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Pharmacological Management of Spasticity in Children With Cerebral Palsy

      Abstract

      Cerebral palsy (CP), a nonprogressive disease of the central nervous system, is the most common motor disability in childhood. Patients with CP often have a multitude of associated comorbidities, including impact on muscle tone. There are four main types of CP, with spastic as the most commonly diagnosed. Reduction in spasticity is important because it can affect not only the patient's quality of life, functional abilities, and well-being but also the lives of caregivers. The American Academy of Neurology and Child Neurology Society released a practice parameter regarding the pharmacological management of CP-related spasticity in 2010. Since then, data have been published evaluating the safety and efficacy of oral and parenteral medications to manage spasticity. This continuing education review evaluates the available safety and efficacy evidence for oral and parenteral pharmacological agents used to reduce spasticity in children with CP and provides a reference for practitioners managing these patients.

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      • 1.
        Read the article carefully.
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        Read each question and determine the correct answer.
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      OBJECTIVES

      • 1.
        Recognize available medications used to manage cerebral palsy–associated spasticity.
      • 2.
        Evaluate the pharmacology of and current efficacy and safety data on oral and parenteral medications used to manage spasticity in children with cerebral palsy.
      • 3.
        Describe practical and patient-specific considerations when choosing between medications used to manage spasticity in children with cerebral palsy.
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      Contact hours: 1.5 (0.25 Controlled Substance)
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      This continuing education activity is administered by the National Association of Pediatric Nurse Practitioners (NAPNAP) as an Agency providing continuing education credit. Individuals who complete this program and earn a 70% or higher score on the Posttest will be awarded 1.5 contact hours, of which 1.5 are Pharmacology CE contact hours and 0.25 are related to Controlled Substance.
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      INTRODUCTION

      Cerebral palsy (CP) is broadly defined as a group of disorders affecting a person's balance and posture and is the most common motor disability in childhood (
      • Arens M.J.
      • Dent J.
      Acid pump blockers: What are their current therapeutic roles.
      ). CP is caused by abnormal brain development or nonprogressive damage to the developing brain early in life (
      • Bax M.
      • Goldstein M.
      • Rosenbaum P.
      • Leviton A.
      • Paneth N.
      • Dan B.
      Executive Committee for the Definition of Cerebral Palsy
      Proposed definition and classification of cerebral palsy, April 2005.
      ). Alterations in sensation, cognition, perception, communication, and behavior accompany the motor disorders seen in CP. According to the Centers for Disease Control and Prevention (CDC), prevalence estimates CP to be from 1.5 to more than 4 per 1,000 live births; an estimate of 1 in 323 children have been identified with CP according to the CDC's Autism and Developmental Disabilities Monitoring Network (

      Centers for Disease Control and Prevention. (2019). Data and statistics for cerebral palsy. Retrieved from https://www.cdc.gov/ncbddd/cp/data.html

      ).
      The etiology of CP may be due to prenatal (most cases), perinatal, or postnatal causes (
      • Worthington M.A.
      Cerebral palsy.
      ). There are four main types of CP: spastic, dyskinetic, ataxic, and mixed (
      • Arens M.J.
      • Dent J.
      Acid pump blockers: What are their current therapeutic roles.
      ). Clinically, CP presents with a broad range of features and is classified by motor abnormalities and the body parts involved (e.g., hemiparesis, diparesis, quadriparesis;
      • Worthington M.A.
      Cerebral palsy.
      ). CP is typically thought to be a heterogeneous disorder with multiple types of movement disorders with spastic and dyskinetic (e.g., dystonic and choreoathetoid) as the most common. Gross motor function is described using the Gross Motor Function Classification System (GMFCS), a 5-level system with GMFCS V representing the most severe limitations. Children with CP often have several other accompanying impairments including, but not limited to, intellectual and developmental disability, seizures, drooling, constipation, urinary incontinence, and gastroesophageal reflux disorder. Spasticity is the most common muscle abnormality and is a form of hypertonia that is characterized by a velocity-dependent resistance to muscle stretch (
      • Delgado M.R.
      • Hirtz D.
      • Aisen M.
      • Ashwal S.
      • Fehlings D.L.
      • McLaughlin J.
      • Vargus-Adams J.
      Practice parameter: Pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      ).
      Spasticity is thought to be a result of an injury to the central nervous system (CNS), which produces an upper motor neuron lesion that subsequently affects the muscle fibers (
      • Deon L.L.
      • Gaebler-Spira D.
      Assessment and treatment of movement disorders in children with cerebral palsy.
      ). Spasticity is associated with limitations in function, pain, and difficulty with caregiving (
      • Worthington M.A.
      Cerebral palsy.
      ). Treating CP-related spasticity is aimed at reducing muscle spasm and pain; facilitating therapies; reducing contractures and deformities; improving posture, mobility, and motor function; and helping with caregiving tasks (
      • Delgado M.R.
      • Hirtz D.
      • Aisen M.
      • Ashwal S.
      • Fehlings D.L.
      • McLaughlin J.
      • Vargus-Adams J.
      Practice parameter: Pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      ). In some cases, reducing spasticity may uncover other symptoms such as weakness. Therefore, when initiating therapies to reduce spasticity, careful monitoring is necessary to ensure benefits outweigh risks. In cases in which improving spasticity is helpful, nonpharmacological therapies such as physical and occupational therapies, stretching, and the use of orthotics must first be optimized before initiating pharmacotherapy.
      In 2010, the American Academy of Neurology and the Child Neurology Society published a practice parameter focused on the pharmacological treatment of spasticity in children and adolescents with CP (
      • Delgado M.R.
      • Hirtz D.
      • Aisen M.
      • Ashwal S.
      • Fehlings D.L.
      • McLaughlin J.
      • Vargus-Adams J.
      Practice parameter: Pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      ). Nearly a decade has passed since publication, and additional evidence and clinical experience are now available. The purpose of this article is to review available pharmacological agents to treat spasticity and supporting literature and to provide the pediatric practitioner with a hands-on guide to managing CP-related spasticity.

      PHARMACOLOGICAL MANAGEMENT OF CP-RELATED SPASTICITY

      Several pharmacological agents, both oral and parenteral options, exist for the management of CP-associated spasticity (Table 1). Available agents for spasticity have a variety of pharmacological targets including neurotransmitters such as acetylcholine, a neurotransmitter released at the neuromuscular junction, and γ-aminobutyric acid (GABA), an inhibitor neurotransmitter, and directly on the skeletal muscle. A discussion of each agent is provided including a review of pharmacology, supporting efficacy and safety data, and clinical and practical considerations. When evaluating the supporting evidence and individual response to intervention, an understanding of available spasticity assessment tools, outcome measures, and scales is necessary (Table 2).
      TABLE 1Pharmacotherapy for the management of cerebral palsy–associated spasticity in children
      Data in this table have been compiled and extrapolated from studies discussed and presented in this review and the LexiComp and Micromedex databases. Although these dosing recommendations are meant to provide guidance on the usual dosing ranges, prescribing clinicians should always consult drug information resources and/or consult with a clinical pharmacist for the most up-to-date and patient-specific dosing recommendations when initiating therapy. Clinicians are urged to prescribe the most conservative initial dose, with titration to the lowest effective dose.
      Pharmacologic agentMechanism of actionFDA-approved for spasticity in children?Available data/level of evidenceAge ranges studied, yearsDosingDosage formsCommon adverse effectsClinical considerations(+) pro/benefit() con/risk
      Baclofen (oral)GABAB analog that inhibits both monosynaptic and polysynaptic reflexes at the spinal cord level, resulting in reduction of muscle spasticityNoSystematic review; dose-finding study, retrospective study, RCT2–17

      Fixed dosing:

      ≥ 4 months to < 2 years: 10–20 mg daily divided every 8 hr; max: 40 mg/day

      < 8 years: 20–40 mg daily divided every 8 hr; max: 60 mg/day

      ≥ 8 years 30–40 mg daily divided every 8 hr; max: 60–80 mg/day
      Tablet; extemporaneously compounded suspensionSomnolence (dose limiting); asthenia; hypotonia; headache; confusion(+) quick onset of action

      (+) crosses the BBB at higher doses

      (−) higher doses lead to more adverse events

      (−) must be tapered off to avoid withdrawal syndrome (e.g., spasms, hallucinations, confusion, seizures)
      DiazepamBinds to GABAA receptors within the spinal cord and motor neurons to produce its muscle relaxant effectsYesDouble-blind, placebo-controlled trial; RCT; double-blind crossover study; randomized prospective follow-up study1–18Weight-based dosing, oral:

      0.01–0.3 mg/kg divided in 2 or 4 doses daily

      Fixed dosing (children ≥ 5 years and adolescents), oral: initial: 1.25 mg TID; titrated to 5 mg QID

      Low-dose (nightly), oral:

