1. Appropriate Medication Usage After TBI: Cognition, Behavior and Beyond
David X. Cifu, M.D.
The Herman J. Flax, M.D. Professor and Chairman
Department of Physical Medicine and Rehabilitation
Virginia Commonwealth University/Medical College of Virginia

2. Guidelines for Medication Usage After TBI
Define the problem as objectively and specifically as possible.
Use medicines that have some proven efficacy; don’t just use “something” (e.g. Neurontin).
Develop clear cut goals and metrics to assist in determining when to stop treatment.
Begin low but get to a therapeutic dosing before abandoning usage.
Be alert to side effects and undesired effects.

3. Alterations in Cognition and Behavior After TBI
Hypoarousal
Hypoattention
Memory Deficits
Depression
Delirium
Agitation

4. Factors Affecting Cognitive and Behavioral Function After TBI
Effects of the TBI
Medical Instability
Infection
Metabolic Disturbances
Hormonal/NeuroEndocrine Disturbances
Hypoxia
Sleep-Wake Disturbances
Pain
Seizures

5. Factors Affecting Cognitive and Behavioral Function After TBI
Medications
Cognitive-Impairing Medications
Central Acting Antihypertensives (Clonidine)
Central Acting Antispasmodics (Tizanidine)
GI Agents (H2 Blockers, Reglan)
Pain Medications (Narcotics, ? NSAID’s)
Sedatives (Benzodiazepines, Sleep Aids)
Anticonvulsants (Phenytoin, Carbamazepine, Phenobarbital)

6. Factors Affecting Cognitive and Behavioral Function After TBI
Cognitive-Improving Medications
Stimulants [Methylphenidate, Dextramphetamine]
Amantadine [Symmetrel]
Bromocriptine [Parlodel]
Selective Serotoninergic Re-Uptake Inhibitors [Prozac, Zoloft, Paxil,Celexa]
Combination Antidepressants [Wellbutrin]
? Levodopa-Carbidopa [Sinemet]
? Anti-Alzheimer's Agents [Aricept, Exelon]

7. Coma Intervention
Directed Multisensory Stimulation (DMS) demonstrated superior (increased responsiveness, improved RLAS, improved GCS) versus Non-Directed Stimulation (NDS) in RLAS II patients
Hall:Brain Injury 1992:6:435-45

8. Coma Intervention
Comatose receiving greater therapy intensity (by 60%) demonstrated a 31% decrease in length of stay.
Blackerby:Brain Injury 1989;4:167-73

9. Cognitive Interventions: Hypoarousal
No reliable data to support the efficacy of pharmacologic intervention in the comatose (RLAS I) or vegetative (RLAS II) patient. All you get is a very “alert”-looking comatose or vegetative patient.
Small trials do support use of neurostimulants (Amantadine 150 mg bid) in “emerging” patients (RLAS III).
Kaelin: Arch Phys Med Rehabil 1996;77:6-9

10. Cognitive Interventions: Hypoattention
Neurostimulants have been demonstrated to improve attention (and +/- function) in responsive patients (RLAS IV-VIII) .
Methylphenidate has the most clinically demonstrated efficacy for individuals who have progressed out of coma.
Dosing 5-30 mg q 7am and 12 pm.
Kaelin: Arch Phys Med Rehabil 1996;77:6-9

11. Methylphenidate (Ritalin)
Modes of Action
Release of Dopamine from reserpine sensitive presynaptic pool
Braestrup: J Pharm. Pharmacol. 1977, 29:
Inhibition of Dopamine uptake
Ferris,Tang: J of Pharmacol. Exp. Ther. 1979, 210:
Inhibition of Monoamine Oxidase
Szporny, Gorog: Biochem. Pharmacol. 1961, 8:

12. Methylphenidate (Ritalin)
Pharmacokinetics
Peak serum levels are reached within 2 hours (Half life = 2-4 hrs)
Both a wide inter-individual and intra-individual variability in serum concentrations exist
MPH levels are not different in responders and non-responders
Gualtieri, CT, et al. J of Amer Acad of Child Psych 1982, 21(1):

13. Selective Serotonin Re-Uptake Inhibitors (SSRI’s)
Prozac, Zoloft, Paxil, Celexa
Inhibit CNS reuptake of Serotonin
Activating antidepressants, however somnolence present w/ Paxil at doses >20 mg/day
Increase dosage q 4-6 weeks
If treating depression, need to commit to 12 month course (or increase recurrence)

14. Bromocriptine (Parlodel)
Dopamine receptor agonist
Adjunctive treatment for Parkinson’s disease
Suggested for low level patients, however limited proven efficacy
Dosage: mg/day in 2 doses
Increase dosage weekly
High incidence of N/V and Headaches with increasing dosages.

