiving intrathecal baclofen therapy must be monitored closely in a fully equipped and staffed environment during the initial test for responsiveness and dosage-titration period immediately following implantation of the pump.113 Resuscitative equipment should be immediately available for use in case of life-threatening or intolerable adverse effects.113
Extemporaneously Compounded Oral Suspension
An extemporaneously compounded 5 mg/mL oral suspension of baclofen has been prepared using the commercially available 20-mg tablets and Simple Syrup, NF.136
Standardized concentrations for an extemporaneously prepared oral liquid formulation of baclofen have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 252Multidisciplinary expert panels were convened to determine recommended standard concentrations. 252Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 252 For additional information on S4S (including updates that may be available), see [Web].252
Concentration Standards |
|---|
5 mg/mL |
Oral dosage of baclofen should be individualized according to the patient's requirements and response using the lowest dosage that produces optimum response.128 Initially, low oral dosages of the drug should be administered.128
For the management of spasticity, the initial oral dosage of baclofen is 5 mg 3 times daily.128 Oral daily dosage may be increased by 15 mg at 3-day intervals (i.e., 5 mg 3 times daily for 3 days, then 10 mg 3 times daily for 3 days, then 15 mg 3 times daily for 3 days, then 20 mg 3 times daily for 3 days) until optimum effect is achieved (usually at dosages of 40-80 mg daily).128 In patients with psychiatric or brain disorders and in geriatric patients, oral dosage should be increased more gradually. In some patients, a smoother antispastic effect is obtained by administering the oral daily dosage in 4 divided doses. Some clinicians suggest that daily oral dosages of up to 150 mg are well tolerated and provide additional therapeutic benefit in some patients; however, the manufacturers state that total dosage should not exceed 80 mg daily (i.e., 20 mg 4 times daily128 ). Some patients require 1-2 months of treatment for full benefit; however, the length of baclofen trial should be determined by the clinical state of the patient. If benefits are not evident after a reasonable trial, baclofen therapy should be discontinued by slowly reducing the daily dosage.128
Prior to implantation of the controlled-infusion device (e.g., Medtronic SynchroMed® pump) and initiation of chronic intrathecal baclofen therapy, the patient must exhibit a positive response (defined as a clinically important decrease in muscle tone and/or frequency and/or severity of spasms over a 4- to 8-hour observation period) to initial intrathecal baclofen test dose(s).110, 113, 115 Initially, a dose containing 50 mcg (1 mL of a 50-mcg/mL solution) of baclofen is administered into the intrathecal space by barbotage over a period of at least 1 minute.113 If response observed at 4-8 hours after the initial test dose is less than desired, a second injection containing 75 mcg (1.5 mL of a 50-mcg/mL solution) of baclofen may be administered 24 hours after the first dose.113 If response observed at 4-8 hours after the second test dose remains inadequate, a final injection containing 100 mcg (2 mL of a 50-mcg/mL solution) of baclofen may be administered 24 hours after the second dose.113 In pediatric patients, the initial test dose is the same as in adults (i.e., 50 mcg); however, in very small children, an initial dose of 25 mcg may be considered.113 Patients not responding to the 100-mcg intrathecal test dose of the drug are not considered candidates for chronic intrathecal baclofen therapy.110, 113, 115
Following establishment of responsiveness to intrathecal baclofen and implantation of a compatible pump (e.g., SynchroMed® infusion system), the initial intrathecal dose of baclofen for the management of spasticity is twice the test dose that produced a positive response with a duration not exceeding 8 hours; this dose is infused intrathecally over 24 hours.113, 115 For patients in whom a positive response to the test dose persisted for longer than 8 hours, the initial intrathecal dose is the same as the test dose that produced a positive response; this dose also is infused intrathecally over 24 hours.113, 115 Dosage should not be increased within 24 hours after the initial intrathecal dose (i.e., until steady state is achieved).113 Following the initial infusion dose in adults with spasticity of spinal cord origin, the daily dose can be increased slowly by 10-30% increments at 24-hour intervals until the desired clinical response is achieved; in pediatric patients with spasticity of spinal cord origin and adult and pediatric patients with spasticity of cerebral origin , the daily dose can be increased slowly by 5-15% increments at 24-hour intervals until the desired clinical response is achieved.113, 115 If no substantive increase in response is observed with upward titration of intrathecal baclofen dosage, the function of the pump and patency of the catheter should be checked.113, 115
