Benefit of enteral baclofen in the management of spasticity in cerebral palsy

Abbreviations

Spasticity is a movement disorder that is commonly associated with cerebral palsy (CP) and can be managed by various treatment options. It can be increased or worsened by any noxious stimulus like infection, constipation, gastroesophageal reflux disease (GERD), tight clothes, and growth spurts.

Indications to treat spasticity include decreasing muscle spasms, improving posture, improving mobility, decreasing pain, improving use and tolerability of adequate braces, decreasing risk of pressure ulcers, preventing or decreasing the rate of contracture formation, and improving quality of life [1].

There are several pharmacologic treatment options used to treat spasticity which include chemodenervation with botulinum toxin injections; chemoneurolysis with phenol or alcohol; oral medications like diazepam, baclofen, tizanidine, and dantrolene; and intrathecal baclofen (ITB) [1]. Baclofen has been used as a mainstay for treatment of spasticity and was approved by the U.S. Food and Drug Administration (FDA) for the same recently on December 7, 2021, in the form of granules [2]. Though baclofen is not specifically approved by the U.S. FDA for CP-associated spasticity, it has been a first line oral treatment for children with spastic CP since the 1960 s [3]. Baclofen can be given orally, intravenously, and intrathecally. Side effects are described in Table 2.

Although oral baclofen is not as effective for cerebral spasticity as it is for spinal spasticity, it is nonetheless one of the most commonly used medications to treat cerebral spasticity in children [4]. Of its side effects, drowsiness is by far the most common [5]. Baclofen can also promote epileptogenesis by blocking inhibitory interneurons, shifting the balance in neuronal networks toward excitation [6]. Tolerance has been reported after prolonged oral administration but is infrequently a clinically significant problem.

The effect of baclofen is due to a balance between inhibition of neurotransmitter release, mediated by presynaptic GABA_B receptors, and inhibition of neuronal excitability, mediated by postsynaptic GABA_A receptors [7]. Baclofen decreases muscle spasticity, which can help ease caregiving, improve range of motion, and optimize positioning. The highest density of GABA_B binding sites is found in thalamic nuclei, the molecular layer of the cerebellum, the cerebral cortex, the interpeduncular nucleus, and the dorsal horn of the spinal cord [8]. GABA_B receptor agonists have several pharmacological effects in the central nervous system (CNS): central muscle relaxation, suppression of cocaine and narcotic drug self-administration, antinociception, cognitive impairment, inhibition of hormone release, synaptic plasticity, development of some neuronal pathways, as well as improvement of conduction in demyelinated axons [8].

While baclofen is rapidly absorbed after enteral administration, it has low lipid solubility and 30% is bound to protein, thereby making the crossover via the blood-brain barrier very poor [4]. At high oral doses (in adults, more than 120 mg/day), CNS drug levels are low [9]. Serum levels peak two to three hours after oral administration; the half-life is three to four hours, requiring repeated daily doses. Approximately 70% to 85% of the drug is excreted in the urine within 24 hours, hence the need to be dosed daily [1, 4]. It also has moderate systemic side effects listed in Table 2. Variability in response to oral baclofen can be multifactorial, including genetic causes [10, 11].

2 Clinical presentation of spasticity

Spasticity, an increase in tone, can present with delayed motor milestones, difficulty with and/or decreased range of motion, poor ability to maintain optimal hygiene, difficulty with performing activities of daily living, and increased exertion with mobility, transfers, proper positioning, and optimal fitting of braces. It is important to differentiate between severe spasticity or dystonia and GERD presenting as increased tone as the management differs. Spasticity increases metabolic rates, contributing to poor weight gain. It can also present as a cause of pain, negatively impact sleep, and greatly affect a person’s quality of life.

3 Indications for use in children and adults and side effects

The decision to treat spasticity is always based on in-depth discussion with the provider(s), with the patient (if able to communicate), and/or with the family/caregiver(s). The focus of treatment is to improve function, help improve pain, allow for a better fit with bracing, enable better quality sleep, improve positioning, and/or improve caregiver ease (See Table 1).

