Understanding Medications Used in the Treatment of Traumatic Brain Injury Flora Hammond, MD Chairman & Covalt Professor, Dept Physical Medicine & Rehabilitation.

Understanding Medications Used in the Treatment of Traumatic Brain Injury
Flora Hammond, MD Chairman & Covalt Professor, Dept Physical Medicine & Rehabilitation Indiana University School of Medicine Chief of Medical Affairs, Rehabilitation Hospital of Indiana Project Director, Indiana University TBI Model System

Outline Neurotransmitter systems Basic principles
Evidence for medications Specific medication considerations Summary Case examples

Principles for medication treatments

Pharmacologic Management Steps
History & Assessment Diagnose: Look for & treat possible causes (see next slide) Medications as the problem Develop treatment plan Eliminate/taper, substitute, optimize dose (reduce or increase) Add meds targeted at profile enhance nighttime sleep & daytime function Pharm Vs. Non-pharm approaches Combining pharm with non-pharm treatments Individual, family, cognitive, behavioral, environmental Medications are not always the right answer

Look for and Treat Other Causes
Sleep disturbance Pain Occult fracture Substance withdrawal Dehydration Hypoxemia / Pulmonary embolism Infection / sepsis Seizure / temporal lobe sz Need to specify “temporal or nasopharyngeal leads” when EEG ordered Autonomic instability Neuroendocrine or metabolic dysfunction Electrolyte imbalance, thyroid, adrenal insufficiency, testosterone Hypoglycemia, hepatic Depression Anxiety Stress / environment Substance use Musculoskeletal injury Medication side effects or toxicity or drug interaction

Common Problems With Past & Current Treatments
Misdiagnosis Duration too short Dose too low or too high Not actually taken Treatments never tried Not combined with other treatments Contribute to/cause problem Allergic or adverse reaction

Dosing: 1, Low, Slow One change at a time Start low Give enough time
Gradually increase Don’t give up too early Follow progress Objectively measure irritability Dose

Medications as the Problem
Aggression Bromorcriptine, benzos, antipsychotic, hypnotics, levodopa, phenelzine, digitalis Depression Antidepressants, anticonvulsants, propranolol, narcotics, levodopa, metoclopramide, oral contraceptives, benzos Hallucinations Anticonvulsants, propranolol, bromocriptine, amantadine Paranoia Bromocriptine, amphetamines, propranolol, corticosteroids, NSAIDS Cognitive decline Anticonvulsants, propranolol Sedation Baclofen, clonidine, antichol phenytoin, narcotics, benzodiazepam, phenergan, metaclopramide, antipsychotics Slowed motor recovery NA blockade

Eliminating or Substituting Medications
Eliminate or substitute meds that are: unnecessary potential for causation hinder function (arousal, cognitive function, recovery)

Adding Medications Select potential candidates:
Consider evidence for effect in BI & other diagnoses, experience, pharmacologic mechanism, symptoms, injury mechanism, MOA See Tables Consider symptoms, context and precipitators of behavior(s) Depression, anxiety, psychosis, confusion, slow processing, attn, initiation Consider priority issues Choose agents that accomplish >1 need e.g.: tachycardia, headache, seizure, pain, insomnia, arousal, cognition, processing speed, depression, anxiety, agitation Consider drug-drug interactions, side effects & contraindications, risk : benefit

Consider Mechanism May need more than 1 medication for optimal response & multiple symptoms Different mechanisms Augment partial response thru similar mechanisms

Duration of Treatment Remission / carry-over effect Vs. ongoing need
Depends on treatment purpose Emergence : likely shortterm Anticonvulsants: Sz, pain, behavior Seizure: Depends on reason for use Prophylaxis: No role after 1 week post-injury Treatment: 2 years seizure free; negative EEG?, risk of sz? Pain & Behavior: likely need to continue indefinitely Antidepressants: Depression, insomnia, lability Depression: American Psychiatric Assn for major depression: Minimum weeks after complete remission of symptoms Trial off Observations with skipped dose(s)

Role of Neurotransmitters

Neurotransmitters (NT)
Carry messages to control arousal, initiation, memory, cognition & behavior Some hinder function Some enhance function BI changes NT availability & function Modulated via medications Medications often influence more than one NT system

