Baclofen for spasticity

Implantable drug delivery systems are defined as longterm (>30 days) implantable products that are resorbable or removable. The resorbable implants are injectables incorporating lyophilized microspheres. The removable version is typically a subcutaneous implant, requiring minor outpatient procedures for insertion and removal. The main commercialized product in this category is Norplant , a contraceptive implant. Medtronic Corporation has two products in the implantable area that allow drug delivery into the intrathecal space (where the spinal fluid circulates). One of these products delivers baclofen for spasticity, and the other delivers anaesthetics for pain control. Both products utilize Medtronic s SynchroMed infusion pump, which can be electronically programmed to deliver any type of preset dose. 

Pregnancy In a review of neonatal inpatient medical records from four pregnancies in three women receiving intrathecal baclofen for spasticity, two of the infants were bom preterm, one by urgent cesarean... 

Kofler M, Quirbach E, Schauer R, Singer M, Saltuari L. Limitations of intrathecal baclofen for spastic hemiparesis following stroke. Neurorehabil Neural Repair 2009 23(1) 26-31. 

Taira T, Hori T. Clinical application of drug pump for spasticity, pain, and restorative neurosurgery other clinical applications of intrathecal baclofen. Acta Neu-rochir Suppl. 2003 87 37-38. 

Abel NA, Smith RA. Intrathecal baclofen for treatment of intractable spinal spasticity. Arch Phys Med Rehabil 1994 75(l) 54-8. 

Ward A, Hayden S, Dexter M, Schleinberg A. Continuous intrathecal baclofen for children with spasticity and/or dystonia goal attainment and complications associated with treatment. J Paediatr Child Health 2009 45(12) 720-6. 

Currently, baclofen is the only clinically used GAB Ab receptor agonist. It is used as a muscle relaxant for treatment of spasticity in spinal injury and multiple sclerosis. The cloning of GABAb receptors has renewed the interest in the search for more selective diugs and novel therapeutic indications. 

The enantiomerically pure 3-arylglutaric ester are precursors for the synthesis of (—)-paroxetine [10], a selective serotonin reuptake inhibitor used in the treatment of depression, obsessive compulsive disorder, and panic, and (i )-Baclofen [11], a GABAb receptor agonist, which is used cHnically in the treatment of spasticity (Chart 5.1). 

Intrathecal Management of severe spasticity of spinal cord origin in patients who are unresponsive to oral baclofen therapy or experience intolerable CNS side effects at effective doses. Intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only in implantable pumps approved by the FDA specifically for the administration of baclofen into the intrathecal space. 

Baclofen is a GABA agonist at GABA B receptors and it has a presynaptic inhibitory function by reducing calcium influx. Its indication is increased extensor tone and clonus. Intrathecal administration may control severe spasticity pain. It is used for the treatment of spastic movement, especially in instances of spinal cord injury, spastic diplegia, multiple sclerosis and amyotrophic lateral sclerosis. Its central nervous system effects include drowsiness, somnolence and seizure activity in epileptic patients. 

Baclofen is an agent of choice for treating spinal spasticity and spasticity associated with multiple sclerosis. It is not useful for treating spasticity of supraspinal origin. Doses should be increased gradually to a maximum of 100 to 150 mg per day, divided into four doses. 

The three agents traditionally used in the treatment of spasticity are baclofen, diazepam, and dantrolene sodium (see Table 13-3, Fig. 13-2). Two newer agents, gabapentin and tizanidine, are also available for treating spasticity in various conditions. All of these agents are addressed below. 

When baclofen is administered intrathecally for the long-term tteatment of spasticity, a small catheter is usually implanted surgically so that the open end of the catheter is located in the subarachnoid space and the other end is attached to some type of programmable pump. The pump is implanted subcutaneously in the abdominal wall and is adjusted to deliver the drug at a slow, continuous rate. The rate of infusion is adjusted over time to achieve the best clinical reduction in spasticity. 

Uses. Intrathecal baclofen can result in decreased spasticity and increased comfort in many people with severe spasticity. This intervention can also result in functional improvements, especially in cases where voluntary motor control was being masked by spasticity.16 Ambulatory patients with spasticity resulting from a CVA, for example, may be able to increase their walking speed and increase their functional mobility after intrathecal baclofen therapy.37,74... 

These functional improvements, however, may not occur in all types of spasticity. Patients with severe spasticity of spinal origin, for example, may not experience improvements in mobility or decreased disability.103 If these patients do not have adequate voluntary motor function there is simply not enough residual motor ability to perform functional tasks after spasticity is reduced. Nonetheless, these patients may still benefit from intrathecal baclofen because of decreased rigidity and pain, which can result in improved self-care and the ability to perform daily living activities.37,74,76... 

