By: Ada Seldin, Staff Editor

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Intrathecal baclofen (ITB) is indicated for the treatment of intractable spasticity caused by spinal cord injury, multiple sclerosis, spinal ischemia or tumor, transverse myelitis, cervical spondylosis, cerebral palsy, and degenerative myelopathy.¹ Baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal cord level by decreasing excitatory neurotransmitter release from primary afferent neurons. An analog of gamma-aminobutyric acid (GABA), the drug may act as an agonist at GABAb receptor sites.² Activation of the G protein-coupled GABAb receptors on presynaptic terminals leads to a decrease in calcium influx, and therefore a decrease in neurotransmitter release.³

The intrathecal route of administration allows for the achievement of therapeutic cerebrospinal fluid (CSF) concentrations while maintaining a safe plasma concentration. To achieve the same CSF levels by oral administration, the plasma concentration would be increased 100-fold. Continuous infusion of intrathecal baclofen generally produces antispastic effects six to eight hours after initiation, reaching its peak effect at 24 to 48 hours. Continuous delivery of baclofen is accomplished via the use of a surgically implanted pump into the abdomen.²

Prior to pump implantation, patients must demonstrate a positive clinical response to a bolus dose of intrathecal baclofen (Lioresal^®). During this screening phase, 50 mcg of baclofen in 1 ml is injected into the intrathecal space over at least one minute, and the patient is observed for the next four to eight hours. A positive response is defined as a significant decrease in muscle tone, and in frequency and/or severity of spasms. If the response is subclinical, a second bolus injection of 75 mcg in 1.5 ml may be administered 24 hours after the first, and finally a third at 100 mcg in 2 ml, another 24 hours later.

Once the pump is implanted, the agent should be titrated, beginning at an initial daily dose (over 24 hours) of twice the screening dose that produced a positive response. If the therapeutic response lasted for more than 8 hours in the screening phase, the titration dose should be limited to the screening dose. In either case the dose should not be increased in the first 24 hours. Afterwards, the daily dose is slowly increased by 10-30% every 24 hours for adults with spasticity of spinal cord origin and by 5-15% for adults with spasticity of cerebral origin to achieve a desired clinical effect. Maintenance doses usually fall between 300 mcg and 800 mcg per day in patients with spasticity of spinal cord origin and between 90 mcg and 703 mcg to treat spasticity of cerebral origin. During periodic refills of the pump, the daily dose should be increased by no more than 40% in spinal cord spasticity and 20% in cerebral spasticity.²

In 2008, Baclofen (Lioresal^®) ranked third amongst all prescription drugs for reported serious, disabling, and fatal injuries. These may have been caused by complications in the catheter that delivers the drug directly to the CSF. Medtronic, which markets the delivery system—Synchromed^® pump and delivery catheters—as well as the medication, issued an urgent safety alert warning healthcare providers and patients that sudden discontinuation of baclofen can result in substantial morbidity and mortality.⁴ Symptoms of withdrawal include high fever, altered mental status, exaggerated rebound spasticity and muscle rigidity. In rare cases, symptoms can progress to rhabdomyolysis, multiple organ-system failure, and death. Abrupt drug discontinuation is mainly attributed to disconnection or blockade of the catheter to the pump, low volume in the pump reservoir, and end of pump battery life.² One of the changes that may indicate such a complication is a sudden increase in the required therapeutic dose.

Another risk of intrathecal baclofen administration is the potential for overdose.  Overdose of intrathecal baclofen can produce drowsiness, lightheadedness, dizziness, respiratory depression, and seizures. In an acute, large overdose, patient may be driven into a coma. Multiple factors, including pump malfunction, improper refilling procedures, and dosing error, can lead to overdose. The following are some case reports of what may result in an overdose.