Dopamine (DA) Predominant location & action Actions TBI changes
Subcortex, including basal ganglia, frontal lobe & hypothalmus Actions Screening out information, arousal, apathy, initiation, attention, memory, hypothalamic function/ autonomic stability, pleasure, drive, extrapyramidal / motor movements TBI changes Acutely elevated Chronically decreased? Medication Examples Direct DA: bromocriptine, carbidopa/levodopa Indirect DA: Amantadine, memantine, modafanil , lamotrigine DA & NA: methylphenidate, amphet

Norepinephrine (NE) Predominant location & action Actions TBI changes
Brainstem (locus ceruleus), frontal lobe Actions Arousal, attention, memory, initiation, executive function, behavior, motor function TBI changes Acutely elevated Chronically decreased? Medication Examples Dexedrine, Tricyclic antidepressants

Serotonin (SE) Predominant location & action Actions TBI changes
Brainstem (caudal linear nucleus, nucleus raphe, reticular formation), frontal lobe, hippocampus, substantia nigra Actions Arousal, depression, anxiety, emotional lability, obsessive-compulsive disorder, appetite suppression, aggression, motor control, memory TBI changes Acutely: site of injury may dictate Unsure chronically Medication Examples Prozac, zoloft, paxil, luvox, trazodone, effexor, BuSpar

Acetylcholine (Ach) Predominant location & action Actions TBI changes
Medial temporal lobe, thalamus, amygdala, hippocampus, basal ganglia, olfactory bulb, cerebral cortex, brainstem Actions Declarative memory, learning, executive function, attention, mood, motivation, aggression, award, cortical arousal, motor coordination, social intelligence, induction of REM sleep, sensory gating, EEG fast wave activity TBI changes Acutely elevated Chronically decreased Medication Examples ↑ Ach: Physostigmine Inhibit Ach Esterase: Aricept, Exelon, Cognex/ Tacrine

GABA Predominant location Main CNS inhibitory neurotransmitter Actions
hypothalamus, hippocampus, cerebral cortex & cerebellar cortex Main CNS inhibitory neurotransmitter Actions Sedation, confusion, long-term cognitive deficits, n/v, dryness of mouth, abnormal eye movements, fatigue, immunosuppression Glutamate–GABA balance Glutamate increases aggression; GABA decreases aggression Thought to play a role in Alzheimer’s behavior Medication Examples Benzodiazepines, non-benzodiazepine hypnotics (e.g.: zolpidem), baclofen, barbiturates, progabide (gabrine), tiagabine (gabatril), ethanol

Role of Neurotransmitters in Cognition & Behavior
Catecholamine Dopamine Norepinephrine Serotonin Acetylcholine GABA * Complex interactions simplified here

Catecholamine (DA & NE) impact on Cognition
May improve arousal, processing speed, sustained attention/vigilance, possibly executive aspects of attention Signal-to-noise ratio Deficient DA / NE: “signal” misses target Too much DA / NE: Increased cognitive “noise” irrelevant task / distractions

Alpha-1 NA Blockade Vs Augmentation Impact on Fxn
Prazosin, haloperidol, risperdone, clonidine, tizanadine, phenoxybenzamine, & other drugs reducing NA levels, reinstates deficits. Enhanced recovery from hemiplegia by drugs increasing NA synaptic activity: amphetamine. Compliments of Dennis Feeney, PhD

Cholinergic Deficiency and Delirium
Anticholinergic activity may cause delirium Common in many drugs Significant: amitriptyline, desipramine, diphenhydramine (cold & sleep aids), hydroxyzine, imipramine, meclizine, nortriptyline, olanzapine, oxybutynin, paroxetine (paxil), promethazine, quetiapine, scopolamine, tolterodine (detrol), trihexyphenidyl (artane) Moderate: amantadine, carbamazepine, cyproheptadine (periactin), meperidine (demerol), oxycarbamazepine Mild: alprazolam, atenolol, buproprion, captopril, codeine, diazepam, digoxin, dipyridamole (persantine), fentanyl, furosemide, haloperidol, isosorbide, loperamide, metoprolol, morphine, nifedipine, prednisone, quinidine, ranitidine, risperdone, theophylline, trazodone, warfarin, xanax Trzepacz PT. Sem Clin Neuropsychiatry 2000;5:

Anti-Cholinergic Impact on longer-term cognitive function
• Each anticholinergic may increase the risk of cognitive impairment by 46% over 6 years. • For each one point increase in total ACB total, a decline in MMSE score of 0.33 points over 2 years has been suggested. • Each 1 point increase in the ACB total score has been correlated with a 26% increase in the risk of death. Boustani MA, Campbell NL, Munger S, Maidment I, Fox GC. Impact of anticholinergics on the aging brain: a review and practical application. Aging Heatlh. 2008;4(3):

Non-TBI Aggression Biology of Aggression: Initiation & Modulation
Siever LJ: Neurobiology of Aggression Am J Psychiatry 2008;165:

Non-TBI Aggression Implications for Pharmacotherapy of Aggression Siever LJ: Neurobiology of Aggression. Am J Psychiatry 2008;165: -Side effect profiles should be considered, especially relevant to brain injury

What is the evidence for medication treatments?

Evidence for Medication Treatment
Little research to support or refute Case studies Open-label case series Few randomized, controlled trials (RCTs), & thus, most evidence at level of options Trial and error Clinician experience Literature in other diagnostic populations

Cognition Summary of Literature Warden 2005
Problem Standards Guidelines Options General cognition - Avoid phenytoin Methylphenidate (DA) Amantadine (DA) Attention & Processing Speed Donepezil (Ach) Dextroamphetamine (DA/NE) Physotigmine (Ach) Memory CDP Choline 1 gram (cytidine diphosphate choline) Executive Function Bromocriptine (DA)

Mood & Behavior Summary of Literature Warden 2005
Problem Standards Guidelines Options Depression - TCA (Amitriptyline, Desipramine) (NE & SE) Sertraline (SE) Watch out for side effects (attn, conc, mem, arousal, seizure) Anxiety Psychosis Atypical antipsychotics (watch for weight gain & sedation) Apathy SSRI (SE) if part of depression; could make worse if not part of depression Stimulants & DA enhancers Irritability Beta-Blockers Methylphenidate (DA), SSRI (SE), valproate, lithium, TCA (amitriptyline & desipramine) (NE & SE), buspirone (SE) , amantadine (DA), carbamazepine

Evidence-based Reviews of BI Aggression Tx
Medication Fleminger 2003 ABI Warden 2006 TBI (LOE) ABIKUS 2007 ABI (consensus) ERABI 2012 ABI (LOE) Beta-Blockers 4 RCT Guideline Recommended A Level 1 Methylphenidate 1 RCT Option Recommended B Level 2 SSRIs No evidence TCA Option (amitriptyline & desipramine) Level 4 (Trazadone) Valproic Acid & Divalproex Level 4 (Divalproex) Carbamazepine * Level 4 evidence Amantadine * * (now 3 RCTs) Not helpful?/uncertain; LOE 2 children Buspirone * Level 5 Neuroleptic Avoid (C) Haldol not negative (LOE 4)?; Methotrimeprazine safe & effective (4) Lithium carbonate XXXXXXX.

Beta-Blockers for Agitation
Brooke 1992 Propranolol 420 mg/day Severe TBI (N = 21); Agitation (Overt Aggression Scale) Significant reduction in intensity, but not frequency Greendyke 1986a: Propranolol up to 520 mg/day Crossover design; n = 9; mixed violent BI pop Significantly fewer assaults Greendyke 1986b: Pindolol mg/day Crossover design; n = 11; mixed violent BI pop Significantly fewer assaults & other aggression ratings Greendyke 1989: Pindolol 20 mg/day Crossover design; n = 13; mixed violent BI pop Trend but not statistically significant (lower dose?)

