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Baclofen efficacy and safety trials (best): lack of consensus on oral baclofen dosing practices for children with cerebral palsy

JE BRUNSTROM-HERNANDEZ MD 1, 2, E STASHINKO PHD 3,
LE KRACH MD 4,5, LL THIO MD PHD 1,2, MM KURODA PHD MPH 6,7,
K BJORNSON PHD PT 8, 9, A HOON MD 3, 10, D GAEBLER MD 6, 7,
RJ HAAKE PHD 11, DR MATTISON MD 12

1. Neurology Pediatrics, Washington University School of Medicine, St. Louis, MO;
2. Pediatric Neurology Cerebral Palsy Center, St. Louis Children’s Hospital, St. Louis, MO;
3. Neurology, Developmental Pediatrics, Kennedy Krieger Institute, Baltimore, MD;
4. Physical Medicine and Rehabilitation, University of Minnesota, St. Paul, MN;
5. Physical Medicine and Rehabilitation, Gillette Children’s Specialty HealthCare, St. Paul, MN
6. Physical Medicine and Rehabilitation, Rehabilitation Insitute of Chicago, Chicago, II;
7. Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago II;
8. Pediatrics, Seattle Children’s Research Institute, Seattle, WA;
9. Pediatrics, University of Washington School of Medicine, Seattle, WA
10. Neurology, Developmental Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
11. Biostatistics, Premier Research Group, Limited, Philadelphia, PA;
12. Obstetric and Pediatric Pharmacology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA


Background/Objectives: Oral baclofen has been used for decades to treat spasticity in children with cerebral palsy (CP) based on adult studies. Few data exist regarding its pharmacokinetics (PK) and pharmacodynamics (PD) in children. This study (and an ongoing PKPD study) was carried out to describe clinical dosing practices at seven academic centers in preparation for a subsequent randomized controlled trial.

Design: Multicenter retrospective chart review.

Participants and Setting: A total of 1968 medical records were screened. One hundred and eighty five subjects met inclusion criteria (diagnosis of spastic CP, age 2-16 years at the start of oral baclofen, followed at site for at least 1 year, started on baclofen at the site, on baclofen within 5 years prior to start date of the chart review).

Materials/Methods: Sites screened charts of every patient evaluated in their CP clinic on or before 11-22-2006 until 30 eligible subjects were identified at each site for complete chart review. Demographic and baseline characteristics were obtained. Prior and concomitant medications, therapies and surgeries were recorded. Prior and concomitant medications, therapies and surgeries were recorded. Oral baclofen dosing data was collected, including date, dose/frequency, formulation, and route of administration at initial, maximum and final doses. Dose change data and reason for dosage change or discontinuation of baclofen were recorded. Descriptive analysis was employed across all subjects and by age group.

Results: One hundred and eighteen males and 67 females were included. Most subjects were Caucasian (61.6%) or African-American (22.7%), had four –limb involvement (84%) and a GMFCS score of IV or V (≥ 71%). The most common etiology/risk factor for CP was prematurity (54%). Most subjects (62%) were on no additional tone medications, and 31% were taking one additional tone medication. Mean age at start of baclofen was 6.9(SD 4 years): 90 subjects ≥ 2 to ≤6, 65 subjects ≥6 but <12 years; 30 subjects ≥12 to ≤ 16 years. Length of time on baclofen ranged from <1 month to 11.75 years. Mean initial dose of baclofen was 7.7 mg. Most subjects started at once daily dosing (49.7%). Mean maximum dose was 31.4 mg with the most frequent schedule being three times a day (44.9%).Mean escalation rate (initial to max dose) was 3.47 months with different rates of escalation in each age group. Correlation was found between maximum dose and age, but not between maximum dose and weight. Lack of efficacy was the primary reason for dosing changes. Comparison of dose or dosing strategy among the seven sites showed no consensus, overall or by age group (e.g. overall initial dose varied from 5.27 to 10.3 mg, maximum dose from 27.92 to 34.81 mg, escalation rate from 1.76 to 5.51 months).

Conclusions/Significance: Baclofen dosing in children with CP varies widely and there is no consensus among practitioners for any dosing parameter in any age group. These data indicate the need for prospective clinical trials to establish safe and effective oral baclofen dosing practices in children with CP.

 
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