Adverse Effects. The most common side effects associated with tizanidine include sedation, dizziness, and dry mouth.40 As indicated, however, tizanidine tends to have a more favorable side effect profile than other alpha-2 agonists, and this drug produces less generalized weakness than oral baclofen or diazepam. Tizanidine may therefore be a better alternative to these other agents in patients who need to reduce spasticity while maintaining adequate muscle strength for ambulation, transfers, and so forth. 

Most muscle relaxants are absorbed fairly easily from the gastrointestinal tract, and the oral route is the most frequent method of drug administration. In cases of severe spasms, certain drugs such as methocarbamol and orphenadrine can be injected intramuscularly or intravenously to permit a more rapid effect. Likewise, diazepam and dantrolene can be injected to treat spasticity if the situation warrants a faster onset. As discussed earlier, continuous intrathecal baclofen administration may be used in certain patients with severe spasticity, and local injection of botulinum toxin is a possible strategy for treating focal dystonias and spasticity. Metabolism of muscle relaxants is usually accomplished by hepatic microsomal enzymes and the metabolite or intact drug is excreted through the kidneys. 

Therapists can therefore play a vital role in facilitating the substitution of normal physiologic motor control for the previously used spastic tone. This idea seems especially true when one of the parenteral antispasticity techniques is used, such as intrathecal baclofen or botulinum toxin injections. For example, patients who receive intrathecal baclofen through programmable pump systems often require a period of intensive rehabilitation to enable the benefits from decreased spasticity and increased voluntary motor function to occur. Therapists must therefore be ready to use aggressive rehabilitation techniques to help patients adapt to the relatively rapid and dramatic decrease in muscle tone that is often associated with antispasticity drug therapy. 

Albright AL, Gilmartin R, Swift D, et al. Long-term intrathecal baclofen therapy for severe spasticity of cerebral origin. J Neurosurg. 2003 98 291-295. 

Sampson FC, Hayward A Evans G, et al. Functional benefits and cost/benefit analysis of continuous intrathecal baclofen infusion for the management of severe spasticity. J Neurosurg. 2002 96 1052-1057. 

Febrile reactions after intrathecal baclofen stopped a patient from receiving this treatment for spinal spasticity (14). 

A 33-year-old woman with spasticity caused by a myelopathy after numerous operations on her spine received a single bolus dose of baclofen 50 pg via a lumbar puncture, which resulted in complete resolution of her spasticity for almost 24 hours. However, her temperature increased to 39.0 C within 2 hours after the injection, and she had flu-like sjmptoms. Influenza was assumed to be the most likely explanation, as a child in her house had influenza at that time. Subsequently, an intrathecal catheter was placed and a baclofen pump implanted. However, her temperature rose again after baclofen administration had been started and the pump was halted. Subsequently, several attempts were made to restart the infusion, followed each time by spikes of fever. In the end, continuous intrathecal baclofen therapy had to be abandoned, and the fever did not recur. Several investigations to identify other causes of fever were mostly negative. However, based on bilateral hilar adenopathy on the... 

A 20-year-old woman was referred for implantation of an intrathecal baclofen pump (11). She had had severe dystonia and spasticity following a suicide attempt with disulfiram at age 14 years. T1-weighted MRI scanning of her brain showed bilateral globus pallidus infarction. She had profound rehef of spasticity after intrathecal test injections of baclofen and underwent implantation of an intrathecal baclofen pump. Her spasticity subsequently improved. 

Hassan N, McLellan DL. Double-blind comparison of single doses of DS103-282, baclofen and placebo for suppression of spasticity. J Nerrrol Nerrrosurg Psychiatry 1980 43(12) 1132-6. 

Relatively hydrophilic dmgs such as methotrexate (log P = -0.5) which do not cross the blood-brain barrier in significant amounts, have been infused intrathecally to treat meningeal leukaemia, and baclofen (log P =-1.0) to treat spinal cord spasticity. High lumbar CSF concentrates are achieved as a result. Figure 9.56 shows the anatomy of the epidural space and routes of dmg transport. The spinal CSF has a small volume (70 cm ) and a relatively slow clearance (20-40 cm h ) for hydrophilic dmgs. 

Other drugs for different spasticities include baclofen (this chapter, earlier), which is useful in multiple sclerosis and spinal cord trauma but not rheumatoid conditions the centrally acting orphenadrine (Chapter 8, Fig. 8-4) for Parkinson-like symptoms and the BZDs, particularly diazepam (considered later). 

Baclofen is absorbed orally, reaching peak plasma concentration in 2 hours, having a half-life of 3 to 4 hours, and being excreted unchanged by the kidneys. The onset and duration of action of baclofen are 4 and 8 hours, respectively. It should be given cautiously in patients with renal impairment. The administration of baclofen via spinal catheter or lumbar puncture in a single bolus test dose of 50 to 100 meg, or via an implantable pump for administration into the intrathecal space, has been approved for severe spasticity and pain in patients with cerebral palsy not responding to oral medications. 

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