Specific Medications

Amantadine (Dopaminergic)
Trade name: Symmetrel MOA: Dopamine agonist & NMDA receptor antagonist Literature: Irritability: First RCT for TBI irritability & aggression completed finding substantial improvement for amantadine group (Hammond, et al) Vegetative State/Minimally Conscious State (Giacino & Whyte, et al) Other uses: Arousal, disinhibition, hypersexual, lability, impulsivity, poor initiation, cognitive impairment, irritability, general cognitive function 100 mg q AM & 12 Noon; only occasionally go higher Side effects: Hypotension, confusion, hallucinations, seizure, coma, death Dose-related! Creatinine clearance is critical! 30-50: 100 mg /day 15-29: 100 mg every 48 hours <15: 200 mg every 7 days

Bromocriptine (Dopaminergic)
Trade name: Parlodel Mechanism of action: Stimulates Dopamine receptors Literature: Executive function & initiation (RCT) Other uses: Coma/VS/MCS emergence Dose: 2.5 – 7.5 mg / day (increasing gradually up to 12.5 – 15 mg bid for coma) -q AM & noon not bid Side effects: Dizziness, drowsiness, faintness, syncope, nausea, vomiting, constipation, diarrhea, hallucinations

Methylphenidate (Dopaminergic)
Trade name: Ritalin Mechanism of action: Inhibits the postsynaptic reuptake of dopamine Thought to activate the brainstem reticular activating system and cortex Cognitive & behavioral effects are not fully understood May improve post-TBI behavior through effects on attention, arousal, and initiation. Literature: Arousal, processing speed, and aggression/anger Reduces aggression in ADHD & TBI populations (2 RCT’s) at doses 10mg-60mg/day Other uses: Initiation, attention, distractibility, vigilance, memory, ADHD, motor impairment, apathy, fatigue, agitation, depression Contraindications: MAOI (monomamine oxidase inhibitors) Don’t use with Linezolid (Zyvox) or until 2 weeks off May increase drug levels of other meds Can worsen psychosis

Modafinil (DA, NA, Histamine)
Trade name: Provigil (narcolepsy agent) Mechanism of action: Increases the release of monoamines Also elevates hypothalamic histamine levels leading some researchers to consider Modafinil a "wakefulness promoting agent" rather than a classic amphetamine-like stimulant Literature: Fatigue Use especially if: Poor arousal, fatigue, depression, cocaine addiction Side effects: H/A, nausea, insomnia, anorexia, nervousness, increased anxiety, dry mouth, hypertension, tachycardia, chest pain, PVC’s, dizziness, parasthesias, pharyngitis, severe skin reactions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms Contraindications: Cardiovascular condition

Acetylcholine Esterase Inhibitors (Cholinergic)
Examples: Donepezil (Aricept), Exelon (Rivastigmine) Mechanism of action: Reversible inhibitor of the enzyme acetylcholinesterase Literature: Attention and memory, processing speed (post-hoc analysis) Uses: Deficits in executive function Dosing considerations: Dose at night time Steady state is not achieved for 15 days Side effects related to rate of dose escalation & generally temporary Start at 5 mg and then wait 4-6 weeks to increase to 10 mg Side effects: Most common: Nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue, anorexia Influenza, chest pain, urinary incontinence or retention or frequency, irritability, aggression, restlessness, nervousness, lability, vertigo, ataxia, nystagmus, increased or decreased libido, depression, seizure, paranoia, delusions, tremor, dysarthria, dysphasia, neuralgia, paresthesia, coldness, hyponatremia, neurodermatitis, bradycardia, heart block, syncope, cholinergic crisis Contraindications: Hypersensitivity to topiperidine derivatives, asthma, COPD Zhang 2004, Silver 2006

Summary of Cholinesterase Inhibitor Studies
Physostigmine evidence: single case (1) w/double-blind (1), open-label case series (1), single-site double-blind placebo-controlled (2) Donepezil single-case report (1), open-label case series (8), single-site double- blind placebo-controlled trial (3), two-site double-blind placebo- controlled trial (1), 1 multi-site in progress Rivastigmine multicenter RCT (1) with open-label extension (1), single-site double- blind placebo-controlled (1) Galantamine Open-label case series (1) (Bogdanovitch et al. 1975; Eames and Sutton 1995; Goldberg et al. 1982; Levin et al. 1986; Cardenas et al. 1994; Taverni et al. 1998; Whelan et al. 2000; Masanic et al. 2001; Bourgeois et al. 2002; Morey et al. 2003; Kaye et al. 2003; Walker et al. 2004; Zhang et al. 2004; Khateb et al. 2005; Tenovuo 2005; Trovato et al. 2006; Foster and Spiegel 2008; Kim et al. 2009; Tenovuo et al. 2009)