      < 8.5 kg: 0.5–1 mg at bedtime

      8.5–15 kg: 1–2 mg at bedtime
      Tablet, oral solution, oral concentrate, IM + IV injection, rectal gel (IM, IV, and rectal routes reserved for emergent management of seizures)Sedation (dose limiting); urinary retention, weakness, constipation(+) inhibitory effect on both the spinal cord and supraspinal levels

      (−) can develop dependence if used long-term; recommended to taper when discontinuing
      DantroleneInhibits the release of calcium from sarcoplasmic reticulum in muscle resulting in muscle relaxationYes (oral formulation approved in patients ≥ 5 years)Double-blind crossover study; within-subject, crossover study; two-phase study; double-blind, randomized study1.5–17Weight-based dosing:

      < 50 kg, oral:

      initial: 0.5 mg/kg/dose once daily for 7 days; titrate to 2 mg/kg/dose TID (max. 400 mg/day)

      Fixed dosing:

      ≥ 50 kg, oral:

      initial: 25 mg once daily for 7 days; titrate to 100 mg TID (max. 400 mg/day)
      Oral capsule, powder, may be compounded into an oral suspension, IV injection (reserved for management of malignant hyperthermia)Somnolence, sedation, anorexia, diarrhea, vomiting(+) acts peripherally rather than centrally resulting in decreased sedation in comparison to other agents

      (−) black box warning for hepatotoxicity

      (−) although rare, has the potential to exacerbate seizures
      Tizanidineα2-adrenergic agonist that reduces spasticity by increasing presynaptic inhibition of motor neuronsNoRetrospective review; retrospective study2–14Initial dosing:

      2 to < 10 years: 1 mg at bedtime

      ≥ 10 years: 2 mg at bedtime

      Maintenance dosing:

      titrate to 0.3–0.5 mg/kg/day in 3–4 divided doses (max. 24 mg/day)
      Oral tablet, oral capsule



      Tablets and capsules are not bioequivalent under nonfasting conditions
      Sedation (dose limiting), hypotension, constipation, dizziness(+) effective in tone reduction

      (−) only available as a tablet or capsule

      (−) under nonfasting conditions, capsules associated with 20% increased absorption
      Baclofen (intrathecal)Injected directly into the subarachnoid space around spinal cord and acts as a GABAB agonistYesRandomized, placebo-controlled, dose-finding study; systematic review; consecutive case series; retrospective cohort study4.5–17.4Test dose

      < 4 years: 25 µg

      ≥ 4 years: 50 µg

      Following positive response from test dose

      Initial: double the test dose and give over 24 hr; do not further increase dose in first 24 hr.

      Maintenance dosing: increase daily dose by 5%–20% once every 24 hr until satisfactory response achieved (> 1,000 µg daily has limited data)
      Injectable solutionLethargy, somnolence, hypotonia, dry mouth, decreased appetite, headache, nausea(+) Used in severe spastic CP after failing oral baclofen or intolerable CNS side effects

      (+) useful for widespread spasticity

      (+) bypass BBB with better access

      and minimizing side effects

      (−) child must be at least 15 kg

      (−) surgical complications

      (−) risk of pump failure and withdrawal syndrome
      BTX-AHigh affinity and specificity to presynaptic membranes of cholinergic motor neurons (reduces acetylcholine release from presynaptic neuron])Yes (abobotulinumtoxinA)RCTs; prospective, open-label study; prospective observational studyEfficacy: 2–17

      Safety:

      10 months–20
      AbobotulinumtoxinA recommended dose range per muscle per limb

      gastrocnemius: 6–9 units/kg/dose divided in up to four injections

      soleus: 4–6 units/kg/dose divided in up to two injections

      Total dose range per treatment session

      Unilateral limb:

      15 units/kg/dose

      Bilateral limbs:

      30 units/kg/dose (max. 1,000 units)
      Injection solutionMuscle soreness, injection site pain, leg cramps, flu-like symptoms, infection(+) localized spasticity—can be injected directly into the muscle

      (+/−) injection every 3 months

      (+/−) 3–4-month clinical response

      (−) production of antibodies leads to ineffectiveness
      PhenolProduces chemical neurolysis by protein denaturation and blocking efferent signals by targeting α and γ motor neuronsNoCase-controlled study; retrospective cohort study1.2–18.95% or 6% solution: no set dose; usually 3–5 mL/dose (max dosage per treatment: 20 mL)Injection solutionPain at site of injection, generalized weakness, bruising(+) useful for localized spasticity

      (+) quicker onset of action and longer duration (approximately 12 months) than BTX-A

      (−) Increased side effects compared to BTX-A

      (−) Requires general anesthesia and careful administration technique
      Note. BBB, blood brain barrier; BTX-A, botulinum toxin A; CNS, central nervous system; CP, cerebral palsy, FDA, Food and Drug Administration; GABA, γ-aminobutyric acid, IM, intramuscular; IV, intravenous; QID, four times a day; RCT, randomized controlled trial; TID, three times a day.
      a Data in this table have been compiled and extrapolated from studies discussed and presented in this review and the LexiComp and Micromedex databases. Although these dosing recommendations are meant to provide guidance on the usual dosing ranges, prescribing clinicians should always consult drug information resources and/or consult with a clinical pharmacist for the most up-to-date and patient-specific dosing recommendations when initiating therapy. Clinicians are urged to prescribe the most conservative initial dose, with titration to the lowest effective dose.
      TABLE 2Assessment tools, outcome measures, and scales used to evaluate spasticity
      AssessmentsOutcome measuresScales
      Ashworth Scale and MAS (
      • Mutlu A.
      • Livanelioglu A.
      • Gunel M.K.
      Reliability of Ashworth and Modified Ashworth scales in children with spastic cerebral palsy.
      )
      • Measuring resistance during passive stretching to determine the level of muscle spasticity
      • Lower scores indicate less muscle spasticity
      • Grading scale from 0 to 4
      • MAS includes 1+ on scale
      BADS (
      • Monbaliu E.
      • Ortibus E.
      • Roelens F.
      • Desloovere K.
      • Deklerck J.
      • Prinzie P.
      • Feys H.
      Rating scales for dystonia in cerebral palsy: Reliability and validity.
      )
      • Evaluates dystonia in eight body regions
      • Numerical scale (0–4)
      COPM
      • Children with CP and their parents or caregivers identify five activities they want to do or would like to do better during therapy or intervention
      • Each activity or goal is scored on a 10-point scale over two domains:
        • o
          Performance
        • o
          Satisfaction with performance
      CPCHILD
      • Measures caregiver's perspective on their child's health status, well-being, functional abilities, and ease of caring
      • Scale of 0–6 (“almost impossible” to “no problem at all”)
      • Measures level of assistance: total to independent
      CCHQ (
      • Hwang M.
      • Kuroda M.M.
      • Tann B.
      • Gaebler-Spira D.J.
      Measuring care and comfort in children with cerebral palsy: The care and comfort caregiver questionnaire.
      )
      • Perceived effort of caregivers in providing care for their children
      • Numerical scale from “very easy” to “impossible”
      • Higher the score, the harder the tasks
      CHQ (
      • Schneider J.W.
      • Gurucharri L.M.
      • Gutierrez A.L.
      • Gaebler-Spira D.J.
      Health-related quality of life and functional outcome measures for children with cerebral palsy.
      )
      • Disease-specific HRQL for children with CP completed by parents or caregivers
      • Measures physical and psychosocial well-being of children age > 5 years
      • Consists of 14 basic content domains representing the most essential components of a child's HRQL
      • Scaled to 0–100 with higher scores indicative of best possible health state
      CPQOL-child (
      • Copeland L.
      • Edwards P.
      • Thorley M.
      • Donaghey S.
      • Gascoigne-Pees L.
      • Kentish M.
      • Boyd R.N.
      Botulinum toxin A for nonambulatory children with cerebral palsy: A double blind randomized controlled trial.
      )
      • Measures parent reported changes in their child's social well-being, community access, pain and impact of disability, and family health
      • Overall quality of life
      • Survey of questions with a score system from 0 to 9 (“unhappy” to “happy”)
      GAS
      • Children with CP or parents or caregivers set goals to work on during therapy or certain interventions
      • Goals could be related to everyday activities or certain life situations
      • Five-point scale
      • Each goal begins at −2 before therapy
      • Zero indicates desired goal was reached; anything above or below zero indicates greater than or less than expected
      GMFM (
      • Russell D.J.
      • Rosenbaum P.L.
      • Avery L.M.
      • Lane M.
      Gross motor function measure (GMFM-66 and GMFM-88) user's manual.
      )
      • Observational instrument designed and validated to measure change in gross motor function over time in children with cerebral palsy
      • Larger positive scores associated with greater change in gross motor function over time
      • Negative scores associated with decreased gross motor function over time
      PEDI
      • Interview-based assessment
      • Ask parent or caregiver about self-care, mobility, and social abilities of their child
      • Appropriate for children age < 7 years (or older children with functional abilities age < 7 year)
      • Four-point scale (“unable” to “easy”)
      PPP
      • Behavior rating scale to assess pain
      • Twenty behaviors rated on a scale of 0–3 (not at all to a great deal)
      PGA
      • Assessment made by the physician to determine severity of disease
      • Higher scores indicative of improved functioning
      ROM Improvement (
      • Goyal V.
      • Laisram N.
      • Wadhwa R.K.
      • Kothari S.Y.
      Prospective randomized study of oral diazepam and baclofen on spasticity in cerebral palsy.
      )
      • Flexion–Extension arc in elbow, wrist, knee, and ankle assessed with a universal goniometer
      • Degree used as standard unit to measure ROM
      • Higher scores indicative of greater ROM
      Tardieu Scale and MTS ()
      • Measure the muscle's response to stretch by moving the limb at different velocities
      • First measure determines the full RoM for a specific muscle
      • Second measure moves the same muscle group at different velocities
      • Angle is measured where muscle resistance is felt
      VAS (
      • Hoving M.A.
      • van Raak E.P.
      • Spincemaille G.H.
      • Palmans L.J.
      • Sleypen F.A.
      • Vles J.S.
      Dutch Study Group on Child Spasticity
      Intrathecal baclofen in children with spastic cerebral palsy: A double-blind, randomized, placebo-controlled, dose-finding study.
      )
      • Measures pain intensity using various scales
      • Cartoon faces
      • Numerical scale (1–10)
      Note. BADS, Barry–Albright Dystonia Scale; CCHQ, Care and Comfort Hypertonicity Questionnaire; CHQ, Child Health Questionnaire; COPM, Canadian Occupational Performance Measure; CP, cerebral palsy; CPQOL-child, Cerebral Palsy Quality of Life Questionnaire for Children; CPCHILD, caregiver priorities and child health index of life with disabilities; GAS, Goal Attainment Scale; GMFM, Gross Motor Functional Measurement; HRQL, health-related quality of life; MAS, Modified Ashworth's Scale; MTS, Modified Tardieu Scale; PEDI, Pediatric Evaluation of Disability Inventory; PGA, Physician's Global Assessment; PPP, Pediatric Pain Profile; ROM, Range of Motion; RoM, range of movement; VAS, Visual Analog Scale.

