Spasticity Slide Library Version All Contents Copyright © WE MOVE 2001 Spasticity Pharmacological Treatment Part 4 of 6

Oral Medications Benzodiazepines Baclofen Dantrolene sodium Tizanidine Clonidine Cyproheptadine Cannabinoids Orphenadrine

Benzodiazepines Long- and short-acting formulations –diazepam –clonazepam –clorazepate –ketazolam –tetrazepam Mechanism of action (CNS) –brain stem and spinal cord –post-synaptic site of action –potentiates presynaptic inhibitory effect of GABA

Benzodiazepines, cont’d Clinical indications: spinal cord injury, multiple sclerosis Possible applications: traumatic brain injury, cerebral palsy, cardiovascular accident Clinical effects: –decreased resistance to passive ROM –decrease in hyperreflexia –reduction in painful spasms –sedation and reduced anxiety

Diazepam (Valium ® ) Initial adult dosing: 2 mg twice daily Slow titration to maximum of 60 mg/day Bedtime dosing for nocturnal spasms: 5-10 mg Pediatric dosing: mg/(kg day) Adverse effects: sedation, weakness, hypotension, GI symptoms, memory impairment, incoordination, confusion, depression, ataxia Intoxication uncommon at recommended dosing; dependency and withdrawal possible

Oral Baclofen (Lioresal ® ) Mechanism of action –GABA B selective agonist –pre- and post-synaptic actions –mono- and polysynaptic pathways

Oral Baclofen, cont’d Clinical indications –spasticity of spinal origin (intrathecal baclofen approved for spinal and cerebral spasticity) Clinical effects: –decreased resistance to passive ROM –decrease in hyperreflexia –reduction in painful spasms –reduced anxiety

Oral Baclofen, cont’d Initial dose: 5 mg 3x daily Slow titration to 20 mg 4x day (higher doses have been reported) Adverse effects: weakness, sedation, hypotonia, ataxia, confusion, fatigue, nausea, dizziness, lower seizure threshold May potentiate antihypertensives Sudden withdrawal may cause seizures, hallucinations, rebound spasticity

Dantrolene Sodium (Dantrium ® ) Mechanism of action: –reduces calcium release from sarcoplasmic reticulum –uncouples excitation and contraction Clinical indications: cardiovascular accident, multiple sclerosis, spinal cord injury, cerebral palsy Possible applications: traumatic brain injury Clinical effects: –decreased resistance to passive range of motion –decreased hyperreflexia and muscle tone –reduction in spasms and clonus

Dantrolene Sodium, cont’d Obtain baseline serum liver function tests Hepatotoxicity associated with long-term maximum dose, especially in women >30 Recommended dosing: –initial dose 25 mg 2x day –typical maintenance dose mg/day (max. 400 mg/day) Adverse effects: weakness (including ventilatory muscles), drowsiness, lethargy, nausea, diarrhea

Tizanidine (Zanaflex ®, Sirdalud ® ) Mechanism of action: alpha-2 noradrenergic agonist –blocks release of excitatory amino acids from spinal interneurons –inhibition of facilitory coeruleospinal pathways Clinical indications: multiple sclerosis, spinal cord injury; possibly cerebral spasticity Clinical effects: –reduced tone, spasm frequency, hyperreflexia –no decrease in strength –antinociceptive in animal studies

Tizanidine, cont’d Obtain liver function tests at baseline and months 1, 3, and 6 Initial dose: 2-4 mg at bedtime Titrate in 2-4 mg steps Maintenance dose mg/day (max. 36 mg/day) Adverse effects: drowsiness, dizziness, dry mouth, orthostatic hypotension

Other Oral Antispasmodics (I) Clonidine (Catapres ®, Dixirit ® ) –alpha-2 agonist –may allow decreased baclofen dose –limited tolerability –available as a patch

Other Oral Antispasmodics (II) Cyproheptadine (Periactin ® ) –histamine and serotonin antagonist –limited experience; well tolerated in open trials

Other Oral Antispasmodics (III) Cannabinoids (Cesamet ®, Marinol ® ) –placebo? general relaxation effect? specific antispastic? –limited experience; anecdotal efficacy, 1 single-patient double-blind trial –effective in multiple sclerosis mouse for spasticity and tremor Orphenadrine citrate (Norflex ® ) –NMDA antagonist –fast-acting, short duration –possibly useful as preparation for physical therapy session