Tricyclic Antidepressants (NE & SE)
Mechanism of action: (poorly understood) Inhibits the re-uptake of norepinephrine and serotonin Also possess affinity for muscarinic & histamine H1 receptors to varying degrees Literature: Acute agitation: Amitriptyline 150 mg Depression: Amitriptyline, desipramine Other uses: Poor sleep maintenance and neurogenic pain Examples: Amitriptyline (Elavil): insomnia, neuropathic pain, lability, depression Nortriptyline (Sensoval, Aventyl, Pamelor, Norpress, Allegron and Nortrilen): chronic fatigue syndrome, chronic pain, migraines, labile affect Desipramine (Norpramin, Pertofane): ADHD, arousal Side effects: (differing profiles) Sedation, seizure, lethal if overdose, dysrhythmias, myocardial infarction, hepatic dysfunction, hypertension, worsened depression, suicidal thoughts, leukopenia, aplastic anemia, weight gain, decrease effects of clonidine Levels may be increased by Selective Serotonin Reuptake Inhibitors Contraindications: Acute myocardial infarction

Serotonin Reuptake Inhibitors (Serotonergic)
Examples: Sertraline (Zoloft), citilopram (Celexa), paroxetine (Paxil), fluoxetine (Prozac) [Antidepressant agent] Literature: Depression: Sertraline (Case series, 1 RCT); fluoxetine Irritability: Sertraline (Case series) Affective lability: Fluoxetine, sertraline, paroxetine (case studies) Uses: Depression and anxiety 1st line for depression due to TCA SE’s May cause increase in carbamazepine levels Side effects: H/A, nausea, vomiting, diarrhea, constipations, insomnia, sedation, abnormal dreams, anxiety, tremor, dizziness, fatigue, impaired concentration, agitation, anorexia, weight gain, rash, sexual dysfunction Contraindications: Monoamine Oxidase Inhibitors (MAOI)

Trazodone (Serotonergic)
Trade names: Desyrel, Beneficat, Deprax, Desirel, Molipaxin, Thombran, Trazorel, Trialodine, Trittico [antidepressant] Mechanism of action: Serotonin reuptake inhibitor (less anticholinergic effect than the TCAs) Literature: Reported helpful for aggression due to organic mental disorders Not studied in regards to brain injury irritability & aggression Use especially if: Poor sleep initiation Side effects: Priapism, dysrhythmias, hypotension, hypertension, seizure, worsened depression, suicidal thoughts, potential for serotonin syndrome, leukocytosis, hemolytic anemia Cannot use with many antipsychotics (geodon, risperdol)

Buspirone (Dopamine & Serotonin)
Trade name: BuSpar [anxiolytic agent] Mechanism of action: Affinity for brain D(2)-dopamine receptors (both an antagonist and agonist) and for the 5-HT(1A) receptors (agonist) Buspirone does not block the neuronal reuptake of monoamines and, on chronic administration, it does not lead to changes in receptor density in the models investigated Literature: Aggression: Open case series Other uses: anxiety, depression, somatic preoccupation, inattention, distractibility Dosing: 15 mg three times daily Expect lag of 2-3 weeks; allow 4 weeks to know if dose is effective Side effects: headache, dizziness, nausea, insomnia Contraindications: May increase antipsychotic (haloperidol) levels Monoamine Oxidase Inhibitors (MAOI)

Beta-Blockers Literature:
Agitation & aggression Propranolol (Inderal) (2) [1 agitation, 1 aggression] Pindolol [behavior issues in general; mixed population] Nadolol (Corgard) [aggression, non-traumatic BI] Other uses: Hyperadrenergic state, migraine headache Use lipophilic B-blockers for agitation Lipophilic: Propranolol, oxprenolol, metoprolol CNS effect appears beneficial for agitation Hydrophilic: Atenolol, nadolol Lower incidence of CNS-related side effects in general population Consider if patient is sedated on lipophilic agent Side effects: Sedation, delirium, dizzy, light-headed, clinical depression, lower HDL, increase LDL, decreased BP & pulse (switch to pinodol) Drug interactions: Increased plasma levels of antipsychotics & AED Contraindications: Asthma, poor circulation, diabetes, thioridazine