Due to its design, one model of the Medtronic SynchroMed^® infusion pump demands special care to be taken during refills to avoid potentially fatal consequences. The pump has two access ports: one central injection port leading to the drug reservoir, and a peripheral port that leads directly into the catheter connected to the intrathecal space. The latter is mainly used for myelography, removal of CSF, or catheter troubleshooting. In an attempt to curb errors, Medtronic provides distinct kits with instructions and warnings for each port. The refill kit (for the central port) contains a thicker needle that is not compatible with the catheter port, which will only accept a thinner needle. However, the warnings written on the packaging may be overlooked, resulting in using the catheter kit for refills instead of the designated refill kit. Doing so would introduce large doses of drug directly into the CSF, resulting in overdose. The FDA has received reports of fatal overdoses of concentrated morphine through the catheters of these pumps.⁵

Errors can also occur in the programming of the pumps. SynchroMed II^® pumps have several programming options, one of which is the “flex mode,” permitting programmable dosing variations throughout the day depending on the severity of symptoms. In early 2010, a physician accidentally changed the total daily delivery of baclofen instead of the morning bolus dose he had intended to increase, which lead to an overdose for the patient who was suffering from muscle spasticity. This resulted in 13 days of hospitalization for persistent weakness in his legs.⁶

Another case of baclofen overdose sheds light on the potential for erroneous calculations if the drug remaining in the space between the reservoir and catheter access port is not taken into account. A 45-year-old woman had her pump and catheter emptied of baclofen 2000 mcg/mL in order to adjust the dose to 1000 mcg/mL. Because the subsequent priming bolus did not account for the baclofen remaining in the space between the reservoir and catheter access port, an overdose occurred.⁷ In the event of an overdose, the baclofen solution should be removed from the pump as soon as possible and the patient should be intubated, if necessary, until the drug is cleared. The mean CSF clearance of intrathecal baclofen is 30 ml/hr.  If lumbar puncture is not contraindicated, 30-40 mL of CSF can be withdrawn to reduce the baclofen concentration in the CSF.²

      Although intrathecal baclofen is effective in increasing the functionality and quality of life of patients with spasticity, 20-30% of these patients experience complications, including overdose, withdrawal, equipment protrusion, CSF leaks, and infections. A retrospective study conducted at the New York University Langone Medical Center (NYULMC) on 87 patients undergoing ITB pump-related procedures concluded that many of the associated complications were preventable with better patient selection, surgical technique, and post-operative follow-up.⁸ As with any medication, it is important to be mindful of potential dangers that may present itself at any point.

 

SOURCES:

1. Lexicomp Online^TM. Baclofen monograph.http://online.lexi.com/lco/action/doc/retrieve/docid/lijmc_f/243426. Accessed April 2, 2014.
2. Medtronic for Healthcare Professionals. Lioresal intrathecal full prescribing information. http://professional.medtronic.com/pt/neuro/itb/fpi/# Last updated March 2013. Accessed April 2, 2014.
3. Olsen RW, DeLorey TM. Basic Neurochemistry: Molecular, Cellular and Medical aspects. 6th ed. Philadelphia: Lippincott-Raven; 1999
4. Institute for Safe Medication Practices. QuarterWatch: 2008 quarter 3. http://www.ismp.org/quarterwatch/2008Q3.pdf Accessed April 2, 2014.
5. Institute for Safe Medication Practices. Template for disaster? Fatal injection into wrong port of implanted infusion pump. http://www.ismp.org/newsletters/acutecare/articles/20040115.asp Accessed April 2, 2014
6. Institute for Safe Medication Practices. Baclofen programming error with SynchroMed II pump. Facility not made aware of company’s software updates. http://www.ismp.org/newsletters/acutecare/articles/20100128.asp Accessed April 2, 2014.
7. Dalton C, Keenan E, Stevenson V. A novel cause of intrathecal baclofen overdosage: lessons to be learnt. Clinical Rehabilitation February 2008 22: 188-190
8. Haranhalli N, Dhanya A, et al. Intrathecal baclofen therapy: complication avoidance and management. Childs Nervous System 2011 27: 421-427.

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