Adjustment of maintenance dosage often is needed during the initial months of intrathecal baclofen therapy as the patient adjusts to changes in life-style secondary to relief of spasticity.113, 115 During periodic refills of the pump, the 24-hour dose may be increased by up to 10-40% or up to 5-20% in patients with spasticity of spinal cord origin or those with spasticity of cerebral origin, respectively, as necessary to maintain adequate control of symptoms.113, 115 In patients who develop intolerable adverse effects, the 24-hour maintenance dose can be decreased by 10-20%.113, 115 During chronic therapy, gradual increases in dosage will be required in most patients to maintain optimal response.113, 115 A sudden increase in dosage requirement should suggest the possibility of pump and/or catheter malfunction (i.e., catheter kink or dislodgement).113 In patients with spasticity of spinal cord origin , maintenance dosage during chronic intrathecal therapy has ranged from 12-2003 mcg daily, with most patients responding adequately to 300-800 mcg daily.110, 113, 115 There is only limited experience with intrathecal baclofen dosages of 1000 mcg daily or greater in these patients.113 In patients with spasticity of cerebral origin , maintenance dosage during chronic intrathecal therapy has ranged from 22-1400 mcg daily, with most patients responding adequately to 90-703 mcg daily.113 In clinical studies in patients with spasticity of cerebral origin, only about 2% of patients required daily dosages exceeding 1000 mcg daily.113
Maintenance dosage recommendations for pediatric patients are similar to those for patients with spasticity of cerebral origin.113 Pediatric patients younger than 12 years of age may require lower daily dosages; in clinical trials, the maintenance daily dosage averaged 274 mcg daily (range: 24-1199 mcg daily).113 Dosage requirements for pediatric patients older than 12 years of age does not appear to be different from that for adult patients.113 Determination of optimum therapy requires individual titration.113 The lowest possible dosage that produces optimum response should be employed.113, 115
During prolonged intrathecal baclofen therapy for spasticity, approximately 5% of patients become refractory to increasing dosages of the drug.113, 115 While experience currently is insufficient to make firm recommendations regarding amelioration of such tolerance, patients occasionally have been hospitalized and subjected to a “drug holiday” in which intrathecal dosage was decreased gradually over a 2- to 4-week period, during which baclofen therapy was alternated with other methods of spasticity management.113, 115 After a few days, sensitivity to baclofen may return and continuous intrathecal baclofen therapy may be resumed at the previously effective initial dosage.113, 115
For patients achieving relatively satisfactory relief via continuous intrathecal infusion employing an implantable pump, further benefit may be possible with more complex dosing schedules.110, 113, 115 For example, patients who commonly experience an exacerbation of spasticity at night that disrupts sleep may require a 20% increase in the hourly infusion rate; such changes should be programmed to begin approximately 2 hours before the time of desired clinical benefit.110, 113, 115
The manual provided by the manufacturer of the implantable infusion device (i.e., pump) must be consulted for additional information, including specific instructions and precautions for programming the pump and/or refilling the reservoir.113Various pumps (with different reservoir volumes) and refill kits are available; clinicians must be familiar with these products in order to select the appropriate refill kit for the particular pump in use.113
Because baclofen is excreted principally in urine as unchanged drug, it may be necessary to reduce either oral or intrathecal dosage in patients with impaired renal function.113, 128 (See Cautions: Precautions and Contraindications.)
