medications to use with caution in the management of tbi susan m. stickevers, md residency program...
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Medications to USE WITH Medications to USE WITH CAUTION in the CAUTION in the
Management of TBIManagement of TBISusan M. Stickevers, MDSusan M. Stickevers, MD
Residency Program Director, Residency Program Director, Physical Medicine & Physical Medicine &
Rehabilitation Rehabilitation SUNY Stony Brook SUNY Stony Brook
Medications …Medications …
Can produce changes in …Can produce changes in … Mood Mood Cognition Cognition Perception Perception AttentionAttention ……in neurologically intact subjects ….in neurologically intact subjects ….
Psychiatric Side Effects of Psychiatric Side Effects of Commonly Used Commonly Used
Medications Medications Depression seen with Depression seen with
use of :use of : Amantidine – common at Amantidine – common at
standard dosesstandard doses Anticonvulsants – usually Anticonvulsants – usually
at higher blood levelsat higher blood levels Steroids / ACTH – Steroids / ACTH –
common at higher doses common at higher doses or drug withdrawalor drug withdrawal
Benzodiazepines Benzodiazepines Opiates Opiates Levodopa – risk Levodopa – risk
increases with prolonged increases with prolonged use use
Oral contraceptives Oral contraceptives
Metoclopramide – at Metoclopramide – at usual doses usual doses
Propanolol – at usual Propanolol – at usual dosesdoses
Antihypertensives – Antihypertensives – with many with many preparations preparations
Barbituates – common Barbituates – common Vinblastine - rareVinblastine - rare Asparaginase – Asparaginase –
common with higher common with higher dosesdoses
Cimetidine Cimetidine Ibuprofen – rare Ibuprofen – rare
Mania is Observed with Mania is Observed with Use of :Use of :
Baclofen, Baclofen, particularly with particularly with sudden withdrawalsudden withdrawal
Bromocriptine – sx Bromocriptine – sx may persist after may persist after drug is withdrawndrug is withdrawn
Captopril – sx may Captopril – sx may persist after drug persist after drug withdrawalwithdrawal
Steroids/ ACTHSteroids/ ACTH
Levodopa : in Levodopa : in elderly, elderly, particularly with particularly with prolonged use prolonged use
Antidepressants, Antidepressants, particularly in pts. particularly in pts. with bipolar with bipolar disorder disorder
Hallucinations May be Hallucinations May be Occur when the Following Occur when the Following
Drugs are Used :Drugs are Used : Amantidine – more Amantidine – more
common in elderlycommon in elderly Anticonvulsants – visual Anticonvulsants – visual
& auditory & auditory hallucinations hallucinations
Antihistamines – esp Antihistamines – esp with higher doseswith higher doses
Anticholinergics – Anticholinergics – usually with deliriumusually with delirium
Corticosteroids Corticosteroids Digitalis – at higher Digitalis – at higher
blood levels blood levels Indomethacin – esp in Indomethacin – esp in
elderlyelderly
Propanolol Propanolol Methylphenidate – Methylphenidate –
more likely in childrenmore likely in children Levodopa – more Levodopa – more
frequently in elderly frequently in elderly with increased doses with increased doses
Ketamine – can induce Ketamine – can induce a dissociative state a dissociative state
Cimetidine – usually Cimetidine – usually in elderly at increased in elderly at increased dosesdoses
Paranoia May Occur with Paranoia May Occur with Use of the Following :Use of the Following :
Bromocriptine – Bromocriptine – not dose relatednot dose related
Amphetamines – Amphetamines – may occur even at may occur even at low doseslow doses
Indomethacin – esp Indomethacin – esp in elderly patientsin elderly patients
Propanolol – may Propanolol – may occur at any dose occur at any dose
Asparaginase – Asparaginase – commonly causes commonly causes paranoiaparanoia
Sulindac Sulindac
Aggression May Occur with Aggression May Occur with Use of :Use of :
Bromocriptine – Bromocriptine – not dose related, not dose related, may persist may persist
Tranquilizers & Tranquilizers & Hypnotics – a Hypnotics – a release release phenomenon phenomenon
Levodopa – often Levodopa – often after dose increase after dose increase
Carbamazepine – Carbamazepine – esp in children & esp in children & adolescents adolescents
Digitalis – may be Digitalis – may be seen with higher seen with higher blood levels blood levels
Phenelzine Phenelzine
Nightmares Nightmares
Baclofen – usually Baclofen – usually after sudden after sudden withdrawal withdrawal
