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Intrathecal baclofen
- Updated 03.02.2021
- Released 02.23.1999
- Expires For CME 03.02.2024
Intrathecal baclofen
Introduction
Historical note and terminology
Baclofen has been the most widely used spasmolytic drug for the past 25 years. For about a decade, the intrathecal route has become the preferred mode of delivery of baclofen. This product was approved by the Food and Drug Administration in the United States in 1996.
Pharmacology
The chemical name of baclofen is 4-amino-3(4-chlorophenyl)butanoic acid. It is slightly soluble in water. Intrathecal solution is sterile and free of any potentially neurotoxic additives; it is compatible with cerebrospinal fluid.
Pharmacodynamics. The exact mechanism of baclofen as a muscle relaxant and anti-spasticity agent is not known. The following are possible modes of action:
• Its effect on the increased muscle tone and spinal neuron hyperexcitability is attributed mainly to its ability to block the release of neurotransmitters at spinal synapses. | |
• Baclofen is a structural analog of inhibitory neurotransmitter GABA(B) and may exert its effect by stimulation of the GABA(A) receptor subtypes. Epidural spinal cord stimulation has been used for pain, spasticity, and dystonia, and the effects are like that of intrathecal baclofen as the action of both involves spinal GABAergic system. | |
• Intrathecal baclofen results in a greater decrease in spasticity by allowing higher concentrations of baclofen in the cerebrospinal fluid at about 1% the daily oral dosage. |
Pharmacokinetics. The important points are as follows:
• The average cerebrospinal fluid elimination half-life is 1.5 hours over the first 4 hours. | |
• Clearance of baclofen bolus injection or infusion corresponds to cerebrospinal fluid turnover. The average cerebrospinal fluid clearance is about 30 mL per hour. | |
• A lumbar cisternal concentration gradient of 4:1 is established along the neuraxis during baclofen infusion. Because of the concentration gradient, there is a higher concentration of administered baclofen around the catheter tip; therefore, the intrathecal catheter tip should be placed close to the targeted spinal level (13). | |
• Direct introduction of baclofen into the intrathecal space enables therapeutically effective concentrations to be achieved in the cerebrospinal fluid with corresponding serum concentration 100 times less than with oral baclofen. | |
• Peak spasmolytic effect is seen approximately 4 hours after administration. |
A systematic review of clinical trials of oral baclofen reveals insufficient data to support or refute the use of oral baclofen for reducing spasticity or improving motor function in children and adolescents with spastic cerebral palsy. Another reason for clinical use of intrathecal baclofen is that it has a better pharmacokinetic profile than oral baclofen.
Clinical trials
Intrathecal baclofen is an effective long-term treatment for spinal spasticity that has not responded to oral baclofen. Reductions in spasticity has been reported in both open-label and placebo-controlled trials. Patients often make substantial gains in activities of daily living following intrathecal baclofen and need for orthopedic surgery for muscle contractures is reduced.
A retrospective study of 25 wheelchair-assisted adults with cerebral palsy showed that intrathecal baclofen improves spasticity, relieves pain, and facilitates wheelchair comfort and nursing care (26).
A systematic review of clinical trials of intrathecal baclofen did not find any randomized trials that met the criteria for inclusion, only 8 non-randomized trials involving 162 patients (18). Results show level 4 evidence that intrathecal baclofen is effective in reducing spasticity.
A randomized, controlled, open-label, multicenter phase IV study titled “Spasticity In Stroke-Randomized Study (SISTERS)” was conducted to evaluate the efficacy and safety of intrathecal baclofen therapy versus conventional medical management with oral antispasm medications for treatment of severe poststroke spasticity, and the data support the use of intrathecal baclofen therapy as an alternative to conventional medical management (Creamer et al 2018).
A retrospective cohort study of intrathecal baclofen infusion pumps spasticity in neurologic disorders, with follow-up time ranging from 9 to 132 months, showed significant improvement in the Ashworth and Penn's scales, and the patients were satisfied with the treatment (22). Despite the long follow-up, the incidence of complications was within the range of other international studies.