The most common adverse effect of oral baclofen therapy is transient drowsiness (10-63%); other common adverse effects of oral baclofen therapy include dizziness (5-15%), weakness (5-15%), and fatigue (2-4%).128
The most common adverse effects of intrathecal baclofen therapy in patients with spasticity of spinal cord origin include somnolence, dizziness, nausea, hypotension, headache, seizures, and hypotonia.113 The most common adverse effects of intrathecal baclofen therapy in patients with spasticity of cerebral origin include agitation, constipation, somnolence, leukocytosis, chills, urinary retention, and hypotonia.113
The incidence of adverse effects during oral administration of baclofen can be minimized by slowly increasing dosage to therapeutic levels. If adverse effects occur, they can be reduced by decreasing dosage. Psychiatric disturbances, including hallucinations, euphoria, mental excitation, depression, confusion or anxiety, occur most commonly in patients with psychiatric or brain disorders, including stroke, and in geriatric patients; any increase in oral dosage should be made slowly in these patients. Many adverse CNS and genitourinary effects also are symptoms of the underlying disease (i.e., multiple sclerosis, spinal cord lesions) and may not be related to baclofen therapy.
Neuropsychiatric disturbances reported during oral baclofen treatment include confusion, headache, insomnia, and, rarely, euphoria, excitement, depression, hallucinations, paresthesia, muscle pain, tinnitus, slurred speech, coordination disorder, tremor, rigidity, dystonia, ataxia, blurred vision, nystagmus, strabismus, miosis, mydriasis, diplopia, dysarthria, and seizures.128 Neuropsychiatric disturbances or adverse CNS effects reported during intrathecal baclofen treatment include hypotonia, somnolence, dizziness, paresthesia, hypertonia, headache, seizures, asthenia, confusion, speech disorder, coma, insomnia, anxiety, depression, abnormal thinking, tremor, agitation, dysautonomia, hallucinations, abnormal gait, amnesia, twitching, vasodilation, cerebrovascular accident, nystagmus, personality disorder, psychotic depression, cerebral ischemia, emotional lability, euphoria, ileus, drug dependence, incoordination, paranoid reaction, ptosis, akathisia, ataxia, opisthotonos, hysteria, insomnia, decreased reflexes, and vasodilation.113
Urinary frequency and, rarely, enuresis, urinary retention, dysuria, impotence, inability to ejaculate, nocturia, and hematuria have occurred during oral baclofen therapy.128 During intrathecal baclofen therapy, urinary retention or incontinence, impotence, urinary frequency, impaired urination, hematuria, kidney failure, abnormal ejaculation, kidney calculus, oliguria, and vaginitis have been reported.113
In female rats, chronic administration of oral baclofen has caused a dose-related increase in the incidence of ovarian cysts and a less marked increase in enlarged or hemorrhagic adrenal glands.113, 128 Ovarian cysts have been found by palpation in about 4% of multiple sclerosis patients receiving oral baclofen for up to 1 year, but these cysts spontaneously disappeared despite continued use of the drug in most patients.113, 128 It should be noted, however, that ovarian cysts are estimated to occur spontaneously in approximately 1-5% of healthy females.113, 128
Adverse cardiovascular effects such as hypotension and, rarely, dyspnea, palpitation, chest pain, and syncope have occurred during oral baclofen therapy.128 Hypotension (including orthostatic hypotension), hypertension, dyspnea, bradycardia, palpitations, syncope, ventricular arrhythmia, deep thrombophlebitis, pallor, and tachycardia have been reported during intrathecal baclofen therapy.113
Adverse GI effects of oral baclofen therapy include nausea and constipation and, rarely, dry mouth, anorexia, taste disorders, abdominal pain, vomiting, diarrhea, and positive tests for occult blood in the stool.128 Nausea, vomiting, constipation, dry mouth, diarrhea, anorexia, increased salivation, flatulence, dysphagia, dyspepsia, gastroenteritis, fecal incontinence, GI hemorrhage, tongue disorder, and abdominal pain have been reported during intrathecal baclofen therapy.113