Ketamine – causes Ketamine – causes emotion lability, emotion lability, changes in body changes in body image, deliriumimage, delirium
Levodopa – often Levodopa – often after dose increaseafter dose increase
Pentazocine Pentazocine
Propanolol Propanolol Digitalis – Digitalis –
particularly with particularly with high drug levels high drug levels
Antidepressants – Antidepressants – particularly with particularly with nighttime dosing nighttime dosing
Amantidine Amantidine
Medications Can Impair Medications Can Impair Neurological Recovery…Neurological Recovery…
Assess all medications of patients Assess all medications of patients with TBI as medications may…with TBI as medications may…
Cause sedationCause sedation Produce memory dysfunctionProduce memory dysfunction Decrease overall arousal & ability to Decrease overall arousal & ability to
participate in therapyparticipate in therapy
Antihypertensives Antihypertensives
Centrally acting antihypertensives, such as Centrally acting antihypertensives, such as methyldopa, have a significantly sedating methyldopa, have a significantly sedating effecteffect
Clonidine is an alpha 2 agonist with central Clonidine is an alpha 2 agonist with central activity which may produce impaired activity which may produce impaired cognition –it may also be used for the cognition –it may also be used for the treatment of spasticitytreatment of spasticity
Both clonidine & prazocin (alpha 1 agonist) Both clonidine & prazocin (alpha 1 agonist) have been shown to reinstate deficits after have been shown to reinstate deficits after sensorimotor cortex ablation (Feeney & sensorimotor cortex ablation (Feeney & Sutton, 1987)Sutton, 1987)
Antihypertensives – Beta Antihypertensives – Beta BlockersBlockers
Lipophilic beta blockers that cross Lipophilic beta blockers that cross the blood – brain barrier (i.e. the blood – brain barrier (i.e. propanolol) are useful in the propanolol) are useful in the treatment of agitation, however….treatment of agitation, however….
These agents may also produce These agents may also produce significant sedation which interferes significant sedation which interferes with the rehabilitation process with the rehabilitation process
Calcium Channel Calcium Channel BlockersBlockers
A decrease in dopaminergic A decrease in dopaminergic transmission has been found with transmission has been found with use of calcium channel blockers in use of calcium channel blockers in experimental models experimental models
No direct effect of calcium channel No direct effect of calcium channel blockers on motor or cognitive blockers on motor or cognitive recovery has been established recovery has been established however in humanshowever in humans
Benzodiazepines Benzodiazepines
Exert their effects on GABA A receptor; Exert their effects on GABA A receptor; increasing the rate of chloride channel increasing the rate of chloride channel opening opening
Rapidly cross blood – brain barrier Rapidly cross blood – brain barrier Produce antegrade amnesia & anxiolysis Produce antegrade amnesia & anxiolysis Decrease new learning & memory Decrease new learning & memory Produce increased confusion & agitation in Produce increased confusion & agitation in
brain injured patients brain injured patients Their use in TBI patients is NOT Their use in TBI patients is NOT
recommendedrecommended
Gastrointestinal AgentsGastrointestinal Agents
Histamine 2 receptor blockers, such as :Histamine 2 receptor blockers, such as : CimetidineCimetidine RanitidineRanitidine Famotidine Famotidine Nizatidine …..Nizatidine ….. ……may have sedating potential in TBI may have sedating potential in TBI
patients and in the elderlypatients and in the elderly Use of PPI is suggested in lieu of H2 Use of PPI is suggested in lieu of H2
blockersblockers
Metoclopramide Metoclopramide Is commonly used to enhance GI motility Is commonly used to enhance GI motility It enhances gastric contraction, raises It enhances gastric contraction, raises
esophageal pressure, & promotes relaxation esophageal pressure, & promotes relaxation of the pylorus of the pylorus
Has significant D2 receptor antagonist Has significant D2 receptor antagonist effects & can produce impaired cognitive effects & can produce impaired cognitive responses responses
Extrapyramidal side effects can be seen Extrapyramidal side effects can be seen with use of this drug with use of this drug
Its use in TBI patients is NOT recommended Its use in TBI patients is NOT recommended –consider use of erythromycin instead–consider use of erythromycin instead