      Oral and Enteral Pharmacological Agents

      Oral baclofen

      Although not specifically approved by the U.S. Food and Drug Administration (FDA) for CP-associated spasticity in children, baclofen remains a mainstay of treatment with use dating back to the 1960s. Baclofen's use dates back to the 1960s, and it remains a mainstay of treatment (
      • Tickner N.
      • Apps J.R.
      • Keady S.
      • Sutcliffe A.G.
      An overview of drug therapies used in the treatment of dystonia and spasticity in children.
      ). The exact mechanism of action is not fully elucidated; however, baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal level (
      • Albright A.L.
      Baclofen in the treatment of cerebral palsy.
      ;
      • Chung C.Y.
      • Chen C.L.
      • Wong A.M.
      Pharmacotherapy of spasticity in children with cerebral palsy.
      ;
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online
      Baclofen.
      ;

      Micromedex (electronic version) (2020b). Baclofen. IBM Watson Health, Greenwood Village, Colorado, USA. Retrieved fromhttps://www-micromedexsolutions-com.proxy.hsl.ucdenver.edu

      ). Baclofen is an analog of GABAB, but it is unknown whether GABA actions are responsible for its clinical effects (
      Novartis Pharmaceuticals Canada Inc
      Lioresal (baclofen) intrathecal.
      ). Baclofen exhibits a high degree of interpatient pharmacokinetic and dosing variability within the pediatric population (
      • Albright A.L.
      Baclofen in the treatment of cerebral palsy.
      ;
      • He Y.
      • Brunstrom-Hernandez J.E.
      • Thio L.L.
      • Lackey S.
      • Gaebler-Spira D.
      • Kuroda M.M.
      • Jusko W.J.
      Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy.
      ). When given orally, doses are thought to be readily absorbed in a dose-dependent fashion, and the time to peak serum concentrations is reached within 1 hr (
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online
      Baclofen.
      ;
      Novartis Pharmaceuticals Canada Inc
      Lioresal (baclofen) intrathecal.
      ). However, unpredictability in absorption has been observed, potentially attributable to chronic gastrointestinal symptoms experienced by greater than 90% of children with CP (
      • He Y.
      • Brunstrom-Hernandez J.E.
      • Thio L.L.
      • Lackey S.
      • Gaebler-Spira D.
      • Kuroda M.M.
      • Jusko W.J.
      Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy.
      ). Baclofen undergoes hepatic metabolism and is primarily excreted in the urine as unchanged drug and in the feces (
      • He Y.
      • Brunstrom-Hernandez J.E.
      • Thio L.L.
      • Lackey S.
      • Gaebler-Spira D.
      • Kuroda M.M.
      • Jusko W.J.
      Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy.
      ;
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online
      Baclofen.
      ;
      Novartis Pharmaceuticals Canada Inc
      Lioresal (baclofen) intrathecal.
      ). Initial clinical effects can be observed within 3–4 days of initiation with peak effects typically observed within 5–10 days (

      Micromedex (electronic version) (2020b). Baclofen. IBM Watson Health, Greenwood Village, Colorado, USA. Retrieved fromhttps://www-micromedexsolutions-com.proxy.hsl.ucdenver.edu

      ). Baclofen's short half-life (approximately 2–4 hr) requires dosing three to four times daily (
      • Chung C.Y.
      • Chen C.L.
      • Wong A.M.
      Pharmacotherapy of spasticity in children with cerebral palsy.
      ;
      • He Y.
      • Brunstrom-Hernandez J.E.
      • Thio L.L.
      • Lackey S.
      • Gaebler-Spira D.
      • Kuroda M.M.
      • Jusko W.J.
      Population pharmacokinetics of oral baclofen in pediatric patients with cerebral palsy.
      ). Higher doses of oral baclofen may be required to reach optimal effectiveness because of its low lipid solubility; however, adverse effects such as CNS, respiratory, and cardiovascular depression are more frequently observed at higher doses and may limit the ability to reach effective doses (
      • Chung C.Y.
      • Chen C.L.
      • Wong A.M.
      Pharmacotherapy of spasticity in children with cerebral palsy.
      ;
      • Navarrete-Opazo A.A.
      • Gonzalez W.
      • Nahuelhual P.
      Effectiveness of oral baclofen in the treatment of spasticity in children and adolescents with cerebral palsy.
      ). Slow titration to the minimally effective dose with careful and continual monitoring helps mitigate these side effects (
      • Navarrete-Opazo A.A.
      • Gonzalez W.
      • Nahuelhual P.
      Effectiveness of oral baclofen in the treatment of spasticity in children and adolescents with cerebral palsy.
      ). Acute discontinuation of baclofen may cause withdrawal symptoms such as worsening spasms, seizures, confusion, hallucinations, or temperature elevation (
      • Chung C.Y.
      • Chen C.L.
      • Wong A.M.
      Pharmacotherapy of spasticity in children with cerebral palsy.
      ). If discontinuation of therapy is warranted, close monitoring with a slow taper off is required. Oral baclofen is one of the few medications administered in the pediatric population that is not dosed by body weight because of its variable pharmacokinetic properties; therefore, initiating at a low, conservative dose and titrating to the minimally effective dose are recommended with close monitoring for efficacy (e.g., decrease in muscle rigidity and spasticity) and adverse effects.
      A double-blind 4-week crossover study compared baclofen with placebo for the reduction of muscle spasticity in children (n = 20) with CP (age range, 2–16 years;
      • Milla P.J.
      • Jackson A.D.
      A controlled trial of baclofen in children with cerebral palsy.
      ). Patients receiving baclofen were initiated at 10 mg/day in divided doses and titrated over 2 weeks to a maximum dose of 30–40 mg/day in children younger than 8 years and 60 mg/day in children age 8 years or older. The primary outcome, severity of muscle spasticity measured by the Ashworth Scale, was significantly improved with baclofen treatment (60% of participants) compared with placebo (10%), p < .001. Five patients reported adverse effects, with somnolence (75%) and hypotonia (60%) being the most commonly observed. Despite these adverse effects, when asked whether to continue baclofen, physicians, physiotherapists, and parents/caregivers all indicated the desire for therapy continuation.
      In contrast, a double-blind, randomized crossover study compared oral baclofen with placebo to determine the effectiveness in reducing muscle spasticity and improving function in children (n = 15), mean age 7.4 years (4–12 years) with CP and a GMFCS level of IV and V (
      • Scheinberg A.
      • Hall K.
      • Lam L.T.
      • O'Flaherty S.
      Oral baclofen in children with cerebral palsy: A double-blind cross-over pilot study.
      ). Baclofen was titrated to 10 mg three times a day for patients aged < 8 years and 20 mg three times a day for patients aged ≥ 8 years. Therapy was continued for 13 weeks followed by a 2-week washout period before crossing over. At 12 weeks, the Goal Attainment Scale t-scores were higher with baclofen (51.3) compared to placebo (44.7), p = .05. All other outcome measures favored baclofen but did not meet statistical significance. At the end of the study, 66.6% of parents of children treated with placebo versus 53.3% of those treated with baclofen indicated they did not want to continue the medication owing to limited treatment effect and the potential for adverse effects such as lethargy, constipation, poor appetite, and drowsiness.
      Despite the variability of efficacy data, oral baclofen still remains a common therapy and a first-line choice for spasticity. Patients should be monitored for efficacy, with establishment of the minimally effective dose and determination of continuation of therapy made on a case-by-case basis in relation to individual response. Common side effects include somnolence, headache, hypotonia, lethargy, and sedation. Although a causal relationship has not been determined and children with CP may be at a higher risk for seizures at baseline, a retrospective study reported occurrence of new-onset seizures within 1–2.5 months of starting or increasing baclofen in patients aged < 10 years with no history of seizures (
      • Hansel D.E.
      • Hansel C.R.
      • Shindle M.K.
      • Reinhardt E.M.
      • Madden L.
      • Levey E.B.
      • Hoon A.H.
      Oral baclofen in cerebral palsy: Possible seizure potentiation.
      ). Patients should be monitored for increased seizure activity throughout therapy, especially during initiation and dose titration. Another important safety concern is the lack of a commercially available oral liquid, which necessitates extemporaneous compounding. There are several recipes for compounded baclofen (e.g., 5 mg/ml and 10 mg/ml). Families must be appropriately educated on the dose in milligrams and milliliters and counseled to always check the concentration to avoid the potential for under- or overdosing and the risk for serious errors. When possible, practitioners are urged to use commercially available (i.e., tablet) products to avoid dosing and administration errors. In addition, concomitant use of other CNS depressants in combination with baclofen should be done with caution to avoid overlapping CNS depression.