Abrupt discontinuance of oral baclofen therapy, regardless of the cause, has resulted in hallucinations and seizures.127, 128 Abrupt discontinuance of intrathecal baclofen therapy has resulted in high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity that, in rare cases, have progressed to rhabdomyolysis, multisystem organ failure, and death.113 In most cases, manifestations of withdrawal appeared within hours to a few days following discontinuance of baclofen therapy.113 All patients receiving intrathecal baclofen therapy are potentially at risk for withdrawal.113 Early manifestations of intrathecal baclofen withdrawal may include return of baseline spasticity, pruritus, hypotension, and paresthesias.113 Clinical presentation of advanced intrathecal baclofen withdrawal syndrome may resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic malignant syndrome (NMS), or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis.113 (See Cautions: Precautions and Contraindications.) Baclofen therapy should be slowly discontinued to minimize the risk of withdrawal.113, 128
Although fatalities, including one case of unexpected death after administration of 3 test doses and 2 cases of sudden and unexpected death occurring within 2 weeks of pump implantation, have been reported rarely during the use of intrathecal baclofen therapy, the manufacturer states that a causal relationship to the drug could not be established.113
Rash, pruritus, ankle edema, excessive perspiration, weight gain, and nasal congestion have been reported during oral baclofen therapy.128 Increases in blood glucose concentration and serum AST (SGOT) and alkaline phosphatase concentrations also have been reported during oral therapy.128 During intrathecal baclofen therapy, accidental injury, death, pain, amblyopia, hypoventilation, peripheral edema, fever, pneumonia, urticaria, diplopia, back pain, pruritus, rash, sweating, alopecia, contact dermatitis, skin ulcer, chills, respiratory disorder, aspiration pneumonia, hyperventilation, apnea, pulmonary embolus, rhinitis, weight loss, albuminuria, dehydration, hyperglycemia, abnormal vision, abnormality of accommodation, photophobia, taste loss, tinnitus, suicide, hypothermia, neck rigidity, chest pain, chills, face edema, flu syndrome, anemia, carcinoma, malaise, leukocytosis, and petechial rash have been reported.113
Precautions and Contraindications
Deteriorations in seizure control and EEG occasionally have been noted in epileptic patients receiving the drug; the epileptic patient's clinical state and EEG should be monitored at regular intervals during baclofen treatment.128
Because baclofen may cause sedation and/or drowsiness, patients should be warned that therapy with the drug may impair their ability to perform hazardous activities requiring mental alertness or physical coordination such as operating machinery or driving a motor vehicle.113, 128 In addition, additive CNS depression may occur when the drug is administered concomitantly with other CNS depressants, including alcohol.113, 128 Oral or intrathecal baclofen should be used with caution, and it may be necessary to reduce dosage in patients with impaired renal function.113, 128 The drug should be used with caution, with careful dosage titration, in patients who must use spasticity to maintain upright posture and balance in moving or when spasticity is used to obtain increased or optimal body function.113, 128
Patients with psychotic disorders, schizophrenia, or confusional states should be treated cautiously and kept under careful surveillance during intrathecal baclofen therapy, as exacerbations of these conditions have been reported following oral administration of the drug.113
Intrathecal baclofen therapy should be instituted with caution in patients with a history of autonomic dysreflexia, since the presence of nociceptive stimuli or the abrupt withdrawal of therapy may precipitate an episode of dysreflexia.113
The clinical goal of baclofen therapy is to maintain muscle tone as close to normal as possible and to minimize the frequency and severity of spasms without inducing intolerable adverse effects.113 It may be important to maintain some degree of muscle tone and allow occasional spasms to help support circulatory function, minimize the risk of development of deep-vein thrombosis, and optimize activities of daily living and ease of care.113
If intrathecal baclofen therapy is to be employed, an attempt should be made to discontinue concomitant oral antispasmodic drugs, including oral baclofen, to avoid possible overdose and drug interactions, either prior to the screening phase or following implantation of the infusion device.113 Dosage reduction and discontinuance of concomitant oral antispasmodics should be employed slowly, and the patient should be monitored carefully; abrupt dosage reduction or discontinuance of concomitant antispasmodics should be avoided.113