15. Amantadine (Symmetrel)
Potentiates Dopamine (mechanism unclear)
Adjunctive treatment for Parkinson’s disease (tremor)
Dosage: mg/day in bid dosing (elevated seizure risk above 300 mg/day)
Increase dosage weekly
Hallucinations dose limiting side effect.
Probable efficacy in RLAS III patients.

16. Other Antidepressants [Effexor, Wellbutrin]
Effexor and Wellbutrin inhibit Serotonin, NE, and Dopamine reuptake = Activating agents
Effexor Dosage: mg/day in 2-3 doses (Occasional HTN side effects)
Wellbutrin Dosage: mg/day in 3 doses (May have worsening effects on agitation)

17. Levodopa-Carbidopa [Sinemet]
Increases cerebral dopamine
Suggested for low level patients, however limited proven efficacy
Side effects can include dyskinesias and cognitive changes
Dosage: mg Levodopa/day in 2-3 doses (tablets contain either 100 or 200 mg Levodopa)

18. Anti-Alzheimer's Agents [Aricept, Exelon]
Reversible cholinesterase inhibitors = increases cerebral acetylcholine
Effective in improving memory in individuals with Alzheimer’s disease
Limited research suggests efficacy in TBI patients
Extremely expensive, occasional GI side effects

19. Treatment Algorithm: Hypoarousal/Hypoattention
Day 1
Define pathology -> CT/MRI, Mechanism of Injury, Secondary BI
Assess function: DRS, FIM, RLAS (limited efficacy in RLAS I-III)
Assess medical status -> Infections, Oxygenation, Metabolics, Fluid Status, Seizures
Remove medications -> H2 blockers, narcotics, central acting anti-HTN/GI, Benzodiazepines, Sleepers
Day 1-4
Stabilize/Improve medical status
Assess/Improve sleep-wake cycle: Trazadone, Ambien
Assess behavior: ABS, Therapy attendance/participation, Attention to Task

20. Treatment Algorithm: Hypoarousal/Hypoattention
Day 5-10
Initiate Methylphenidate 5 mg q 7 am and 12 pm, increase 5-10 mg/day to 60 mg maximum
Monitor behavior and sleep-wake cycle
Day 10-20
If Methylphenidate effective, continue at lowest effective dose for 2-3 weeks, then wean off in 2-4 days
If Methylphenidate ineffective by 30 mg/day, then initiate wean and begin new agent.
Recommend: SSRI’s may be appropriate if mild but limited response to Ritalin ( if depression is suspected, then Ritalin only effective 4-6 weeks and will need SSRA for 3 months minimum).

21. Cognitive Interventions: Agitation
Agitation occurs in >50% of all TBI patients (RLAS IV), however delirium, seizures, pain, hypoxia can also manifest with agitation.
True TBI agitation should be treated with environmental and behavioral interventions.
Pharmacologic treatment should only be implemented in specific behaviors are identified and goals established.
Agitation is defined as an Agitated Behavior Scale score > 21

22. Cognitive Interventions: Agitation
Etiologies
Environmental
Pain
Seizure activity
Delirium (meds, hypoxia, metabolic)
Inadequate sleep/wake hygiene
… or TBI-related confusion

23. Cognitive Interventions: Agitation
Treatment
Assess for correctable etiology
Sleep/Wake Charting
Medical Management
Behavioral
establish desired behavior
positive reinforcement
shaping
structured therapy
Agitated Behavior Scale
Assess pattern of agitation
Documentation
Evaluate effectiveness of intervention
Physical Restraint
Pharmacologic
ABS > 28
ABS score 21 or higher objectively quantifies agitation. Occurs in 20-50% after brain injury.
Note that Pharmacologic intervention is listed last. “Medical Management” implies pain control and correction of metabolic abnormalities.
Trazodone and Ambien are first-line agents. Dose Trazodone in 50mg increments up to 300mg in single dose.
Avoid benzodiazepines, Benadryl, and tricyclics.