Indications
Baclofen is indicated for severe spasticity of the following types:
(1) Cerebral origin (cerebral palsy or traumatic brain injury). |
Off-label uses
(1) Treatment of tetanus. | |
(2) Treatment of stiff-person syndrome. | |
(3) Treatment of foot cramps in patients with Parkinson disease. | |
(4) Hereditary spastic paraparesis. | |
(5) Hiccups. | |
(6) Alcohol use disorder (AUD). A review of controlled clinical trials has shown that individualized treatment with high-dose baclofen (30 to 300 mg/d) may be a useful second-line approach in heavy drinkers who wish to reduce levels of alcohol intake, but the risk of serious adverse events with high-dose baclofen and its pharmacodynamic interaction with alcohol must both be kept in mind (03). A randomized trial has shown that in patients with unhealthy alcohol use receiving mechanical ventilation, treatment with high-dose baclofen, compared with placebo, resulted in a statistically significant reduction in agitation-related events (29). | |
(7) For the prevention of cluster headache. | |
(8) Intrathecal baclofen can control otherwise unresponsive sympathetic storm phenomena such as hypertension and tachycardia, which can occur in patients with severe brain injury. | |
(9) Children with Tourette syndrome may benefit from treatment with baclofen. | |
(10) Intrathecal baclofen may be efficacious in treating patients with long-standing complex regional pain syndrome, type I, who have failed treatment with multiple drugs and procedures. | |
(11) Patients with post-stroke spastic hemiplegia have shown improvement in ambulation and mobility following intrathecal infusion from baclofen pump. | |
(12) Sporadic episodes of dramatic recovery from persistent vegetative state are reported after intrathecal administration of baclofen. | |
(13) Neuropathic pain including poststroke central pain syndrome. | |
(14) Posttraumatic hemiballismus. | |
(15) Control of hyperthermia in patients with brainstem stroke (14). | |
(16) Intraventricular baclofen infusion has been used to treat secondary dystonia mostly in patients where implantation of intrathecal catheters is difficult or inappropriate due to anatomical reasons (01). Intraventricular baclofen is also an option in patients with history of multiple and increasing pump revisions during intrathecal baclofen therapy, which puts them at risk for spinal arachnoiditis (27). | |
(17) Intrathecal baclofen has been used to treat secondary myoclonus of spinal origin (07). | |
(18) Stiff-person syndrome resistant to oral therapy (20). | |
(19) Intrathecal baclofen has been reported to facilitate recovery of consciousness in some patients with vegetative state or minimally conscious state, and the hypothesis is that it may act by reducing the overload of dysfunctional sensory stimuli reaching the injured brain (21). | |
(20) Drug-resistant essential tremor (12). | |
(21) Painful muscle spasms in Friedreich ataxia (15). |
Contraindications
Hypersensitivity to baclofen is a contraindication.
Infection represents an explicit contraindication to intrathecal baclofen therapy screening and pump implantation. Once the infection is eradicated, the patient can undergo the procedure. Once a pump is in place, however, any infection must be managed properly, with heightened surveillance for the potential of seeding the hardware (catheter or pump). In addition, patients are advised to contact the physician responsible for intrathecal baclofen therapy when they are ill.
Goals and duration of treatment
The objectives of intrathecal baclofen are to administer the lowest dose for optimal effect on spasticity without systemic toxicity and to improve comfort, function, and ease of care of patients with spasticity. In case of spasticity of cerebral origin, intrathecal baclofen treatments should be started as soon as the condition of the patient is stabilized and prior to the development of contractures due to spasticity.
The use of botulinum toxin type A may be an important adjunctive therapy to increase the therapeutic effect of baclofen and the effectiveness of rehabilitation programs in patients after spinal cord injury (24).
Long-term continuous infusion of intrathecal baclofen delivered via an implantable pump can be effective for controlling spasticity resistant to other treatments. In patients with multiple sclerosis, spasm frequency is the single most common variable positively affected by intrathecal baclofen therapy. Continuous intrathecal baclofen can now be used in ambulatory patients with spasticity without causing weakness or interference with other aspects of ambulation. Intrathecal baclofen remains effective for the long-term treatment of spasticity of multiple sclerosis and increases the quality of life and functional independence in these patients (19).
Intrathecal baclofen therapy effectively reduces spasticity in children with cerebral palsy but complications necessitating removal of the baclofen pump can occur. Further research is needed to identify criteria describing the ideal candidate for intrathecal baclofen.
Long term administration of intrathecal baclofen by an implanted pump improves clinical efficacy in controlling spasticity but does not reduce the neurologic disability. The benefit and risk assessment, however, is favorable because the adverse effects do not exceed the benefits of oral and intrathecal baclofen for patients with spinal spasticity.
A review of records of all persons with cerebral palsy who received long-term treatment with intrathecal baclofen for spasticity showed that the treatment did not increase mortality and, rather, contributed to an increase in life expectancy as compared to matched cohorts (17).
Significant improvement in global intense pain, sharp pain, dull pain, and deep pain occurs during the first 6 months following intrathecal baclofen treatment of complex regional pain syndrome, but after this period, the scores level off despite further improvement of dystonia and continued intrathecal baclofen dose escalation (28).
A retrospective study has shown that intrathecal baclofen reduces dystonia and spasticity in dyskinetic cerebral palsy with improvement in sitting, communication, and fine motor function (Eek et al 2018).
Intrathecal baclofen therapy is effective in reducing spasticity in patients with cerebral palsy due to acquired brain injury, traumatic or hypoxic, but an intrathecal bolus injection should be performed to verify beneficial as well as adverse effects prior to implantation of the pump (30).
A single center prospective observational cohort study has concluded that intrathecal baclofen is an effective and safe long-term treatment for refractory spasticity related to multiple sclerosis, and most of patients subsequently discontinued systemic medications (23). A retrospective review of records from patients with spasticity of spinal origin showed that use of the Ashworth scale as a guide for dose adjustment of intrathecal baclofen therapy enabled effective management of patients with a relatively low dose of baclofen and a low rate of drug-related complications (Kawano et al 2018).