Patients undergoing pump implantation for the initiation of intrathecal baclofen therapy should be without concurrent infection, as the presence of infection may interfere with assessment of the patient's response to the baclofen test dose(s), increase surgical complications after pump implantation, and complicate attempts to adjust dosage.113, 115
Development of intrathecal mass at the tip of the implanted catheter, usually involving pharmacy compounded analgesic admixtures, has been reported in patients receiving long-term intrathecal baclofen therapy.113 The most common sequelae or manifestations associated with intrathecal mass include decreased therapeutic response (i.e., worsening spasticity, return of spasticity despite previous response, withdrawal symptoms, poor response to escalating doses, frequent or large dosage increases), pain, and neurologic deficit or dysfunction.113 Patients receiving intraspinal therapy should be carefully monitored for any new neurologic manifestations.113 If new neurologic manifestations suggestive of an intrathecal mass occur, a neurosurgical consultation should be considered, since many of the symptoms of inflammatory mass are similar to those observed in patients with severe spasticity.113 In some cases, performance of an imaging procedure may be appropriate to confirm or rule out the diagnosis of an intrathecal mass.113
Because of the possibility of potentially life-threatening CNS depression, cardiovascular collapse, and/or respiratory failure, baclofen should be administered intrathecally only by qualified individuals familiar with the techniques of administration and patient management problems.113, 115 When an implantable pump is used, familiarization with the device is essential, including specific instructions and precautions for programming the pump and refilling the reservoir.113 The patient, their caregivers, and health-care providers must receive adequate information regarding the risks of such therapy, including information on recognition and management of potential overdosage and proper care of the pump and catheter insertion site.113 Because of the risks involved, the initial test for responsiveness to intrathecal baclofen, implantation of the pump, and subsequent periods of dosage titration must be performed in a medically supervised setting that is adequately equipped for the management of potential complications; resuscitative equipment should be readily available.113, 115 Filling of the drug reservoir of the device should be performed under aseptic conditions (to avoid bacterial contamination and serious infection) and only by fully trained and qualified personnel, following the directions provided by the device's manufacturer.113 The pump should be filled with extreme caution and should be refilled only through the reservoir refill septum of the device.113 If the reservoir refill septum is not properly accessed, inadvertent injection into the subcutaneous tissue can occur, possibly resulting in life-threatening overdosage or early depletion of the reservoir.113 Some pumps also are equipped with a catheter access port that allows direct access to the intrathecal catheter; direct injection into this catheter may cause life-threatening overdosage of the drug.113 During chronic therapy, care should be taken in employing the proper refill frequency so that depletion of the drug reservoir during use is avoided; symptoms of spasticity (e.g., rigidity) usually return within a few days if dosing is discontinued, and manifestations of withdrawal (e.g., hallucinations, seizures) could emerge.113, 114, 115 Careful patient monitoring is particularly important during the initial phase of pump use, dosage titration, and reservoir refilling so that an acceptable, reasonably stable response is ensured.113
Abrupt discontinuance of oral baclofen therapy, regardless of the cause, has resulted in hallucinations and seizures.127, 128 Abrupt discontinuance of intrathecal baclofen therapy has resulted in high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity that, in rare cases, have progressed to rhabdomyolysis, multisystem organ failure, and death.113 Common reasons for abrupt interruption of intrathecal baclofen therapy include malfunction of the catheter (particularly disconnection), low volume in the pump reservoir, end of pump battery life, and, possibly, human error.113 Cases of intrathecal mass at the tip of the implanted catheter (most of which involved pharmacy compounded analgesic admixtures) also have reportedly resulted in withdrawal