In a new review paper, researchers discussed the factors that need to be considered, and the obstacles that must be overcome, to effectively use oral baclofen to treat spasticity in CP children.
Titled “Examining the role of precision medicine with oral baclofen in pediatric patients with cerebral palsy,” the review was published in Current Physical Medicine and Rehabilitation Reports.
Muscle stiffness, specifically spasticity, is the most common movement difficulty seen in children with cerebral palsy. To reduce the observed increase in muscle tone, the medical community uses baclofen — a muscle relaxant with the brand names Lioresal and Gablofen—to reduce abnormal muscle stiffness.
Baclofen acts on receptors in the brain and spinal cord, called gamma-aminobutyric acid B (GABA-B) receptors. But it first needs to actually get to those GABA-B receptors for it to work.
The medicine can be delivered orally, as a pill. It also can be administered directly into the central nervous system (CNS) — the brain and spinal cord — via an intrathecal route, using a pump that is surgically implanted under the skin of the abdomen. However, that approach is far more invasive.
The researchers began their discussion of the muscle relaxant by highlighting some of the ways oral baclofen treatment can be more complicated than it seems. They noted that the dose, or how much of a medicine is ingested, and the exposure — how much ends up in circulation — are usually intuitively related. However, there are factors in the body, and variation between individuals, that can impact this in unexpected ways.
For instance, certain genetic factors can lead to faster or slower clearance of a medicine, making it stick around in the body for different periods of time. Emblematic of this, a variation in a gene called ABCC9 is known to be associated with faster clearance of baclofen.
The researchers also noted that, as the body develops throughout childhood, levels of enzymes that metabolize medicines may fluctuate, and certainly may vary between individuals.
In addition, baclofen doesn’t just have to get into the blood, but into the central nervous system. Transport into the CNS is tightly regulated by a number of factors that also can also vary person-to-person, further complicating the process.
And, figuring out how much baclofen gets into the system from a given dose doesn’t tell the whole story about how well it will work in an individual. Differences in how the compound affects its targets can manifest variation as well. For instance, some people may naturally express more or fewer GABA-B receptors, which would be expected to affect how effective the therapy is.
“In an ideal world,” the researchers said, “the relationship between the expression and function of GABA-B receptor and the degree of spasticity in a cerebral palsy patient would be known, as well as the amount of [baclofen] that needs to be in the CNS to interact with the GABA-B receptor to elicit the desired therapeutic response. Similarly, tools would be available to individualize the dose for that patient to achieve the plasma concentration that corresponds to the desired CNS exposure to achieve the desired response.”
In reality, the process is much more complicated — particularly with children, they said.
“Unfortunately, many factors influencing the continuum of the dose→exposure→response relationship remain uncharacterized for the pediatric cerebral palsy population,” the researchers said.
Understanding these factors will be necessary for baclofen to be used safely and effectively in children with CP, they said.
“Ultimately, this would lead to a more anticipated clinical response when initiating treatment with oral baclofen and limits adverse events,” the investigators said.