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MOA and Pharmacology

While the exact mechanism of action (MOA) of baclofen is not understood, it is clear that baclofen works by affecting monosynaptic and polysynaptic reflexes at the spinal level. Therefore, to be effective baclofen must be present within the cerebrospinal spinal fluid (CSF).1

When taking oral baclofen, a much larger dose is needed to have an effect because much of the medication does not make it to the CSF due to its low lipid solubility and poor ability to cross the blood-brain barrier.2-5 Lioresal® Intrathecal is administered directly into the CSF, so much less medication is needed to have an effect on spasticity.1

Lioresal® Intrathecal: The Benefit of Targeted Drug Delivery

With Lioresal® Intrathecal, there is 100 times less medication flowing through
your bloodstream than with oral baclofen.1

Even with lower dosages compared to oral baclofen, spasticity is significantly less frequent and less severe with ITB TherapySM with Lioresal® Intrathecal, as demonstrated in improvements in Modified Ashworth Scale (MAS) scores within 1 hour of therapy (maximal effect 2-4 hours) in 12 spasticity patients. Improvements increased with increasing dose (21% of patients noted improvements at 25 mcg, 50% at 50 mcg, and 57% at 75 mcg).6

MAS Scores After Continuous Dosing of Oral Baclofen and Bolus Dosing of ITB therapy7

Adapted from Reference 7: Heetla HW, Proost JH, Molmans BH, Staal MJ, van Laar T. A pharmacokinetic-pharmacodynamic model for intrathecal baclofen in patients with severe spasticity. Br J Clin Pharmacol. 2016;81(1):101-112.

Learn more about the mechanism of action, pharmacokinetics, and pharmacodynamics of ITB therapy here. To learn more about dosing Lioresal® Intrathecal, please see Dosing and Administration.

 

An attempt should be made to discontinue concomitant oral antispasticity medication to avoid possible overdose or adverse drug interactions, either prior to screening or following implant and initiation of chronic Lioresal® Intrathecal infusion. Following pump implantation, and for each adjustment of the dosing rate of the pump and/or concentration of Lioresal® Intrathecal, the patient should be monitored closely until it is certain the patient’s response to the infusion is acceptable and reasonably stable.

  1. Lioresal® Intrathecal (baclofen injection) for intrathecal injection [prescribing information]. Saol Therapeutics, Roswell, Georgia; January 2019.
  2. KemstroTM (baclofen orally disintegrating tablets) for oral use [prescribing information]. Milwaukee, WI: Schwarz Pharma; Revised October 2003.
  3. Knutsson E, Lindblom U, Martensson A. Plasma and cerebrospinal fluid levels of baclofen (Lioresal®) at optimal therapeutic responses in spastic paresis. J Neurol Sci. 1974;23(3):473-484.
  4. Faigle JW, Keberle H. The chemistry and kinetics of Lioresal®. Postgrad Med J. 1972;48(Suppl 5):9-13.
  5. Muller H, Zierski J, Dralle D, Krauss D, Mutschler E. Pharmacokinetics of intrathecal baclofen. Local-spinal therapy of spasticity.1988:223-226.
  6. McCormick ZL, Chu SK, Binler D, et al. Intrathecal versus oral baclofen: a matched cohort study of spasticity, pain, sleep, fatigue, and quality of life. PM R. 2016;8(6):553-562.
  7. Heetla HW, Proost JH, Molmans BH, Staal MJ, van Laar T. A pharmacokinetic-pharmacodynamic model for intrathecal baclofen in patients with severe spasticity. Br J Clin Pharmacol. 2016;81(1):101-112.
  8. Albright AL. Baclofen in the treatment of cerebral palsy. J Child Neurol. 1996;11(2):77-83.
  9. Heetla HW, Staal MJ, Proost JH, van Laar T. Clinical relevance of pharmacological and physiological data in intrathecal baclofen therapy. Arch Phys Med Rehabil. 2014;95(11):2199-2206.
  10. Elovic E. Chapter 5: Assessment tools and treatment outcomes. In: Brashear A, Elovic E, eds. Spasticity: Diagnosis and Management. 2nd ed. New York, NY: Demos Medical Publishing, LLC, 2016.
  11. Francisco GE, Saulino M. Chapter 19: Intrathecal baclofen for spasticity. In: Brashear A, Elovic E, eds. Spasticity: Diagnosis and Management. 2nd ed. New York, NY: Demos Medical Publishing, LLC, 2016.

Baclofen

Baclofen (4-amino-3-(4-chlorophenyl) butanoic acid) is a gamma-aminobutyric acid (GABA) agonist that acts at the spinal cord level to impede the release of excitatory neurotransmitters that cause spasticity due to hyperexcitability of the stretch reflex.1,8,9

Plasma and CSF Baclofen Concentrations Following Oral Delivery7

Even after large oral doses, orally delivered baclofen reaches relatively low concentrations in the CSF

10 mg TID

Mean level: 120 mcg/L
Range: 50–203 mcg/L

 <12 mcg/L
20 mg TID

Mean level: 275 mcg/L
Range: 155–445 mcg/L

<12–64 mcg/L
8 of 10 patients did not reach CSF concentrations above 30 mcg/L
CSF concentrations reached 5 to 100 mcg/L with continuous oral dosing of 30 to 125 mg/day.