Neuroleptics Neuroleptics
Neuroleptics block dopamine in Neuroleptics block dopamine in addition to acting as cholinergic & addition to acting as cholinergic & adrenergic antagonists adrenergic antagonists
Use of dopaminergic antagonists is Use of dopaminergic antagonists is relatively contraindicated due to relatively contraindicated due to depletion of dopamine post brain injury depletion of dopamine post brain injury
Feeney has raised concerns that Feeney has raised concerns that neuroleptics impair motor & cognitive neuroleptics impair motor & cognitive recovery after TBI (Feeney et al, 1982)recovery after TBI (Feeney et al, 1982)
Neuroleptics Neuroleptics
Potential side effects include :Potential side effects include : Extrapyramidal symptoms Extrapyramidal symptoms Anticholinergic side effectsAnticholinergic side effects Lowered seizure threshold Lowered seizure threshold Neuroleptic malignant syndrome Neuroleptic malignant syndrome Detrimental effects on learning & Detrimental effects on learning &
memory memory
Neuroleptic Agents Neuroleptic Agents
The majority of these agents act at the The majority of these agents act at the D2 receptor D2 receptor
Rao et al, 1985 Rao et al, 1985 : a retrospective chart : a retrospective chart review of 26 TBI Patients in which 11 review of 26 TBI Patients in which 11 were treated with haldol revealed…were treated with haldol revealed… Significantly longer periods of post Significantly longer periods of post
traumatic amnesia, however… traumatic amnesia, however… The acute rehabilitation outcome did not The acute rehabilitation outcome did not
differ from those not treated with this differ from those not treated with this medicationmedication
Neuroleptic Agents Neuroleptic Agents
Patients with brain injury are more Patients with brain injury are more sensitive to the development of sensitive to the development of extrapyramidal side effects when extrapyramidal side effects when treated with typical antipsychotic treated with typical antipsychotic agents agents
( Rosebush & Stewart, 1989, Vincent et ( Rosebush & Stewart, 1989, Vincent et al, 1986, Wolf et al, 1989, Yassa et al, al, 1986, Wolf et al, 1989, Yassa et al, 1984)1984)
Atypical Antipsychotics Atypical Antipsychotics for TBI?for TBI?
There is a dearth of literature to There is a dearth of literature to guide treatment selection amongst guide treatment selection amongst the atypical antipsychotic drugs, the atypical antipsychotic drugs, despite extensive documentation of despite extensive documentation of the ill effects of the typical the ill effects of the typical antipsychotic agents ….antipsychotic agents ….
Atypical AntipsychoticsAtypical Antipsychotics
Clozapine is one of the newer agents Clozapine is one of the newer agents with both dopaminergic & with both dopaminergic & serotoninergic blocking properties serotoninergic blocking properties
Clozapine has action at both the D1 & Clozapine has action at both the D1 & D4 receptors, as well as the 5HT-1 site D4 receptors, as well as the 5HT-1 site
2/9 patients placed on this drug for 2/9 patients placed on this drug for psychosis post TBI developed seizures, psychosis post TBI developed seizures, 7/9 showed improved aggression, 7/9 showed improved aggression, fewer outbursts & fewer fewer outbursts & fewer hallucinations hallucinations (Michals et al, 1993)(Michals et al, 1993)
Clozapine (Clozaril) Clozapine (Clozaril)
Burke et al (1999)Burke et al (1999) Improvement in refractory psychotic Improvement in refractory psychotic
symptoms after TBI with clozapine use symptoms after TBI with clozapine use **Risk of seizures is increased** **Risk of seizures is increased** Risk of neutropenia and anemia warrants Risk of neutropenia and anemia warrants
monitoring CBC monitoring CBC Has greater anti-aggressive effects Has greater anti-aggressive effects
than other antipsychotic medications than other antipsychotic medications (Michals et al, 1993, Ratey, 1993)(Michals et al, 1993, Ratey, 1993)
Clozapine (Clozaril) Clozapine (Clozaril) Study Study N= 9 study subjects :7 controls N= 9 study subjects :7 controls
AggressiveAggressive TBI patients with psychotic TBI patients with psychotic symptoms or rage outbursts.symptoms or rage outbursts.
Marked decrease in aggression in 2 Marked decrease in aggression in 2 subjects, less bizarre behavior in 1, mild subjects, less bizarre behavior in 1, mild improvement in agitation and hallucination improvement in agitation and hallucination in 3, indeterminate response in 3. in 3, indeterminate response in 3.