Anticonvulsants Evidence: Aggression: Case reports, Case series
Uses: Seizure, aggression, dysinhibition, impulsivity, neuropathic pain Carbamazapine (Tegretol): 3 case studies/series; RCT in progress Side effects: drowsiness, cognitive impairment, SJS, aplastic anemia, hyponatremia, hepatic dysfunction Valproic acid (Depakote): Case reports Side effects: Weight gain, hemorrhagic pancreatitis, leukopenia, thrombocytopenia, neural tube defect risk, hepatic dysfxn Newer anticonvulsants: limited literature Oxycarbamazapine (hypoNa), lamotrigine/Lamictal, gabapentin Avoid phenytoin & phenobarbital which are more sedating Lab monitoring

Lithium Consider for: Side effects: Contraindications:
Severe aggression, associated major depression, bipolar disorder Side effects: Toxicity, H/A, nausea, vomiting, diarrhea, polyuria, weight gain, tremor, dizziness, sedation, rash, leukocytosis, dysrhythmia, hypothyroidism Contraindications: Renal failure, severe renal disease, dehydration, significant cardiac disease, pregnancy, lactation, under 12 years of age, caution with diuretics Many drug interactions: NSAIDs, ACEI, diuretics, thyroid agents Lab monitoring required

Benzodiazepines (GABA)
Examples: lorazepam (Ativan), diazepam (Valium) Mechanism of action: Enhance GABA receptor function Uses: Agitation: Generally reserve use for imminent danger Anxiety: Avoid. Use SSRI or Buspirone instead. Myoclonus Lots of drug interactions! Side effects particularly common in TBI! Side effects: drowsiness, dizziness, ataxia, slurred speech, memory impairment, agitation, akathisia, psychomotor impairment (including driving) Contraindications: Severe liver disease, COPD, sleep apnea

Antipsychotics (Dopamine Blocking)
1st generation vs. 2nd generation 1st generation: Haloperidol (Haldol) 2nd generation: risperdone (Risperdol), olanzapine (Zyprexa), quetiapine (Seroquel) Atypicals have less propensity for extrapyramidal symptoms Both tend to block receptors to brain’s dopamine pathways, but encompass a wide range of receptor targets Generally, don’t solve the problem. Exclude other causes for psychosis. AVOID. If needed, use short-acting. Sparingly for imminent danger. Side effects: CONTRAINDICATED WITH TRAZODONE Tardive dyskinesia, neuroleptic syndrome, seizure, weight gain, diabetes, sedation, prolongs PTA (Rao 1985), decreased arousal, weakness, diabetes, slowed motor recovery, hemiplegia reinstatement, thrombocytopenia

Zolpidem Selective for a subtype of GABA receptors
Could block the inhibitory inputs from the globus pallidus to the thalamus allowing the thalamus to excite the cortex and help restore cognitive and motor functions Increase interaction in some people in VS/MCS: <10% Dosing: uncertain. Wears off. Tolerance? AMBIEN videos:

Nuedexta (dextromethorphan & quinidine)
Pseudobulbar affect (Hammond, in press): large open label case series Aggression?: case studied; study in Alz Dementia Irritability: Study in progress

Summary

Summary Get diagnosis right Look for & treat other causes
including medications History of meds tried and reactions are important Trial & error 1 at a time, start low, gradually increase, reach max-typical dose before giving up Augment response with other treatments or mechanisms, consider drug-drug interactions and side effects Often need more than 1 approach

Summary of BI Cognitive & Behavioral Pharmacotherapies
Cognition catecholaminergic augmentation / balance cholinergic augmentation mixed catecholamine and cholinergic augmentation Behavior Anticonvulsants Mixed Critical variables for treatment selection cognitive & behavioral target(s) impact on life functions

