1. www.wemove.org Spasticity Slide Library Version 2.3 - All Contents Copyright © WE MOVE 2001 Spasticity Pharmacological Treatment Part 4 of 6

2. Oral Medications Benzodiazepines Baclofen Dantrolene sodium Tizanidine Clonidine Cyproheptadine Cannabinoids Orphenadrine www.wemove.org

3. 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 www.wemove.org

4. 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 www.wemove.org

5. 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: 0.12-0.8 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 www.wemove.org

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

7. 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 www.wemove.org

8. 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 www.wemove.org

9. 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 www.wemove.org

10. 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 100-200 mg/day (max. 400 mg/day) Adverse effects: weakness (including ventilatory muscles), drowsiness, lethargy, nausea, diarrhea www.wemove.org

11. 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 www.wemove.org

12. 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 12-36 mg/day (max. 36 mg/day) Adverse effects: drowsiness, dizziness, dry mouth, orthostatic hypotension www.wemove.org

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

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

15. 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 www.wemove.org