Dosing
The screening dose is 50 µg baclofen in 1 mL solution administered through a lumbar puncture over a period of not less than 1 minute. If there is a positive response over the next 4 to 8 hours, a second bolus dose of 75 µg is given and can be repeated after 24 hours.
Special considerations
Precautions/alerts. In 2015, the FDA issued a safety alert warning that certain lots of baclofen active pharmaceutical ingredient manufactured by Taizhou of China may be at risk for contamination with particulate matter and should not be used to prepare sterile injectable drugs.
Pediatric. Safety of baclofen in children under the age of 4 years has not been established. For children from 4 to 12 years of age, half the initial dose, ie, 25 µg should be used.
Geriatric. No special precautions.
Pregnancy. There are no studies of the systematic use of baclofen during pregnancy in humans. It should be used in pregnant patients only if the benefits outweigh the potential risks to the fetus. Oral baclofen passes into the milk of nursing mothers. It is not known if intrathecal baclofen does the same. Caution should be exercised in breast feeding during baclofen treatment. However, there are several case reports of intrathecal baclofen administered during pregnancy, and it is safer for the infant than oral baclofen (09; 10).
Anesthesia. A rare complication of stiff person syndrome has been reported due possibly to an interaction between the GABAergic effects of baclofen and volatile anesthetics (05). The patient had a slow recovery in spite of reversal of neuromuscular blockade.
Psychiatric disorders. Patients suffering from psychiatric disorders should be observed carefully following baclofen treatment as there is a possibility of exacerbation of these conditions.
Renal insufficiency. Baclofen should be given with caution to patients with renal insufficiency as the mechanism of excretion is renal.
Interactions
Combination of intrathecal baclofen with intrathecal morphine produces hypotension and dyspnea. No information is available for baclofen combination with other intrathecal medications.
Adverse effects
Adverse effects of intrathecal baclofen therapy include the following:
• Complications of lumbar puncture such as cerebrospinal fluid leakage and headache. | |
• Malfunction of intrathecal baclofen delivery systems may occur due to disconnection, fracture, or subdural migration. Conventional imaging may miss these complications, but combination of C-arm fluoroscopy and C-arm cone beam CT performed in 1 imaging session provides useful information for planning treatment (25). | |
• Wound dehiscence may occur over implanted pump in chronically ill children with atrophy of subcutaneous tissues, and it is recommended to place the pump in subfascial tissues rather than subcutaneously as is done routinely (02). | |
• Infections, particularly, meningitis following intrathecally administered baclofen is a rare but serious complication that is difficult to treat without removal of the pump. Intrathecal administration of antibiotic may be required to eradicate the pathogen. Urinary infections and fecal incontinence are risk factors for infection. The infection rate of intrathecal baclofen pumps significantly dropped in one institution after adoption of the guidelines, including preoperative chlorhexidine skin wash and intraoperative vancomycin wash of the fibrous pocket of the replacement site (04). | |
• Drowsiness. | |
• Psychosis has been reported during therapy with baclofen but resolves after discontinuation of the drug. | |
• Autonomic dysreflexia. | |
• Seizures (see the article, Drug-induced seizures). Structural brain disease seems to be a prerequisite for baclofen-induced seizures because they have not been reported to occur in patients receiving intrathecal baclofen for spasticity of solely spinal origin. Abrupt cessation of long-term baclofen therapy in such patients has been associated with various forms of seizure activity. Caution should be exercised with major reductions in dosage or discontinuation of baclofen therapy. Intravenous diazepam or phenobarbital or both is suggested for control of these seizures. | |
• After prolonged use, an increase in intrathecal baclofen dose may result in paradoxical unresponsiveness to baclofen, manifesting as increased tone and functional decline, which can be improved by reduction of dose. | |
• Baclofen withdrawal. Severe withdrawal symptoms can result, however, if intrathecal baclofen is abruptly withdrawn due to equipment malfunctions or human error. Several cases have been reported over the preceding decade, including some deaths. Warning signs of advanced intrathecal baclofen withdrawal syndrome include autonomic dysreflexia, sepsis, malignant hyperthermia, neuroleptic-malignant syndrome, or other conditions associated with hypermetabolic state or widespread rhabdomyolysis. Delirium has been associated with baclofen withdrawal and resolves completely on reinstatement of the drug. High-dose oral or enteral baclofen administration is recommended until restoration of intrathecal baclofen therapy is possible under the guidance of an experienced clinician. If this is not possible or is unlikely to be beneficial, benzodiazepines may be administered intravenously until intrathecal baclofen therapy is restored. Another strategy for prevention of baclofen withdrawal syndrome is tapering of the infusion and simultaneous substitution with progressively higher doses of oral antispasmodics. Withdrawal due to low pump reservoir levels can be avoided by refilling before the lowest level at which the alarm sounds is reached or resetting the alarm at a level higher that recommended. | |
• Impairment of sexual function, particularly erection, can occur following increase of dosage of baclofen, but is reversible after reduction of the dose (06). |
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.
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