Physician Preferences: Francisco 2007
Problem “Expert” PMR Not “expert” PMR Agitation Valproic acid (13) Propranolol (8) Nadolol (6) Trazodone (6) Carbamazepine (5) Lorazepam (9) Carbamazepine (8) Risperdone (8) Anger Valproic acid (6) SSRI (5) Valproic acid (11) Carbamazepine (7) Irritability Valproic acid (8) Sertraline (7) Valproic acid (7) Sertraline (4) Carbamazepine (6) Emotional lability Buspirone (6) Paroxetine (4) Valproic acid (4) Paroxetine (3) Buspirone (2) Anxiety Buspirone (14) Paroxetine (7) Buspirone (13) Paroxetine (5) Depression Paroxetine (11) Sertraline (10) Venlafaxine (10) Methylphenidate (5)

Physician Preferences: Francisco 2007
Problem “Expert” PMR Not “expert” PMR Insomnia Trazodone (21) Zolpidem (15) Nortriptyline (9) Trazodone (16) Zolpidem (9) Nortriptyline (2) Benzodiazepams (7) Hypoarousal Methylphenidate (19) Amantadine (10) Modafanil (6) Methylphenidate (17) Amantadine (5) Abulia Amantadine (14) Methylphenidate (13) Bromocriptine (7) Methylphenidate (14) Amantadine (13) Inattention Modafanil (9) Methylphenidate (18) Slow mental processing Amantadine (9) Modafanil (2) Modafanil (4) Memory Deficit Nothing (8) Donepezil (9) Galantamine (9) Rivastigmine (6) Nothing (9) Galantamine (8) Amantadine (4)

Agitation/ Aggression
Drug Depres Labil/ Irritabil Mania Psychosis Agitation/ Aggression Anxiety Apathy Cognition AE Risk Nortrityline ++ + - Desipramine Amitriptyline +++ --- Protriptyline Fluoxetine Sertraline Paroxetine Lithium Carbamazepine -- Valproate Benzodiazepine Buspirone Typical antipsychotic Atypical antipsychotic Methylphenidat Dextroaphetam Amantadine Bromocriptine L-Dopa/carb Beta blocker Donepezil

Case 1: Irritability and Migraine Headaches
28 yo male s/p mild TBI Frequent irritability and occasional aggressive behaviors Mostly aimed towards spouse Intermittent blurred vision & headaches – migraine characteristics

Case 1 Considerations: Irritability, Migraine Headaches
Consider treatments that may help both the headaches and the behavior Beta-blocker Anticonvulsant: carbamazepine or valproate Headaches alone: topiramate, ca-channel blocker Consider treatments for behavior alone: Catecholaminergic augmentation Buspirone Others: Cholinergic augmentation?, Serotonergic?

Case 2: Poor attn, insomnia, cognition
44 yo female s/p recent severe TBI Poor nighttime sleep & daytime sleepiness Tachycardic Poor intake Poor attention, slow processing Confusion On trazodone & clonidine, propranolol, norco 4 hours PRN

Case 2 Considerations: Poor attn, insomnia, cognition
Treat sleep disturbance Mirtazapine (for sleep and intake), trazodone, melatonin, zolpidem Amitriptyline (if sleep maintenance) If on, stop/taper: ANTIPSYCHOTICS, BENZOs, BENADRYL, NARCOTICS Cannot use trazodone with many antipsychotics Treat attention, slow processing, cognitive function Catecholaminergic augmentation (methylphenidate, amantadine) Cholinergic augmentation Taper off clonidine, propranolol?, narcotics Tachycardia Poor intake Methylphenidate; mirtazepine, other appetite stimulants

Case 3: Agitation & Insomnia
22 yo male night shift worker s/p severe TBI Not sleeping Agitated: hitting, biting, spitting Confused, delusional, hallucinating, paranoid On geodon 40 mg bid, seroquel 25 mg q AM & 100 mg q HS, risperidone 1 mg bid, trazodone 150 mg q HS & amantadine 100 mg bid, clonidine, propranolol, norco 10 mg 4 hours PRN

