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

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.

Alterations in Cognition and Behavior After TBI

Hypoarousal Hypoattention Memory Deficits Depression Delirium Agitation

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

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)

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]

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

Coma Intervention

Comatose receiving greater therapy intensity (by 60%) demonstrated a 31% decrease in length of stay.

Blackerby:Brain Injury 1989;4:167-73

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

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

Methylphenidate (Ritalin)

Modes of Action

– Release of Dopamine from reserpine sensitive presynaptic pool

Braestrup: J Pharm. Pharmacol. 1977, 29: 463 - 470.

– Inhibition of Dopamine uptake Ferris,Tang: J of Pharmacol. Exp. Ther. 1979, 210: 422 - 428.

– Inhibition of Monoamine Oxidase Szporny, Gorog: Biochem. Pharmacol. 1961, 8: 263 - 268.

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): 19-26.

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)

Bromocriptine (Parlodel) Dopamine receptor agonist Adjunctive treatment for Parkinson’s disease Suggested for low level patients, however limited

proven efficacy Dosage: 2.5-15 mg/day in 2 doses Increase dosage weekly High incidence of N/V and Headaches with

increasing dosages.

Amantadine (Symmetrel) Potentiates Dopamine (mechanism unclear) Adjunctive treatment for Parkinson’s disease

(tremor) Dosage: 100-400mg/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.

Other Antidepressants [Effexor, Wellbutrin]

Effexor and Wellbutrin inhibit Serotonin, NE, and Dopamine reuptake = Activating agents

Effexor Dosage: 75-225 mg/day in 2-3 doses (Occasional HTN side effects)

Wellbutrin Dosage: 200-450 mg/day in 3 doses (May have worsening effects on agitation)

Levodopa-Carbidopa [Sinemet] Increases cerebral dopamine Suggested for low level patients, however

limited proven efficacy Side effects can include dyskinesias and

cognitive changes Dosage: 400-1600 mg Levodopa/day in 2-3

doses (tablets contain either 100 or 200 mg Levodopa)

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

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

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).

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

Cognitive Interventions: Agitation

Etiologies– Environmental– Pain– Seizure activity– Delirium (meds, hypoxia, metabolic)– Inadequate sleep/wake hygiene

… or TBI-related confusion

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

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;5:245-254

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;983-1001

EEG has no predictive value for PTS. Yablon: Arch PM&R 1993:74;983-1001

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;497-502

No benefit to use of up to 1 month VPA.Temkin: J NeuroSurg 1999:91;593-600

AANS and AAPM&R recommend 7 days of either PTH or CBZ post-TBI.

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.

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.

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.

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.

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)

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.

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.

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.

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.

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.

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.