      Oral diazepam

      Diazepam is an anxiolytic benzodiazepine that is FDA-approved for the relief of skeletal muscle spasms and muscle spasticity in children age ≥ 6 months and adults (
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online
      Diazepam.
      ;
      Roche Pharmaceuticals
      Diazepam: Highlights of prescribing information.
      ). Diazepam binds at an allosteric site between the α and γ subunits on GABAA receptor chloride ion channels, resulting in the reduced excitability of neurons. Diazepam's unique binding to GABAA receptors within the spinal cord and motor neurons produces the muscle relaxant effects useful for the treatment of spasticity (
      • Dhaliwal J.S.
      • Saadabadi A.
      Diazepam.
      . Oral diazepam is well absorbed with a > 90% bioavailability when administered without food, and peak efficacy is reached at 1.25 hr (range 15 min–2.5 hr;
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online
      Diazepam.
      ;
      Roche Pharmaceuticals
      Diazepam: Highlights of prescribing information.
      ). When given with a moderate fat meal, absorption is slightly decreased with peak effects reached at 2.5 hr. Diazepam is hepatically metabolized, and parent metabolites of oral diazepam have a half-life elimination of 44–48 hr with the active metabolite, desmethyldiazepam, having a half-life of 100 hr (
      • Greenblatt D.J.
      • Harmatz J.S.
      • Friedman H.
      • Locniskar A.
      • Shader R.I.
      A large-sample study of diazepam pharmacokinetics.
      ). Diazepam accumulates with multiple doses, which results in a prolonged half-life.
      Published data regarding the efficacy and safety of diazepam are limited and date back to the 1960s; use today is based largely on clinical experience rather than robust literature (
      • Tickner N.
      • Apps J.R.
      • Keady S.
      • Sutcliffe A.G.
      An overview of drug therapies used in the treatment of dystonia and spasticity in children.
      ). A 1964 double-blind placebo-controlled trial evaluated diazepam (1–2 mg by mouth every 8 hr) in 13 children with CP (aged 1–12.5 years;
      • Holt K.S.
      The use of diazepam in childhood cerebral palsy. Report of a small study including electromyographic observations.
      ). Slight variations in responses between younger and school aged children were observed; however, overall improvements with diazepam treatment were reported by caregivers, physiotherapists, and speech therapists. A 1966 double-blind crossover study evaluated diazepam in 20 children (5–16 years old; mean age, 8.8 years) with CP over four 6-week periods (
      • Engle H.A.
      The effect of diazepam (Valium) in children with cerebral palsy: A double-blind study.
      ). Diazepam doses were individualized with final doses ranging from 1.25 mg by mouth three times daily to 5 mg by mouth four times daily. Patients were assessed by motion pictures taken while the patient performed a variety of motor tasks at baseline and at the end of each 6-week course of therapy. Patients were also subjectively assessed by parents, school personnel, a physiotherapist, and a speech therapist. Ten patients improved while on diazepam (very good, n = 1; good, n = 2; and fair, n = 7). The families of eight patients reported sufficient improvement and chose to continue therapy following study completion. The authors concluded that those with the most severe spasticity symptoms were the most likely to benefit from diazepam therapy, and those who improved during the first 6-week study period were more likely to improve when diazepam was subsequently administered after regression on the placebo. Both studies observed adverse effects including somnolence, flushing, dilated pupils, erythematous rash, slurred speech, decreased appetite, vomiting and diarrhea, ataxia, and emotional disturbances (
      • Engle H.A.
      The effect of diazepam (Valium) in children with cerebral palsy: A double-blind study.
      ;
      • Holt K.S.
      The use of diazepam in childhood cerebral palsy. Report of a small study including electromyographic observations.
      ).
      More recently, a double-blind, randomized, placebo-controlled trial evaluated the effect of bedtime doses of diazepam (0.1 mg/kg administered as a single dose) on passive stretching exercises in 114 children, most (n = 111) of which were aged younger than 5 years (
      • Mathew A.
      • Mathew M.C.
      Bedtime diazepam enhances well-being in children with spastic cerebral palsy.
      ). Investigators assessed the change in mean scores for the well-being of the children, the burden of care on the family, and the behavior profile of the child, all of which were significantly improved in the diazepam group, p < .001. Patients treated with diazepam were notably happier during the day, which decreased the burden of care on their family members. The single nightly dose resulted in less wakefulness during the night and less daytime sedation.
      Although published data are limited, diazepam is commonly used for spasticity either as monotherapy or in combination with other agents. It is readily commercially available both in an oral suspension and tablets and is cost-effective. However, although both data and clinical practice demonstrate clinical efficacy, common adverse effects include CNS depression, somnolence, and daytime drowsiness. If this occurs, it may be reasonable to administer a single bedtime dose to decrease nighttime awakenings and drowsiness during the day (
      • Mathew A.
      • Mathew M.C.
      Bedtime diazepam enhances well-being in children with spastic cerebral palsy.
      ). Tolerance and dependence occur with prolonged use of diazepam; therefore, doses may need to be escalated over time, leading to an increased risk for side effects (
      • Tickner N.
      • Apps J.R.
      • Keady S.
      • Sutcliffe A.G.
      An overview of drug therapies used in the treatment of dystonia and spasticity in children.
      ). Similar to baclofen, abrupt discontinuation must be avoided (
      • Tickner N.
      • Apps J.R.
      • Keady S.
      • Sutcliffe A.G.
      An overview of drug therapies used in the treatment of dystonia and spasticity in children.
      ). Importantly, diazepam carries the risk for additive CNS depression when used in combination with other CNS active medications and the possibility for drug–drug interactions with medications that go through the cytochrome P450 systems. If CNS depression and sedation are intolerable or drug–drug interactions are present, several alternative options can be considered.

      Comparative data: Oral baclofen versus oral diazepam

      In 2016, a randomized prospective follow-up study compared oral diazepam with oral baclofen among 60 children with CP (mean age, 5 years [2–14 years]) over 3 months with a 1-year follow-up (
      • Goyal V.
      • Laisram N.
      • Wadhwa R.K.
      • Kothari S.Y.
      Prospective randomized study of oral diazepam and baclofen on spasticity in cerebral palsy.
      ). The diazepam group (n = 30) was initiated on 0.1 mg/kg/day in divided doses with weekly increases of 0.1 mg/kg to a maximum of 0.8 mg/kg/day. The baclofen group (n = 30) received 2.5 mg by mouth three times daily in patients aged < 8 years and 5 mg by mouth three times daily in patients aged > 8 years with weekly increases of 5 mg to a maximum of 40 and 60 mg/day, respectively. Spasticity, assessed on the Modified Ashworth's Scale (MAS) and the Range of Motion (ROM) scale, was significantly improved in both groups; however, when comparing the two groups, there was no statistically significant difference at pretreatment or follow-up at 1 and 3 months. Adverse effects were observed in 23% of the diazepam patients and 20% of those receiving baclofen after 3 months of therapy. The most common adverse events seen in both groups included drowsiness and weakness. In addition, patients in the diazepam group experienced drooling, ataxia, constipation, headache, urticaria, and increased urinary frequency; two patients discontinued therapy because of excessive drowsiness and urticaria. The baclofen group experienced behavioral changes, constipation, headache, nausea, paresthesia, and increased urinary frequency; one patient was noted to discontinue therapy because of excessive drowsiness. Overall, it was concluded that oral diazepam and baclofen can be safely used in pediatric patients with CP and that neither medication was found to be superior in efficacy or safety. Practically speaking, the choice of agent may be determined by interacting medications, tolerability of side effects, dosage form availability, and individual response to therapy.