Seizures developed in 2 study subjectsSeizures developed in 2 study subjects Dose : Clozapine 300–750 mg/d.Dose : Clozapine 300–750 mg/d.
Risperadone Risperadone
Risperadone : an atypical antipsychotic Risperadone : an atypical antipsychotic acts at the D2 and 5HT - 2 receptor acts at the D2 and 5HT - 2 receptor
Schreiber et al (1998) Schreiber et al (1998) : Successfully : Successfully used risperadone to treat delusions & used risperadone to treat delusions & sleep disturbance post TBIsleep disturbance post TBI
Successfully used to treat refractory Successfully used to treat refractory paranoid delusions & auditory paranoid delusions & auditory hallucinations after TBI with 4 mg QD hallucinations after TBI with 4 mg QD dosing dosing (Silver et al, 2005)(Silver et al, 2005)
Atypical Antipsychotics Atypical Antipsychotics
Olanzapine (Zyprexa) – More sedating than most Olanzapine (Zyprexa) – More sedating than most antipsychotics – avoid use in TBI patients if antipsychotics – avoid use in TBI patients if possible possible
Aripiprazole (Abilify) : Case Reports support the Aripiprazole (Abilify) : Case Reports support the use of Aripiprazole in TBI as well. Dose 10-15 mg use of Aripiprazole in TBI as well. Dose 10-15 mg QD to start, maximum dose 30 mg po QD QD to start, maximum dose 30 mg po QD
Quetiapine (Seroquel) – **one of the medications Quetiapine (Seroquel) – **one of the medications least likely to produce EPS in vulnerable patients, least likely to produce EPS in vulnerable patients, such as persons with TBI and Parkinsons Disease such as persons with TBI and Parkinsons Disease **** **Has a lower incidence of EPS than **Has a lower incidence of EPS than
risperadone** risperadone**
Quietapine (Seroquel) Quietapine (Seroquel) Study Study
Quetiapine - 7 TBI subjects at least 3 Quetiapine - 7 TBI subjects at least 3 months postinjurymonths postinjury
Pilot study open-label flexible dose Pilot study open-label flexible dose schedule schedule
84.5% reduction in Overt Aggression 84.5% reduction in Overt Aggression Scale–Modified and Clinical Global Scale–Modified and Clinical Global Impression Scale of Agitation and Impression Scale of Agitation and Aggression reduced from 4.14 to 2.29. Aggression reduced from 4.14 to 2.29.
Sedation reported in 3 patients. Sedation reported in 3 patients. Quetiapine dose 25–300 mg/d for 6 weeks.Quetiapine dose 25–300 mg/d for 6 weeks.
Ziprasidone (Geodon) Ziprasidone (Geodon)
Ziprasidone Ziprasidone : : Case series of 5 severe Case series of 5 severe head injury patients with head injury patients with posttraumatic amnesia and posttraumatic amnesia and agitation.agitation.
Agitated Behavior Scale decreased Agitated Behavior Scale decreased from 27.2 to 18.0 with Ziprasidone from 27.2 to 18.0 with Ziprasidone 40–80 mg/d for 2 weeks.40–80 mg/d for 2 weeks.