symptoms.113 Therefore, the manufacturer states that careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms is necessary to prevent abrupt discontinuance of intrathecal baclofen therapy.113 Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be informed of the early signs and symptoms of baclofen withdrawal.113 (See Abrupt Withdrawal under Cautions: Adverse Effects.) Special attention should be given to patients at apparent risk for withdrawal (e.g., spinal cord injury at the T6 level or above, communication difficulties, history of withdrawal symptoms from oral or intrathecal baclofen).113 Rapid, accurate diagnosis and treatment in an emergency room or intensive care setting are important in order to prevent the potentially life-threatening CNS and systemic effects of intrathecal baclofen withdrawal.113 Treatment of intrathecal baclofen withdrawal includes restoration of intrathecal baclofen at or near the dosage used prior to interruption of therapy.113 However, if reinstitution of intrathecal delivery is delayed, therapy with drugs that enhance GABA effects (e.g., oral or enteral baclofen; oral, enteral, or IV benzodiazepines) may prevent potentially fatal sequelae.113 However, the manufacturer states that oral or enteral baclofen alone should not be relied upon to halt the progression of intrathecal baclofen withdrawal.113
Oral and intrathecal baclofen are contraindicated in patients with a history of hypersensitivity to the drug.113, 128 Baclofen injection for intrathecal administration is not recommended or intended for IV, IM, subcutaneous, or epidural administration.113, 115
The manufacturers state that safety of oral or intrathecal baclofen therapy in pediatric patients younger than 12 or 4 years of age, respectively, has not been established.113, 128 Pediatric patients undergoing pump implantation for the initiation of intrathecal baclofen therapy should have sufficient body mass to accommodate the pump.113 Directions provided by the device's manufacturer should be consulted.113
Reproduction studies in rats receiving oral baclofen at a dosage approximately 13 or 3 times the maximum recommended human oral dosage on a mg/kg or mg/m2 basis, respectively, demonstrated an increased incidence of omphaloceles (ventral hernias) in the fetuses; substantial reductions in food intake and weight gain occurred in pregnant rats receiving this dosage.113, 128 An increased incidence of omphaloceles did not occur in mice or rabbit fetuses.113, 128 An increased incidence of incomplete sternebral ossification occurred in the fetuses of rats receiving approximately 13 times the maximum recommended human dosage, and an increased incidence of unossified phalangeal nuclei of the forelimbs and hindlimbs occurred in the fetuses of rabbits receiving approximately 7 times the maximum recommended dosage.128 No teratogenic effects occurred in mice, although reduction in mean fetal weight with consequent delay in skeletal ossification occurred in offspring of mice receiving 17 or 34 times the human daily dosage of baclofen.128 There are no adequate and controlled studies using baclofen in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.113, 128
Baclofen is distributed into milk following oral administration; it not known whether the drug distributes into milk following intrathecal administration.113 At least one manufacturer states that nursing should not be undertaken by women receiving oral baclofen.128 Nursing should be undertaken by women receiving intrathecal baclofen only if the potential benefit justifies the potential risks to the infant.113
Experience with concomitant use of intrathecal baclofen with other drugs is insufficient to predict specific drug-drug interactions.113
Concomitant use of baclofen with other CNS depressants (e.g., alcohol) may result in additive CNS depression.113, 128
Concomitant use of intrathecal baclofen with epidural morphine reportedly has resulted in hypotension and dyspnea.113
Following ingestion of about 1 g of baclofen by a patient attempting suicide, reflexes were absent, and vomiting, muscle hypotonia, marked salivation, drowsiness, visual accommodation disorders, coma, respiratory depression, and seizures occurred. Serum lactic dehydrogenase and AST (SGOT) concentrations were also elevated. Supportive treatment consisted of endotracheal intubation and positive-pressure ventilation; after 3 days, some signs of muscle flaccidity still persisted. If oral baclofen overdosage occurs, the manufacturer recommends that the stomach be emptied promptly (i.e., by inducing emesis followed by gastric lavage) if the patient is alert.128 If the patient is obtunded, the airway should be secured with a cuffed endotracheal tube before beginning lavage, and adequate respiratory exchange should be maintained; induction of emesis and use of respiratory stimulants should be avoided.128