Case 3 Considerations: Agitation & Insomnia
Treat sleep disturbance Trazodone isn’t helping and contraindicated with anitpsychotics Melatonin, zolpidem, Mirtazapine Amitriptyline (if sleep maintenance; may also help agitation) will likely need combo Check TSH Treat agitation Wean sedating meds (clonidine, narcotic, & antipsychotics) Treat sleep disturbance Anticonvulsant (VA or CBZ) Catacholeminergic Stop amantadine methylphenidate Amitriptyline Buspirone Already on a beta-blocker

Case 4: Unresponsive & Spasticity
18 yo female s/p severe TBI with craniectomy Awake (not in coma) Unresponsive (in VS) Spasticity Frequent episodes of grimacing On baclofen 10 mg tid, metoprolol, metoclopramide 5 mg tid, levetiracetam, dilantin 200 mg tid, clonidine .2 mg tid, oxycodone 20 mg q 4 hours

Case 4 Considerations: Unresponsive & Spasticity
Taper off sedating meds Baclofen (slow taper), metoclopramide (reglan), dilantin, clonidine, narcotics, metoprolol?, antipsychotics &benzos if on any Agents to improve arousal, initiation, responsiveness Catecholaminergics (methylphenidate, amantadine, bromocriptine, modafanil); Other stimulants? Ambien trial Treat sleep disturbance if any Check hypopituitary-adrenal axis TSH, FSH/LH/Test, prolactin, AM cortisol, IGF-1 Agents to improve spasticity Avoid baclofen; +/- tizanidine (may be sedating) dantrolene sodium (start low, go slow, stay relatively low) phenol nerve blocks (musculocutaeous, tibial, adductor), botulinum; baclofen pump

Case 5: Neuropathic pain, Insomnia, Depression
55 yo male s/p moderate TBI Burning (neuropathic) pain in arm, worst at night Insomnia Depressed mood

Case 5: Neuropathic pain, Frequent Awakenings, Depression
Neuropathic pain in arm For pain & depression: amitriptyline, duloxetine For pain & insomnia: amitriptyline For pain only: Lidoderm, carbamazepine, neurontin Consider if it is CRPS: if so, steroids. Insomnia Amitriptyline (for sleep maintenance & neuropathic pain) Others: trazodone, melatonin, zolpidem, mirtazapine

Case 6: Paranoia & Hallucinations
43 yo rear-ended by Semi-truck Possible post-concussive syndrome following mild TBI with subsequent symptoms of headaches, dizziness (light-headedness), impaired balance, proprioception, light sensitivity, blurred vision, double vision, noise sensitivity, impaired sleep initiation, jerking in sleep, fatigue, depression, irritability, lability, cognitive and linguistic impairment, paranoia, delusional at times, irrational fears. PMHx: 3 prior mild TBIs; hx violent jerking 6 years ago, daily migraines, htn & hypothyroidism (diagnosed 2 mo prior) ALLERGIES: topamax ("zombie") and keppra (confused). MEDICATIONS: Bystolic 5 mg daily; Armour 30 mg daily (2 mo prior); wellbutrin (5 yrs prior for migraines); imitrex 100 mg prn; lexapro 20 mg daily (started 2 weeks after MVC); allegra 180 mg daily; doxycycline x 3 wks for periorbital dermatitis, xanax PRN for premorbid anxiety).

Case 6: Paranoia & Hallucinations
Assess medications Taking many that might impact her function Asked her if she was taking any over-the-counter sleep meds In this case it was “Advil PM” (diphenhydramine). Stopped in and resolved TSH, Na EEG with temporal leads Treated sleep disturbance with trazodone. Helped but felt she was in a fog. Changed to q HS melatonin & ambien if needed.

Thanks Go one, go low, go slow, but go!

Understanding Medications Used in the Treatment of Traumatic Brain Injury Flora Hammond, MD Chairman & Covalt Professor, Dept Physical Medicine & Rehabilitation.

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Understanding Medications Used in the Treatment of Traumatic Brain Injury Flora Hammond, MD Chairman & Covalt Professor, Dept Physical Medicine & Rehabilitation.

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Presentation on theme: "Understanding Medications Used in the Treatment of Traumatic Brain Injury Flora Hammond, MD Chairman & Covalt Professor, Dept Physical Medicine & Rehabilitation."— Presentation transcript:

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