The decision to use certain options to treat spasticity is based on the provider’s personal preferences, an understanding of the literature, the clinician’s training, and the history of what has worked well for the patient in the past and what has not. After obtaining clinical history, physical examination is performed, and spasticity is identified using either the Modified Ashworth Scale (MAS) or Modified Tardieu Scale (MTS). Treatment is determined based on functional impact, positioning, caregiving, and hygiene. The choice of options utilized is dependent upon the presentation of spasticity. Usually, if the presentation is focal, recommendations include local chemodenervation followed by (or in combination with) therapies and other localized treatments (e.g., serial casting or splinting). For generalized hypertonicity, enteral medications such as baclofen are preferable as botulinum toxin injections and/or casting or splinting do not help with generalized hypertonia. Other enteral medications that are used to manage spasticity include diazepam, tizanidine, dantrolene, and gabapentin. Providers can control severe diffuse hypertonia with a combination of enteral medications to avoid adverse events but to maximize the efficacy. Sometimes, enteral baclofen is also used to manage focal spasticity or dystonia. Interventions to address spasticity have a better response when followed up with therapy via outpatient, home health, or home exercise programs.

For generalized spasticity, I use enteral medications like baclofen. Enteral baclofen has been widely used in the management of spasticity in CP in pediatric and adult patients. Tolerance to baclofen use can be seen in about 3–20% of cases [12]. Increasing the baclofen dose can cause the development of receptor saturation and severe downregulation, leading to unresponsiveness to baclofen. This can present as increasing spasticity in a previously well-controlled patient. Tolerance can be treated with a “baclofen holiday” of 3–37 days, during which another anti-spasticity medication can be used to manage the tone [12]. Baclofen can be restarted as a lower dose than was given before the drug holiday, necessitating a dose increase later due to receptor desensitization (start at a 30–80% lower dose than before the drug holiday with ITB) [12]. Baclofen must be weaned gradually, as stopping it abruptly can cause seizures which can be life-threatening. Despite concern about side effects such as somnolence, fatigue, weakness, and constipation, I usually recommend oral baclofen for children with diffuse spasticity or mixed tone with spasticity and dystonia, while recommending chemoneurolysis for children with focal spasticity to avoid systemic side effects such as constipation and fatigue. I usually start the medication at bedtime to avoid fatigue and help improve sleep, and I gradually increase and/or add doses during the day if spasticity gets better and requires a higher dose. Spasticity can cause pain/cramping in muscles. In the words of one of my patients, “It’s like a charley horse that never goes away.” Using the medicine at nighttime helps with sleep in addition to addressing spasticity, as that is when it is most often experienced. As the body adjusts to the dose at night, there may be a need to add doses during daytime. As half-life of baclofen is between 2–6 hours, its beneficial effect does not last through the day. Hence, doses are added during day with an interval of six to eight hours. I usually ask the family when the tone is most increased and will try to adjust dosing appropriately. Oral baclofen also is considered for patients with hepatic impairment since it is mainly excreted through the kidneys. As baclofen is renally excreted, baseline kidney function studies are obtained and monitored prior to starting this medication. For patients with renal impairment, renal function is monitored and medication is changed if there is worsening renal condition. I obtain both liver and kidney function tests prior to starting baclofen and monitor renal function every six months or, if stable, every year.

Baclofen is a relatively safe drug when used judiciously. It has been used for a long time to manage spasticity. The side effect profile is manageable and easy to troubleshoot. It is affordable, as it is often approved by payers. It is not an invasive treatment option and is a good medication to use with other modalities. Usual side effects that I have seen include drowsiness, which can be managed by using the medication at times of naps/sleep. Constipation is managed with laxatives. Most other enteral medications for spasticity management have the same side effect profile with drowsiness. If a patient cannot tolerate oral baclofen or other enteral medications due to drowsiness, I may consider medication that does not cross blood-brain barriers such as dantrolene or local approaches with chemodenervation or chemoneurolysis. If patients respond well to enteral baclofen for diffuse hypertonia but side effects prevent them from continuing it, I consider ITB.

5 What are the positive things that I expect from baclofen when I prescribe it to a patient?

Enteral baclofen has several positives for clinicians to consider: 1) It is a less invasive approach. Some parents are reluctant to accept invasive approaches such as chemodenervation on chemoneurolysis. 2) Its effect is not selective but systemic, which is good for diffuse hypertonia. 3) It is useful as an adjunctive if chemodenervation and/or chemoneurolysis approaches are not sufficient to cover diffuse spasticity or dystonia. 4) It is good for mixed tone with spasticity and dystonia since baclofen is effective for both. 5) It has an additional effect on external sphincters for spastic bladders and oromandibular dystonia. 6) Patients can be younger than two years old whereas botulinum toxins have not been approved for this age group. 7) It is associated with less hepatotoxicity.

6 Anecdotal use of enteral baclofen and its results

7 Conclusion

In conclusion, enteral baclofen is a safe, effective medication which is easy to administer and has few side effects. It is a very useful adjunct in the treatment of spasticity in CP. As with any medication, it should be judiciously used and attention should be paid to any side effects.