Signs of intrathecal baclofen overdose may appear suddenly or over a period of time.113 Special attention must be given to recognizing the signs and symptoms of overdosage, particularly during the initial test for responsiveness, dosage titration, and reintroduction of therapy following temporary interruption.113 Acute, massive overdose may present as coma; in reports of coma resulting from overdose of intrathecal baclofen, the coma generally has been reversible following discontinuance of the infusion.113, 114 Less sudden and/or less severe forms of overdose may present with drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, hypothermia, seizures, rostral progression of hypotonia, and loss of consciousness progressing to coma persisting up to 72 hours.113 Should overdose appear likely, the patient should be taken immediately to a hospital for assessment and emptying of the pump reservoir.113 The manufacturer states that in cases reported to date, overdose generally has been related to pump malfunction, inadvertent subcutaneous injection, or dosing error; however, symptoms of overdose were reported in a baclofen-sensitive adult patient following intrathecal injection of a 25-mcg dose.113
In the treatment of oral baclofen overdosage, immediate removal of the drug from the GI tract by emesis (if patient is conscious) or gastric lavage and maintenance of adequate respiratory exchange are recommended. If the patient is comatose, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Respiratory stimulants should not be used.
There is no specific antidote for treating overdoses of baclofen intrathecal injection; however, any remaining baclofen solution in the pump should be removed as soon as possible and patients exhibiting respiratory depression should be intubated as necessary until the drug is eliminated.113
If lumbar puncture is not contraindicated, consideration should be given to withdrawing 30-40 mL of CSF in order to reduce CSF baclofen concentration.113
Baclofen decreases the frequency and amplitude of muscle spasms (tonic reflexes) that arise in response to muscle stretching in patients with various spinal cord lesions. The drug simultaneously and equally suppresses cutaneous reflexes and muscle tone but only slightly depresses the amplitude of tendon jerks (phasic reflexes). The mechanism of action of baclofen is not completely understood, but the drug appears to act primarily at the spinal cord level.113, 128 Apparently, baclofen predominantly inhibits spinal polysynaptic afferent pathways but may also inhibit monosynaptic afferent pathways to a lesser extent. The drug may inhibit monosynaptic and polysynaptic reflexes by acting as an inhibitory neuronal transmitter or by blocking excitatory synaptic transmission through hyperpolarization of afferent terminals. Because baclofen contains both GABA and phenylethylamine moieties, it has been postulated, but not proven, that the drug activates one of these putative inhibitory neurotransmitters. Baclofen has been shown to increase the metabolism of dopamine in animals but, in humans, CSF concentrations of 5-hydroxyindole acetic acid or dopamine metabolites are not altered by the drug. Because baclofen produces generalized CNS depression (e.g., sedation with tolerance, somnolence, ataxia, respiratory and cardiovascular depression), it has also been suggested that the drug may act at supraspinal sites.113, 128
Intrathecal administration of the drug in animals has been shown to increase antinociception and decrease muscle rigidity and spasticity.106, 107, 108
Studies with radiolabeled baclofen have shown oral doses of 40 mg to be rapidly and almost completely absorbed from the GI tract, but there is relatively large intersubject variation in absorption and/or elimination.128 GI absorption of baclofen is reduced as dosage is increased.128 Serum concentrations required for therapeutic effects reportedly range from 80-395 ng/mL. Following oral administration of 40 mg of baclofen to healthy patients, peak blood concentrations of 500-600 ng/mL are reached in 2-3 hours and concentrations remain above 200 ng/mL for 8 hours. Beneficial effects of oral baclofen may not be immediately apparent; onset of therapeutic effect may vary from hours to weeks.