      Alpha-2 agonists

      Clonidine and tizanidine are two centrally acting α2-adrenergic agonists that reduce spasticity by increasing presynaptic inhibition of motor neurons (;

      Boehringer Ingelheim Pharmaceuticals, Inc. 2009. Clonidine: Highlights of prescribing information, Ridgefield, CT. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017407s034lbl.pdf

      ;
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online
      Clonidine.
      ,
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online
      Tizanidine.
      ). Both medications decrease peripheral and renal vascular resistance, heart rate, and blood pressure. However, tizanidine has been found to have one tenth to one fiftieth of clonidine's potency in reducing blood pressure (). Specific data for spasticity are lacking for both agents; data for clonidine are limited to a dose-finding study, whereas limited efficacy and safety data are available for tizanidine (
      • Lubsch L.
      • Habersang R.
      • Haase M.
      • Luedtke S.
      Oral baclofen and clonidine for treatment of spasticity in children.
      ). Clonidine may be considered in children with CP to help manage concurrent symptoms such as sleep disturbance or problem behaviors with the potential for an additive benefit for spasticity; however, owing to the lack of data and more profound blood pressure effects, for spasticity alone, tizanidine is favored. Therefore, the remainder of this section is focused on tizanidine (
      • Blackmer A.B.
      • Feinstein J.A.
      Management of sleep disorders in children with neurodevelopmental disorders: A review.
      ;
      • Sabus A.
      • Feinstein J.
      • Romani P.
      • Goldson E.
      • Blackmer A.
      Management of self-injurious behaviors in children with neurodevelopmental disorders: A pharmacotherapy overview.
      ). Pediatric-specific pharmacokinetic parameters of tizanidine are unknown. Extrapolating from the adult population, peak effects are reached at 1–2 hr, and it is relatively short-acting with a duration of 3–6 hr and a half-life of 2.5 hr (;
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online
      Tizanidine.
      ). The bioavailability and peak plasma concentrations are variable dependent on dosage form. Tizanidine is hepatically metabolized by cytochrome P450 1A2 (CYP1A2) and excreted in the urine (60%) and feces (20%).
      Most literature supporting the use for spasticity evaluated tizanidine in combination with other agents (e.g., botulinum toxin [discussed later in this review]) rather than as a monotherapy. A retrospective review of 30 children (mean age, 5.6 years [2–14 years]) evaluated oral baclofen versus oral tizanidine as adjuvant therapy to botulinum toxin type A (BTX-A;
      • Dai A.I.
      • Wasay M.
      • Awan S.
      Botulinum toxin type A with oral baclofen versus oral tizanidine: A nonrandomized pilot comparison in patients with cerebral palsy and spastic equinus foot deformity.
      ). Patients in the baclofen group (n = 17) received doses ranging from 10 to 15 mg/kg/day in three divided doses up to a maximum dose of 40 mg/day if patients were aged < 8 years and a maximum dose of 60 mg/day for those aged ≥ 8 years. Patients in the tizanidine group (n = 13) received doses ranging from 0.3 to 0.5 mg/kg/day in four divided doses. After 3 months of treatment, patients in the tizanidine group were found to have a significantly higher Gross Motor Functional Measurement (76.63 ± 5.88 vs. 68.17 ± 1.99; p < .001) and Child Health Questionnaire (70.23 ± 4.76 vs. 66.69 ± 3.53, p = .03) scores compared with those in the baclofen group. The MAS score favored baclofen. Regarding safety, tizanidine resulted in less anorexia and abdominal pain compared with baclofen.
      In 2016, a similar study comparing efficacy and safety of oral baclofen versus oral tizanidine with adjuvant BTX-A was conducted among 64 pediatric patients (mean age, 4.9 years [2–14 years];
      • Dai A.I.
      • Aksoy S.N.
      • Demiryürek A.T.
      Comparison of efficacy and side effects of oral baclofen versus tizanidine therapy with adjuvant botulinum toxin type A in children with cerebral palsy and spastic equinus foot deformity.
      ). Patients in the baclofen group (n = 31) and tizanidine group (n = 33) received doses similar to those used in the previous study. Gross Motor Functional Measurement scores (74.45 ± 3.72 vs. 68.23 ± 2.66, p < .001) and Child Health Questionnaire scores (72.43 ± 4.29 vs. 67.53 ± 2.67, p < .001) in the tizanidine group were significantly higher than those in the baclofen group. MAS scores significantly improved in the tizanidine group following BTX-A administration (3.79 ± 4.78 to 1.94 ± 2.21, p = .048) compared with the baclofen group. With respect to safety, drowsiness, dizziness, lethargy, fatigue, constipation, and anorexia were observed with tizanidine, whereas baclofen resulted in seizures, drowsiness, dizziness, lethargy, and weakness.
      Based on the limited available literature, tizanidine may be a clinically effective therapeutic option particularly when used as adjunctive therapy with BTX-A. Although the aforementioned studies support the use of tizanidine for spasticity in pediatric patients with CP, it is important to consider the increased sedative effects, potential constipation, and dizziness that tizanidine may have on patients. Its use may be limited by appropriate dosage form availability. Furthermore, tizanidine is a substrate of CYP1A2; therefore, concomitant use of CYP1A2 inhibitors or inducers should be evaluated for interactions and managed accordingly.

      Dantrolene

      Dantrolene, originally used in 1967 as a muscle relaxant for the long-term management of skeletal muscle spasticity, is now FDA-approved in patients aged ≥ 5 years for the treatment of spasticity associated with upper motor neuron disorders including spinal cord injury, stroke, CP, and multiple sclerosis (

      JHP Pharmaceuticals, LLC. (2011) Dantrium (dantrolene sodium): Highlights from prescribing information. Rochester, MI. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf

      • Snyder H.R.
      • Davis C.S.
      • Bickerton R.K.
      • Halliday R.P.
      1-[(5-arylfurfurylidene)amino]hydantoins. A new class of muscle relaxants.
      ). Compared with other available agents, dantrolene acts directly on skeletal muscle rather than centrally, dissociating excitation–contraction coupling and interfering with the release of calcium from the sarcoplasmic reticulum (

      JHP Pharmaceuticals, LLC. (2011) Dantrium (dantrolene sodium): Highlights from prescribing information. Rochester, MI. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf

      ). Pediatric-specific pharmacokinetic parameters of dantrolene are not entirely known; data are extrapolated from the adult population. Dantrolene is readily absorbed orally with a bioavailability of 70% and has a volume of distribution of 36.4 L (

      JHP Pharmaceuticals, LLC. (2011) Dantrium (dantrolene sodium): Highlights from prescribing information. Rochester, MI. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf

      ;
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online
      Dantrolene.
      ). It is primarily hepatically metabolized to the active metabolites, 5-hydroxy dantrolene and an acetylation metabolite of dantrolene. The half-life elimination in children age 2–7 years is roughly 10 hr with fecal excretion as the primary route of elimination (45%–50%).
      Most of the published efficacy and safety data for dantrolene for CP-associated spasticity come from the 1970s and 1980s. A double-blind, crossover study compared dantrolene suspension with placebo in children with a mean age of 6.5 years (1.5–17 years) with spasticity (
      • Haslam R.H.
      • Walcher J.R.
      • Lietman P.S.
      • Kallman C.H.
      • Mellits E.D.
      Dantrolene sodium in children with spasticity.
      ). Patients received 15 days of dantrolene (n = 12; initial 1 mg/kg/dose four times daily, titrated to 3 mg/kg/dose four times daily) or placebo (n = 14), a 10-day washout period, and then 15 days of continuation of dantrolene or placebo. Of the 23 included in the final analysis, dantrolene resulted in statistically significant improvements in passive ROM, reflexes, muscle tone, and scissoring; clonus and spontaneous ROM were the only variables of the spasticity severity score that were not improved. Dantrolene also had a significant positive effect on occupational-therapy assessment. Dantrolene did not result in changes in a patient's complete blood counts, liver function tests (LFTs), or renal function panels. Minimal lethargy was observed during the first 48 hr of therapy, which resolved thereafter. Five patients included in this study continued on dantrolene long-term for a mean duration of 12 months (8–15 months); one patient developed nonspecific chest pain, which resolved with dantrolene discontinuation. Although this study was limited by a small sample size and a short duration, dantrolene appeared to improve neurological symptoms with no serious effects.
      Another double-blind, within-subject, crossover study evaluated dantrolene in 28 children with a mean age of 7 years (18 months−12 years) with spastic CP (
      • Denhoff E.
      • Feldman S.
      • Smith M.G.
      • Litchman H.
      • Holden W.
      Treatment of spastic cerebral-palsied children with sodium dantrolene.
      ). Dantrolene was initiated at 1 mg/kg/dose by mouth four times daily and increased by 1 mg/kg/dose weekly to a maximum of 3 mg/kg/dose four times daily (12 mg/kg/day) for a total treatment duration of 6 weeks. Neurological findings (e.g., muscle strength, spasticity, tendon jerk reflexes, and clonus in the upper and lower extremities) were significantly improved (p < .04) during dantrolene therapy with seven children showing marked changes and 13 showing moderate or marginal changes versus zero and four when treated with placebo, respectively. Motor performance, activities of daily living, and general behavior were also improved with dantrolene, however cognitive performance was not improved. Adverse effects were observed more commonly in the dantrolene group (16 vs. 7, p < .03) and included irritability, lethargy, drowsiness, and general malaise. Nine children continued dantrolene after study completion and four developed or had increased seizures. In addition, one patient was found to have elevated LFTs 2 months following dantrolene therapy.
      A double-blind study conducted in 1980 evaluated dantrolene (mean dose: 8.35 mg/kg/day; range: 0.75–14.78 mg) compared with placebo in 20 children (age 4–15 years) with spasticity secondary to CP over the course of 15 weeks (
      • Joynt R.L.
      • Leonard Jr., J.A.
      Dantrolene sodium suspension in treatment of spastic cerebral palsy.
      ). After 3 weeks of therapy, patients treated with dantrolene (n = 11) reported reduced spasms and improved ROM, though improvements did not reach statistical significance. Further subjective reporting of reductions in spasms or improvement in ROM on subsequent visits was not observed, but the initial reductions were sustained over time. Objective physical examination findings showed no significant differences in tone, clonus, strength, reflexes, or spasms in the dantrolene group compared with the placebo group; however, dantrolene resulted in improvements in activities of daily living. Several patients in the dantrolene group reported side effects including fatigue (n = 5), drowsiness (n = 3), anorexia (n = 2), diarrhea (n = 1), and vomiting (n = 1), after 3 weeks of therapy (p < .008). Despite these side effects, there were no further significant differences at subsequent visits, suggesting that side effects become tolerable over time.
      Dantrolene's peripheral site of action makes this an appealing option in patients who may be overly sedated because of centrally acting agents; however, efficacy is variable across the pediatric population. Dantrolene may improve ROM, muscle strength, and spasticity and has sustained effects over time. In practice, dantrolene is most often chosen for patients for whom avoidance of CNS side effects is desired. In the studies reviewed above, side effects such as lethargy and drowsiness were reported, but in clinical practice, observance of these side effects is rare. Other side effects may include anorexia, diarrhea, and vomiting. Dantrolene carries a risk for seizure potentiation and hepatotoxicity (U.S. black box warning); therefore, seizures and LFTs must be monitored during initiation and throughout therapy particularly as dosing increases are made (
      • Nogen A.G.
      Effect of dantrolene sodium on the incidence of seizures in children with spasticity.
      ). The risk of hepatic injury appears greater in patients older than 35 years, in females, and at doses > 400 mg/day (

      JHP Pharmaceuticals, LLC. (2011) Dantrium (dantrolene sodium): Highlights from prescribing information. Rochester, MI. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/017443s043s046s048s049lbl.pdf

      ;
      • Tickner N.
      • Apps J.R.
      • Keady S.
      • Sutcliffe A.G.
      An overview of drug therapies used in the treatment of dystonia and spasticity in children.
      ). Dantrolene is contraindicated in patients with active hepatic disease including cirrhosis or hepatitis.

      Parenteral Pharmacological Agents

      Intrathecal baclofen

      One approach to minimizing side effects while maximizing the efficacy of baclofen is by intrathecal administration (
      • Tickner N.
      • Apps J.R.
      • Keady S.
      • Sutcliffe A.G.
      An overview of drug therapies used in the treatment of dystonia and spasticity in children.
      ). Intrathecal baclofen (ITB) is FDA-approved for the treatment of muscle spasticity in children with CP and recommended for severe spasticity that is unresponsive to oral baclofen (
      Novartis Pharma for Medtronic Inc
      Lioresal® intrathecal (baclofen injection).
      ). ITB requires surgical placement of a catheter into the intrathecal space for continuous, direct delivery via a pump (
      • Buizer A.I.
      • Martens B.H.M.
      • Grandbois van Ravenhorst C.
      • Schoonmade L.J.
      • Becher J.G.
      • Vermeulen R.J.
      Effect of continuous intrathecal baclofen therapy in children: A systematic review.
      ). Factors considered in baclofen pump placement include the following: (1) child size—the child must be large enough for the pump (e.g., the abdominal wall must physically accommodate the pump), (2) positive clinical response—a positive clinical result evidenced by a significant decrease in muscle tone and in the severity or frequency of muscle spasms during a screening test dose, (3) no known hypersensitivities to baclofen, (4) no signs of infection, and (5) patient–caregiver ability to consistently follow-up with baclofen pump refills and pump care (
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online
      Baclofen.
      ;
      Novartis Pharma for Medtronic Inc
      Lioresal® intrathecal (baclofen injection).
      ). Once the pump is implanted, test doses are given, with subsequent titration and individualization (
      Novartis Pharma for Medtronic Inc
      Lioresal® intrathecal (baclofen injection).
      ). The onset of effect for ITB via continuous infusion is 6–8 hr after initiation with a peak effect occurring at 24–48 hr after initiation (
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online
      Baclofen.
      ). The cerebrospinal fluid (CSF) elimination half-life is 1.5 hr in the first 4 hr until steady state is reached (
      Novartis Pharma for Medtronic Inc
      Lioresal® intrathecal (baclofen injection).
      ;
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online
      Baclofen.
      ). ITB is primarily renally eliminated; although no specific renal dose adjustments are recommended, close monitoring is recommended when renal insufficiency is present.
      A double-blind, randomized, placebo-controlled, dose-finding study evaluated the efficacy and safety of ITB in 17 children (mean age, 13 years 2 months [7–16 years]) with GMFCS level III–V (
      • Hoving M.A.
      • van Raak E.P.
      • Spincemaille G.H.
      • Palmans L.J.
      • Sleypen F.A.
      • Vles J.S.
      Dutch Study Group on Child Spasticity
      Intrathecal baclofen in children with spastic cerebral palsy: A double-blind, randomized, placebo-controlled, dose-finding study.
      ). Rather than administration via a pump, patients underwent catheter insertion and were monitored in the hospital while given blinded test doses of alternating baclofen and placebo (maximum eight test days). All 17 patients clinically responded to intrathecal baclofen. Visual analog scale scores significantly improved in the ease of care and pain after the administration of baclofen compared with baseline: 7.4 versus 2.3 (p = .001) and 6.5 versus 3.2 (p = .010), respectively. On the Ashworth Scale score, ITB resulted in a significant decrease in muscle spasticity across most muscle groups. The most common side effects were lethargy, decreased appetite, dry mouth, dizziness, pallor, nausea, vomiting, and headache.
      A retrospective cohort study investigated the effect of ITB (via pump) on function and activity in 25 children (mean age, 10.9 ± 4.75 years) with dyskinetic CP and GMFCS levels of IV and V (
      • Eek M.N.
      • Olsson K.
      • Lindh K.
      • Askljung B.
      • Påhlman M.
      • Corneliusson O.
      • Himmelmann K.
      Intrathecal baclofen in dyskinetic cerebral palsy: Effects on function and activity.
      ). The primary outcomes of dystonia and muscle spasticity measured by the Barry–Albright Dystonia Scale and MAS were significantly improved with ITB. The mean Barry–Albright Dystonia Scale score at rest decreased from 7.1 to 1.5 (p < .001) and during activity from 19.2 to 9.9 (p < .001). A reduction in muscle tone was also observed by MAS scores in 19 of the 25 children, p < .001. Daily activities and goal attainment per parent report were also improved in areas of sitting (73%), communication (67%), and daily living (80%), which aided in attaining goals set by parents. The major adverse effects that were reported, infection and CSF leakage, were due to the pump device rather than the medication.
      A consecutive case series over a 48-month period was performed to determine the efficacy of ITB in the reduction of muscle spasticity and to identify complications of the baclofen pump (
      • Murphy N.A.
      • Irwin M.C.
      • Hoff C.
      Intrathecal baclofen therapy in children with cerebral palsy: Efficacy and complications.
      ). Twenty-three children received a baclofen pump (mean age, 8.8 years [4.5–17.4 years]). At 6 months, the mean MAS score of spasticity decreased from 3.26 to 2.34 (p ≤ .01) in the lower extremities and from 2.69 to 2.00 (p ≤ .05) in the upper extremities. These results remained consistent at 12 months of treatment. Regarding safety, 44% of the pumps required removal, primarily owing to wound complications. Other complications included meningitis, CSF leak, and catheter failure.
      Overall, ITB improves muscle spasticity and goal attainment and aids in daily activities in children with CP. Side effects observed with oral baclofen such as somnolence, dizziness, nausea, hypotension, headache, and hypotonia are less common with ITB but may still be observed. ITB is associated with other pump-specific complications such as site infection and pump failure. ITB has a black box warning regarding abrupt withdrawal if the pump malfunctions or if the pump is not refilled in a timely fashion. Symptoms of withdrawal include hyperpyrexia, altered mental status, rebound spasticity, and muscle rigidity, which could result in multisystem organ failure and death (
      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online
      Baclofen.
      ;
      Novartis Pharma for Medtronic Inc
      Lioresal® intrathecal (baclofen injection).
      ). Extensive education about the importance of pump alarms, attending all scheduled pump refilling visits, and early signs of baclofen withdrawal is required for parents and caregivers (
      Novartis Pharma for Medtronic Inc
      Lioresal® intrathecal (baclofen injection).
      ). Patients should always have rescue oral baclofen available to be administered as needed in case of pump failure or missed pump refilling visits to avoid withdrawal.