Atypical Antipsychotics Atypical Antipsychotics
Have lower potential for extrapyramidal Have lower potential for extrapyramidal effects effects
Their effect on cognitive outcome in brain Their effect on cognitive outcome in brain injury survivors is not well described injury survivors is not well described
Neuroleptics should not be considered Neuroleptics should not be considered agents of first choice in the treatment of agents of first choice in the treatment of behavioral disturbance in TBI patients, behavioral disturbance in TBI patients, but if patients are refractory to other but if patients are refractory to other treatments, trial of atypical antipsychotic treatments, trial of atypical antipsychotic agents should be considered agents should be considered
Anticonvulsants Anticonvulsants
Practice Parameters of the AAN, Practice Parameters of the AAN, AANS & AAPM&R : Anticonvulsant AANS & AAPM&R : Anticonvulsant prophylaxis is warranted for only one prophylaxis is warranted for only one week after closed head injury week after closed head injury ( Brain ( Brain Injury Special Interest Group, Injury Special Interest Group, AAPM&R, 1998)AAPM&R, 1998)
The role of anticonvulsant prophylaxis The role of anticonvulsant prophylaxis in patients with penetrating head in patients with penetrating head injury remains controversial injury remains controversial
Anticonvulsants & Anticonvulsants & Cognition in the TBI Cognition in the TBI
PatientPatient Long term use of phenytoin has been Long term use of phenytoin has been
reported to have adverse cognitive reported to have adverse cognitive effectseffects
Phenytoin has been described to have Phenytoin has been described to have more profound effects on cognition more profound effects on cognition than tegretol than tegretol (Gallassi et al, 1988) (Gallassi et al, 1988)
The deleterious effect of phenobarbital The deleterious effect of phenobarbital on cognition has been well described on cognition has been well described in the literature in the literature (Corbett et al, 1985)(Corbett et al, 1985)
Tegretol & Valproic Acid Tegretol & Valproic Acid
Glenn & Wrobleski have advocated use of Glenn & Wrobleski have advocated use of these agents for the management of post these agents for the management of post traumatic seizures in TBI patientstraumatic seizures in TBI patients
Controversy remains as to the relative Controversy remains as to the relative cognitive disturbance these agents can cognitive disturbance these agents can cause cause
Dikmen et al, 2000 : Valproic acid had no Dikmen et al, 2000 : Valproic acid had no adverse effect on cognition when adverse effect on cognition when administered for up to 12 months to TBI administered for up to 12 months to TBI survivors survivors
Valproic Acid for Post Valproic Acid for Post Traumatic Seizures?Traumatic Seizures?
Temkin, 1999 : Valproate did not Temkin, 1999 : Valproate did not demonstrate any efficacy in demonstrate any efficacy in preventing late post traumatic preventing late post traumatic seizures seizures
There was a non significant trend in There was a non significant trend in his study which demonstrated higher his study which demonstrated higher mortality during treatment with mortality during treatment with valproate valproate
Tegretol Tegretol
Smith et al, 1994 : Tegretol Smith et al, 1994 : Tegretol produces more cognitive & motor produces more cognitive & motor slowing than placebo in TBI patients slowing than placebo in TBI patients
Persinger, 2000 : 12/14 TBI patients Persinger, 2000 : 12/14 TBI patients treated with tegretol reported treated with tegretol reported improvements in confusion, improvements in confusion, depression, reduction in symptoms depression, reduction in symptoms of psychosis, improved attention & of psychosis, improved attention & ability to focus, ability to focus,
Second Generation Second Generation AnticonvulsantsAnticonvulsants
Gabapentin, lamictal, & topiramate are examples Gabapentin, lamictal, & topiramate are examples Often used as adjuvants agents for management Often used as adjuvants agents for management
of seizure disorder rather than monotherapy of seizure disorder rather than monotherapy Topiramate has been shown to adversely affect Topiramate has been shown to adversely affect
cognition in healthy young adults ( Martin et al, cognition in healthy young adults ( Martin et al, 1999)1999)
The effects of lamictal & gabapentin on TBI The effects of lamictal & gabapentin on TBI patients have not yet been fully described, patients have not yet been fully described, however…however…
Anticonvulsant polytherapy has been associated Anticonvulsant polytherapy has been associated with increased adverse neuropsychiatric with increased adverse neuropsychiatric reactions reactions (Reynolds & Trimble, 1985)(Reynolds & Trimble, 1985)
Opiates Opiates
Can produce sedation, Can produce sedation, hallucinations, decreased attention hallucinations, decreased attention in the TBI patient in the TBI patient
Use lowest possible doses, opt for Use lowest possible doses, opt for short acting agents if possible or short acting agents if possible or consider the use of opiate agonists / consider the use of opiate agonists / antagonists. antagonists.
““Go low and slow” with dose Go low and slow” with dose titration titration
Aminophylline Aminophylline
Can cause : Can cause : Agitation Agitation Lower seizure threshold Lower seizure threshold Hallucinations Hallucinations Avoid its use if possible Avoid its use if possible
AntiemeticsAntiemetics
Bind with dopamine receptors Bind with dopamine receptors Have the ability to have effects Have the ability to have effects
similar to the antipsychotic agents similar to the antipsychotic agents Avoid their use if possible Avoid their use if possible
Antidepressants Antidepressants
Avoid those with anticholinergic Avoid those with anticholinergic activity activity
Tricyclic antidepressants lower the Tricyclic antidepressants lower the seizure threshold seizure threshold
SSRIs are the drugs of choice for the SSRIs are the drugs of choice for the treatment of depression in the TBI treatment of depression in the TBI patient – trazadone may also be usedpatient – trazadone may also be used
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