Following intrathecal administration of the drug, concurrent plasma baclofen concentrations are expected to be low (0-5 ng/mL); plasma concentrations of baclofen following intrathecal administration are 100 times lower than those achieved following oral administration.113 In pediatric patients 8-18 years of age who were receiving a continuous intrathecal infusion of baclofen at dosages of 77-400 mcg daily, plasma baclofen concentrations were near or below 10 mg/mL.113
When baclofen is administered via intrathecal injection, the onset of action in adult patients generally is 0.5-1 hour following injection; peak spasmolytic effect is seen approximately 4 hours after dosing and effects may last 4-8 hours, although onset, peak, and duration of action are subject to interindividual variation, depending on the dose and severity of symptoms.113 Onset and duration of action and peak effects of baclofen in pediatric patients are similar to those reported in adult patients.113
Following continuous intrathecal infusions of the drug, initial spasmolytic action is seen within 6-8 hours in adult patients; peak spasmolytic effect is observed within 24-48 hours.113 Pharmacokinetic data following continuous intrathecal infusion in pediatric patients currently are not available.113
In animals, orally administered baclofen is widely distributed throughout the body, but only small amounts of the drug cross the blood-brain barrier.
Limited data suggest that a lumbar-cisternal gradient of approximately 4:1 is established along the neuroaxis during infusion of baclofen injection, based on simultaneous CSF sampling via lumbar and cisternal taps in a limited number of patients receiving continuous lumbar infusion of the drug at doses associated with therapeutic efficacy; however, there was wide interindividual variation.113 This gradient was not affected by patient position.113
Baclofen crosses the placenta. Baclofen is distributed into milk following oral administration; it is not known whether the drug is distributed into milk following intrathecal administration.113
At blood concentrations of 10 ng to 300 mcg/mL, 30% of baclofen is bound to serum proteins.
Baclofen has a serum half-life of 2.5-4 hours.
CSF clearance of baclofen following intrathecal administration via injection or continuous infusion approximates CSF turnover, suggesting that elimination of the drug occurs via bulk-flow removal of CSF.113 Following lumbar injection of the drug in doses of 50 or 100 mcg in a limited number of patients, the mean CSF elimination half-life was 1.51 hours for the first 4 hours following injection; mean CSF clearance of the drug was 30 mL/hour.113 Mean CSF clearance of the drug also was 30 mL/hour in a limited number of patients receiving the drug via continuous intrathecal infusion.113
Only about 15% of a dose of the drug is metabolized in the liver, mostly by deamination. Baclofen is almost completely excreted within 72 hours following oral administration; 70-80% of the drug is excreted in urine unchanged or as metabolites and the remainder is excreted in the feces.
Baclofen, the p -chlorophenyl derivative of γ-aminobutyric acid (GABA) containing a phenylethylamine moiety, is a skeletal muscle relaxant. Baclofen occurs as white to off-white crystals and is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform.128 The drug has pKa values of 5.4 and 9.5.
Baclofen tablets should be stored in well-closed containers at 20-25°C.128
Baclofen for injection concentrate for intrathecal administration is a sterile, nonpyrogenic, isotonic solution of the drug in water for injection.113 Each mL of the concentrate contains 0.39 mEq of sodium.113 Baclofen concentrate does not require refrigeration and is stable in solution at 37°C; however, the concentrate should not be stored at a temperature that exceeds 30°C and should not be frozen or autoclaved.113 The pH of the concentrate is 5-7.113 Because baclofen for injection concentrate contains no preservatives, each vial is intended for single use only; any unused solution should be discarded.113 Baclofen for injection concentrate is compatible with CSF, and must only be diluted with sterile, preservative-free 0.9% sodium chloride for injection.111, 113
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
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 | 10 mg* | Baclofen Tablets (scored) | |
20 mg* | Baclofen Tablets (scored) | |||
Parenteral | For injection concentrate, for intrathecal administration via compatible infusion device or for intrathecal injection | 50 mcg/mL | ||
Lioresal® Intrathecal | ||||
0.5 mg/mL | Gablofen® | CNS Therapeutics | ||
Lioresal® Intrathecal | Medtronic | |||
2 mg/mL | Gablofen® | CNS Therapeutics | ||
Lioresal® Intrathecal | Medtronic |
* 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.
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