      Botulinum toxin A

      Botulinum neurotoxin is an exotoxin produced by Clostridium botulinum (
      • Tickner N.
      • Apps J.R.
      • Keady S.
      • Sutcliffe A.G.
      An overview of drug therapies used in the treatment of dystonia and spasticity in children.
      ). Although there are seven neurotoxins produced, only two are available for therapeutic use: A and B. AbobotulinumtoxinA is the only BTX-A that has received FDA approval for the treatment of lower limb muscle spasticity in children aged 2 years and older (

      Micromedex (electronic version) (2020a). Abobotulinumtoxin A. IBM Watson Health, Greenwood Village, Colorado, USA. Retrieved from https://www-micromedexsolutions-com.proxy.hsl.ucdenver.edu/

      ). Nevertheless, other medications within the BTX-A drug class, such as onabotulinumtoxinA, have been used to treat muscle spasticity in children with CP, and there is a large degree of off-label use based on study data and clinical experience. BTX-A is injected directly into the muscle entering the nerve terminals where it then inhibits the release of acetylcholine at the neuromuscular junction by cleaving the protein, SNAP-25, which plays an important role in the docking and release of acetylcholine from nerve endings (;

      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online. (2020f). Onabotulinumtoxin A. Hudson, OH: Wolters Kluwer Clinical Drug Information, Inc.

      ;
      • Matsuda M.
      • Tomita K.
      • Yozu A.
      • Nakayama T.
      • Nakayama J.
      • Ohguro H.
      • Iwasaki N.
      Effect of botulinum toxin type A treatment in children with cerebral palsy: Sequential physical changes for 3 months after the injection.
      ). This leads to focal weakness, reduced muscle tone, and ultimately a reduction in spasticity. BTX-A is not expected to be absorbed into the bloodstream following intramuscular administration; therefore, little is known about the pharmacokinetics. The onset of action occurs anywhere from 4 days to 4 weeks, peak effects within 4–6 weeks, and duration of effect typically around 3 months (
      • Copeland L.
      • Edwards P.
      • Thorley M.
      • Donaghey S.
      • Gascoigne-Pees L.
      • Kentish M.
      • Boyd R.N.
      Botulinum toxin A for nonambulatory children with cerebral palsy: A double blind randomized controlled trial.
      ;
      • Heinen F.
      • Desloovere K.
      • Schroeder A.S.
      • Berweck S.
      • Borggraefe I.
      • van Campenhout A.
      • Molenaers G.
      The updated European Consensus 2009 on the use of botulinum toxin for children with cerebral palsy.
      ;

      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online. (2020f). Onabotulinumtoxin A. Hudson, OH: Wolters Kluwer Clinical Drug Information, Inc.

      ;
      • Matsuda M.
      • Tomita K.
      • Yozu A.
      • Nakayama T.
      • Nakayama J.
      • Ohguro H.
      • Iwasaki N.
      Effect of botulinum toxin type A treatment in children with cerebral palsy: Sequential physical changes for 3 months after the injection.
      ;
      • On A.Y.
      • Kirazli Y.
      • Kismali B.
      • Aksit R.
      Mechanisms of action of phenol block and botulinus toxin Type A in relieving spasticity: Electrophysiologic investigation and follow-up.
      ). Dosing of BTX-A is based on weight and the site of administration, with larger doses administered to larger muscle groups (

      Lexicomp Online, Pediatric and Neonatal Lexi-Drugs Online. (2020f). Onabotulinumtoxin A. Hudson, OH: Wolters Kluwer Clinical Drug Information, Inc.

      ). Common injection sites include gastrocnemius–soleus complex, hamstrings, hip adductors, and posterior tibialis (
      • Delgado M.R.
      • Bonikowski M.
      • Carranza J.
      • Dabrowski E.
      • Matthews D.
      • Russman B.
      • Picaut P.
      Safety and efficacy of repeat open-label AbobotulinumtoxinA treatment in pediatric cerebral palsy.
      ;
      • Matsuda M.
      • Tomita K.
      • Yozu A.
      • Nakayama T.
      • Nakayama J.
      • Ohguro H.
      • Iwasaki N.
      Effect of botulinum toxin type A treatment in children with cerebral palsy: Sequential physical changes for 3 months after the injection.
      ). Although BTX-A has localized effects, systemic side effects may include upper respiratory tract infection, generalized weakness, pharyngitis, dysphagia, and pyrexia (
      • Albavera-Hernández C.
      • Rodríguez J.M.
      • Idrovo A.J.
      Safety of botulinum toxin type A among children with spasticity secondary to cerebral palsy: A systematic review of randomized clinical trials.
      ;
      • Paget S.P.
      • Swinney C.M.
      • Burton K.L.O.
      • Bau K.
      • O'Flaherty S.J.
      Systemic adverse events after botulinum neurotoxin A injections in children with cerebral palsy.
      ). Repeated injections can result in the development of antibody resistance; therefore, injections should occur no more frequently than every 3 months (;
      • Delgado M.R.
      • Hirtz D.
      • Aisen M.
      • Ashwal S.
      • Fehlings D.L.
      • McLaughlin J.
      • Vargus-Adams J.
      Practice parameter: Pharmacologic treatment of spasticity in children and adolescents with cerebral palsy (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.
      ).
      A global, randomized, placebo-controlled single-dose study assessed the efficacy and safety of two doses (10 units/kg/leg and 15 units/kg/leg) of abobotulinumtoxinA in 241 children (mean age, 6 years [2–17 years]) with CP and dynamic equinus foot deformity (GMFCS level of I–III;
      • Delgado M.R.
      • Tilton A.
      • Russman B.
      • Benavides O.
      • Bonikowski M.
      • Carranza J.
      • Picaut P.
      AbobotulinumtoxinA for equinus foot deformity in cerebral palsy: A randomized controlled trial.
      ). The primary efficacy outcome, change in the gastrocnemius–soleus complex MAS score from baseline to Week 4, significantly improved in both treatment groups compared with placebo: adjusted mean changes of −0.38 (p = .003) and −0.49 (p < .001), respectively. Treatment efficacy remained consistent at 12 weeks in both treatment arms. The secondary outcome, adjusted mean Physician's Global Assessment scores at Week 4, also demonstrated clinically meaningful improvement compared with placebo: 1.54, 1.50, and 0.73 for the 10 units/kg/leg, 15 units/kg/leg, and placebo group, respectively. Higher Physician's Global Assessment scores indicate larger improvement in the patient's functionality level. Of the 241 children, 144 reported at least one treatment-emergent adverse event with the most common being an upper respiratory tract infection.
      A long-term prospective, open-label extension trial was offered to those participating in the trial described earlier to evaluate the long-term (1 year) safety of repeated injections of abobotulinumtoxinA (
      • Delgado M.R.
      • Bonikowski M.
      • Carranza J.
      • Dabrowski E.
      • Matthews D.
      • Russman B.
      • Picaut P.
      Safety and efficacy of repeat open-label AbobotulinumtoxinA treatment in pediatric cerebral palsy.
      ). Participants could receive a maximum of four additional treatments of abobotulinumtoxinA at doses of 5–30 units/kg every 12 weeks. Of the original 241, 207 required greater than or equal to one injection cycle. The most common treatment-emergent adverse events (i.e., nasopharyngitis, upper respiratory tract infection, and fever) reported were of mild severity. The highest incidence was seen in cycle 1 (40.8%) and decreased with each injection cycle. Treatment-related adverse events such as injection site pain (3.5%), injection site papule (1%), and influenza-like symptoms (1%) were less common. The severity of adverse events was not associated with the dose or number of limbs injected. Evidence of antibodies was observed in 2.1% of patients treated with BTX-A This study implies that the long-term use of abobotulinumtoxinA appears to be safe in children with lower limb spasticity. The study also evaluated the efficacy over repeat cycles and noted improvement in hypertonia and spasticity. Upper limb spasticity (elbow and wrist flexors) was also measured using MAS scores and found to have clinical improvement. The addition of promising upper limb spasticity efficacy results indicates BTX-A may be used for both upper and lower limb spasticity in children with spasticity associated with CP.
      A double-blind, randomized controlled trial compared onabotulinumtoxinA with placebo in 41 nonambulatory children (mean age, 7.1 years [2.3–16 years]) with severe CP for the reduction of spasticity and improvement in comfort and ease of care (
      • Copeland L.
      • Edwards P.
      • Thorley M.
      • Donaghey S.
      • Gascoigne-Pees L.
      • Kentish M.
      • Boyd R.N.
      Botulinum toxin A for nonambulatory children with cerebral palsy: A double blind randomized controlled trial.
      ). Measured on the Canadian Occupational Performance Measure scale, onabotulinumtoxinA resulted in a clinically significant improvement at 4 weeks in performance and satisfaction in relation to comfort and care of the patient as identified by the parents. The difference of Canadian Occupational Performance Measure scores between the BTX-A and sham treatment groups was 2.2 (p = .001) for performance and 2.3 (p = .007) for satisfaction. However, only satisfaction remained significantly improved at Week 16 (1.8; p = .03). The largest contributors to improvement were comfort, positioning, and communication. Overall, parent satisfaction in reaching their child's goals and clinical improvement was seen more frequently in nonambulatory children receiving BTX-A.
      The efficacy of BTX-A is supported in the literature and in practice and is overall well tolerated. BTX-A improves muscle tone, ease of care, and comfort. It is also associated with comparatively fewer adverse effects than oral medications and should be considered in those patients who fail oral therapies owing to a lack of efficacy or toxicity and/or are not eligible for ITB. Although typically well tolerated, systemic adverse effects such as dysphagia and lower respiratory tract infection may occur, especially in those with a history of dysphagia or aspiration pneumonia (
      • Paget S.P.
      • Swinney C.M.
      • Burton K.L.O.
      • Bau K.
      • O'Flaherty S.J.
      Systemic adverse events after botulinum neurotoxin A injections in children with cerebral palsy.
      ).