24. Agitation: Medications
Day 1-3 Use prn for ABS >28
Ativan
Risperidone
Day 4+
Schedule agents if persistent ABS > 28
Aggression - Beta-Blockers (Propranolol)
Restlessness - AED’s (Tegretol, VPA)
Emotional lability - TCA’s (Nortriptyline)
Wean agent when ABS <21 for 3 days.
Cifu: J NeuroRehabil 1995;5:

25. Post-Traumatic Seizures: Background
TBI-related seizures account for 20% of symptomatic epilepsy. Hauser: Epilepsia 1991:32;429-45
PTS accounts for 5% of all cases of epilepsy.
Hauser: Epilepsia 1991:32;429-45
Late PTS is present in 4-7% all TBI, nearly 20% rehab TBI, and 35-50% penetrating TBI patients.
Yablon: Arch PM&R 1993:74;
EEG has no predictive value for PTS Yablon: Arch PM&R 1993:74;

26. Prophylaxis for PTS
73% reduction in early PTS and 50% reduction in 1 year PTS in individuals given phenytoin for 1 week post-TBI.
No proven benefits to giving prophylaxis >7 days post-TBI. Temkin:N Engl J Med 1990:323;
No benefit to use of up to 1 month VPA.
Temkin: J NeuroSurg 1999:91;
AANS and AAPM&R recommend 7 days of either PTH or CBZ post-TBI.

27. Prophylaxis for PTS
Do not treat seizure in first 24 hours post-TBI longer than initial 7 days, unless status epilepticus.
Seizures in the first week should be treated (1 year) unless there is a non-TBI cause evident (infection, hypoxia, metabolic, hydrocephalus).
Seizures after 1 week must be treated for at least 1 year.

28. GI Ulcer Prophylaxis
Use of H2-Blockers has been demonstrated to decrease ICU-related stress ulceration of the GI tract in specific patient populations (e.g., burns).
No specific information in patients with TBI, with or w/o PEG/J tubes.

29. GI Ulcer Prophylaxis
Newer H2-Blockers, while expensive, have limited CNS effects.
High risk patients (h/o PUD, h/o GERD, comatose, > 65 years old) are appropriate for prophylaxis while in ICU.
No clear indication for all TBI patients in ICU.

30. Spasticity Management
Treatment should be initiated if the spasticity is limiting function, ROM, or is causing pain.
Potential side effects of treatment must be weighed against potential benefits.

31. Spasticity Management: Third Line
Systemic medications are effective, but often have systemic side effects:
Hepatotoxicity (Baclofen, Dantrium)
Generalized weakness (Dantrium)
Lethargy (Zanaflex, Baclofen, Valium)
Hypotension (Zanaflex)
Addiction (Valium)

32. Spasticity Management: Third Line
Dantrolene Sodium (Dantrium)
Acts peripheral by blocking release of Ca++ from the t-tubules of the sarcoplasmic reticulum.
Hepatotoxicity is not uncommon.
May cause generalized weakness.
No central effects.
Most often used in Brain Injury and CVA.
Start 25 mg qid -> Max 100 mg qid.

33. Spasticity Management: Third Line
Tizanidine (Zanaflex)
Central acting alpha-blocker.
Often causes hypotension.
May cause lethargy.
very gradual dose increase.
Most often used in SCI.
Start 1 mg tid -> Max 8 mg tid.

34. Spasticity Management: Fourth Line
Phenol (1-10% Aqueous Solution)
Direct neurocidal agent, effect lasts for 3-6 months (until nerve regenerates). Works immediately.
Eliminates spasticity in specific nerve distribution or muscle.
Nerve/muscle motor point (where nerve innervates) must be isolated electrically.
Inexpensive.

35. Spasticity Management: Fourth Line
Botulinum Toxin (Botox, NeuroTox)
Neurotoxin that prevents the release of acetylcholine (Ach) from presynaptic vacuoles at the neuromuscular junction.
Produces paralysis of the muscle for 2-4 months.
Maximal effects take 2 weeks.
Expensive.

36. Spasticity Management: Fourth Line
Focal blockade needs to be combined with a structured stretching/bracing program.
Focal blockade often reveals underlying connective tissue contractures.
If they are “soft”, they can be improved with stretching.
If they are hard, surgical intervention is indicated.

37. Guidelines for Medication Usage After TBI
Define the problem as objectively and specifically as possible.
Use medicines that have some proven efficacy; don’t just use “something” (e.g. Neurontin).
Develop clear cut goals and metrics to assist in determining when to stop treatment.
Begin low but get to a therapeutic dosing before abandoning usage.
Be alert to side effects and undesired effects.