Modified Ashworth Scale (MAS)10

The MAS is a subjective scale that measures passive activity. A score of 0 to 4 is assigned by the examiner based on the amount of increased resistance perceived while moving the patient’s joint through its available range of motion. The MAS is an attempt to strengthen the Ashworth Scale, first published in 1964, with a more reliable scale, particularly when evaluating the wrist and elbow. Importantly, the Ashworth Scale and MAS are well known, easy to perform, and have a history of use for evaluating spasticity and management outcomes in both clinical trials and practice.10

Ashworth Scale10 Modified Ashworth Scale10
Score Description Score Description
0 No increase in muscle tone 0 No increase in muscle tone
1

Slight increase in muscle tone manifested at end of range of motion

 1

Slight increase in muscle tone manifested by a catch and release at end of range of motion
1+

Slight increase in muscle tone, manifested by a catch followed by minimal resistance throughout the remainder (less than ¼) of the range of motion
2

More marked increase in tone through most of the range of motion but joint easily moved

 2

More marked increase in tone through most of the range of motion but joint easily moved
3

Considerable increase in muscle tone; passive movement is difficult

 3

Considerable increase in muscle tone; passive movement is difficult
4

Affected part is rigid in flexion or extension

 4

Affected part is rigid in flexion or extension

Adapted from Reference 10: Khan AA, Birks-Agnew I, Bullock P, Rushton D. Clinical outcome and complications of intrathecal baclofen pump in multiple sclerosis patients: a retrospective study. NeuroRehabilitation. 2010;27(2):117-120.

Mechanism of Action

The precise mechanism of action (MOA) of baclofen as a muscle relaxant and antispasticity agent is not fully understood.1 During ITB therapy, baclofen is infused directly into the intrathecal space where it mixes with the CSF, binding to gamma-aminobutyric acid (GABA)-β receptors in the dorsal horn and dorsal root ganglion. Receptor binding stimulates a cascade of second messengers that ultimately hyperpolarize the presynaptic membrane at clinical doses and the postsynaptic membrane at substantially higher doses.1,9,11 Interruption of the spinal reflex (sensory peripheral afferent input and spinal motor afferent output) produces an antispastic effect by reducing peripheral motor tone.9

Pharmacokinetics

The pharmacokinetics of ITB therapy have been derived in 4 studies. Based on these studies1,9

  • Because baclofen is hydrophobic, it has difficulty passing the lipophilic membranes of cells in the spinal canal and the bulk of it will remain in the CSF
  • The intrathecal half-life of ITB therapy ranges from 1 to 5 hours (similar to plasma baclofen [3-4 hours])
  • CSF clearance is thought to take place by the turnover of CSF (suggesting elimination is by bulk flow of CSF)
  • After a bolus lumbar injection (n=7) of 50 or 100 mcg Lioresal® Intrathecal, the average CSF elimination half-life was 1.51 hours over the first 4 hours and the average CSF clearance was approximately 30 mL/hour
  • Mean CSF clearance was approximately 30 mL/hour when continuously infused (n=10)
  • Lumbar-cisternal concentration gradient of about 4:1 is established along the neuroaxis during infusion (n=5)
  • In pediatric patients (n=6, aged 8-18 years) receiving continuous infusion (77-440 mcg/day), plasma baclofen levels were near or below 10 ng/mL

Pharmacodynamics1

In adults, the onset of action after lumbar bolus injection is generally 0.5 to 1 hour after lumbar bolus injection. Peak effect is seen approximately 4 hours after dosing and may last 4 to 8 hours. Onset, peak efficacy, and duration of response will vary per individual based on dose and severity of spasticity symptoms. The onset, peak response, and duration of action are similar in pediatric and adult patients.1

Continuous ITB therapy via an implantable infusion pump provides baclofen at a much slower rate than a bolus injection. Antispastic activity is seen 6 to 8 hours after initiation of continuous infusion and maximum activity is observed in 24 to 48 hours.1

Important Safety Information for Lioresal® Intrathecal (baclofen injection)

Abrupt discontinuation of intrathecal baclofen, regardless of the cause, has resulted in sequelae that include high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity, that in rare cases has advanced to rhabdomyolysis, multiple organ-system failure and death.

Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the early symptoms of baclofen withdrawal. Special attention should be given to patients at apparent risk (e.g. spinal cord injuries at T-6 or above, communication difficulties, history of withdrawal symptoms from oral or intrathecal baclofen). Consult the technical manual of the implantable infusion system for additional postimplant clinician and patient information (see WARNINGS).

Indications and Usage

Contraindications

Select Warnings and Precautions

Adverse Reactions

Common Adverse Reactions

Serious Adverse Reactions

Postmarketing Experience

Use in Specific Populations

For more information, including BOXED WARNING, refer to Lioresal® Intrathecal (baclofen injection) prescribing information.