      Phenol

      Phenol injections are an alternative option to BTX-A for specific muscles with a primary motor nerve without a significant contribution for a sensory nerve. After injection, phenol produces chemical neurolysis through protein denaturation and blocking of efferent signals through targeting α and γ motor neurons (
      • On A.Y.
      • Kirazli Y.
      • Kismali B.
      • Aksit R.
      Mechanisms of action of phenol block and botulinus toxin Type A in relieving spasticity: Electrophysiologic investigation and follow-up.
      ) When administered in a mixed nerve area, injections must be guided by the adjunctive use of a nerve stimulator to locate motor nerves and avoid inadvertently affecting sensory nerves (
      • Wong A.M.
      • Chen C.L.
      • Chen C.P.
      • Chou S.W.
      • Chung C.Y.
      • Chen M.J.
      Clinical effects of botulinum toxin A and phenol block on gait in children with cerebral palsy.
      ). Phenol has a quick onset of action and a longer duration of effect (4–12 months) than BTX-A (

      Gillette Children's Specialty Healthcare. Botulinum toxin and phenol (injected spasticity medications). Retrieved from https://www.gillettechildrens.org/conditions-care/botulinum-toxin-and-phenol-injections. Accessed, June 1, 2020

      ). Phenol itself is less costly than BTX-A; however, injections often must be performed under general anesthesia adding to the cost and the risk of complications (
      • Kolaski K.
      • Ajizian S.J.
      • Passmore L.
      • Pasutharnchat N.
      • Koman L.A.
      • Smith B.P.
      Safety profile of multilevel chemical denervation procedures using phenol or botulinum toxin or both in a pediatric population.
      ).
      Limited data regarding phenol injections have been published. A case-controlled study compared the effectiveness of BTX-A and phenol in managing lower limb spasticity in children with CP (
      • Wong A.M.
      • Chen C.L.
      • Chen C.P.
      • Chou S.W.
      • Chung C.Y.
      • Chen M.J.
      Clinical effects of botulinum toxin A and phenol block on gait in children with cerebral palsy.
      ). Twenty-seven children (aged 3–7 years) received either BTX-A (n = 16), 1–3 units/kg in each muscle or phenol 5% solution injections (n = 11), typically 3–5 mL per site (maximum 20 mL per treatment). The most common sites of injection were the adductors, the hamstrings, and the gastrocnemius muscles. A computer-assisted gait analysis system found significant improvement in velocity (p = .001) and cadence (p = .005) after BTX-A injections but not after phenol injections. Phenol was associated with more adverse effects such as leg or calf pain compared with BTX-A (27.3% vs. 6.3%), complaints of dysesthesia (36.4% vs. 0%), and pain at the injection site (100% vs. 18.8%) lasting longer than 3 days.
      A retrospective cohort study of 336 children evaluated the safety of single and repeat injections of BTX-A alone or in combination with phenol (mean age, 7.4 years [1.2–18.9 years];
      • Kolaski K.
      • Ajizian S.J.
      • Passmore L.
      • Pasutharnchat N.
      • Koman L.A.
      • Smith B.P.
      Safety profile of multilevel chemical denervation procedures using phenol or botulinum toxin or both in a pediatric population.
      ). Children underwent general anesthesia and received either BTX-A (onabotulinumtoxinA), botulinum toxin-B (rimabotulinumtoxinB), or phenol 5% solution alone or in combination with botulinum toxin. A total of 56 anesthesia- and injection-related complications occurred with no difference between single and repeat injections. The anesthesia-related complications included upper airway obstruction (four cases), intraoperative dysrhythmias (two cases), intraoperative hypothermia (one case), and postoperative nausea and vomiting (two cases). For the injection-related complications, both systemic and local symptoms were reported. The systemic symptoms were only seen in the combination group (i.e., dry mouth, fever, generalized weakness, and fussiness or irritability). Local symptoms were seen in both the BTX-A alone treatment group and in combination with phenol. The most commonly reported local symptom was tenderness or soreness in the injection site area (32%) followed by bruising (25%) and excessive focal weakness (18%). Although injection-related complications were seen in both treatment groups, the duration of these symptoms was longer in the combination group (< 2–3 weeks) than in those who received BTX-A alone (3–7 days).
      On the basis of the limited data available, BTX-A is the preferred injection in children with CP-associated spasticity. BTX-A may be used for smaller muscles because there is a larger margin for error; whereas, phenol requires careful administration because of its acidic properties and is more commonly injected into larger muscles to avoid affecting other nerves. Phenol may be considered for treatment alone or in combination with BTX-A. However, phenol is generally reserved for patients already undergoing general anesthesia, children whose weight limits the dose of BTX-A, those in which a longer duration of action is desired, or those in which a lack of efficacy, intolerances, or contraindications to BTX-A exist.

      SUMMARY

      Spasticity is one of the most common symptoms for children with CP requiring medical intervention. When nonpharmacological therapies such as physical and occupational therapy fail as monotherapy, initiation of pharmacotherapy is necessary. As outlined in this review, several treatment options including oral and parenteral options are available. Published supporting efficacy and safety data are, at large, lacking in robustness, and additional well-designed trials are needed to investigate comparative and long-term efficacy and safety. These limitations notwithstanding, pharmacotherapy is common in children with CP-associated spasticity, and therapy decisions are guided by clinical experience and in a case-by-case manner. When making therapeutic decisions, the best available evidence should be used in combination with consideration for patient-specific factors (e.g., level of sedation and concomitant medications).
      Practical aspects of medication use such as dosage form availability, ability to administer by means of enteral feeding tubes, dosing frequency, controlled substance status (i.e., diazepam is a C-IV classification), and ongoing monitoring must be employed to determine the appropriateness of therapy continuation and to ensure that the benefits of treatment outweigh associated risks. Although a standardized treatment algorithm does not exist because of patient heterogeneity, a common approach is to initiate therapy with enteral options first (e.g., baclofen or diazepam), with the choice being dependent on symptoms, concomitant medications, and response to therapy. If therapy is ineffective or results must be optimized, then parenteral options such as botulinum toxin, phenol, or intrathecal baclofen are considered. If the patient does not respond well to any of these therapies, the patient should be further evaluated to confirm whether the underlying problem is spasticity versus other symptoms such as dystonia.
      The authors would like to acknowledge Dr. Montida Chowanadisai, Assistant Professor in the Department of Pediatrics and Physical Medicine and Rehabilitation at the University of Colorado School of Medicine/Children's Hospital Colorado for her comprehensive review and editorial assistance in the preparation of this review. Dr. Chowanadisai is board certified in General Pediatrics, Physical Medicine and Rehabilitation, and Pediatric Rehabilitation.

      Appendix. SUPPLEMENTARY MATERIALS

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      Biography

      Mary Reilly, PharmD Post-Graduate Year 1 Pharmacy Resident, University of Kentucky, Lexington, KY.
      Kayley Liuzzo, Pediatric Clinical Pharmacist, Department of Pharmacy, Children's Hospital Colorado, Aurora, CO.
      Allison B. Blackmer, Associate Professor of Pharmacy; University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences and Clinical Pharmacist Specialist, Special Care Clinic, Children's Hospital Colorado, Aurora, CO.