Medications to USE WITH CAUTION in the Management of TBI Susan

Medications to USE WITH CAUTION in the Management of TBI Susan M. Stickevers, MD Residency Program Director, Physical Medicine & Rehabilitation SUNY Stony Brook

Medications Can produce changes in Mood Cognition Perception Attention in neurologically intact subjects .

Psychiatric Side Effects of Commonly Used Medications Depression seen with use Metoclopramide – at of : Amantidine – common at standard doses Anticonvulsants – usually at higher blood levels Steroids / ACTH – common at higher doses or drug withdrawal Benzodiazepines Opiates Levodopa – risk increases with prolonged use Oral contraceptives usual doses Propanolol – at usual doses Antihypertensives – with many preparations Barbituates – common Vinblastine - rare Asparaginase – common with higher doses Cimetidine Ibuprofen – rare

Mania is Observed with Use of : Baclofen, particularly with sudden withdrawal Bromocriptine – sx may persist after drug is withdrawn Captopril – sx may persist after drug withdrawal Steroids/ ACTH Levodopa : in elderly, particularly with prolonged use Antidepressants, particularly in pts. with bipolar disorder

Hallucinations May be Occur when the Following Drugs are Used : Propanolol Amantidine – more common in elderly Anticonvulsants – visual & auditory hallucinations Antihistamines – esp with higher doses Anticholinergics – usually with delirium Corticosteroids Digitalis – at higher blood levels Indomethacin – esp in elderly Methylphenidate – more likely in children Levodopa – more frequently in elderly with increased doses Ketamine – can induce a dissociative state Cimetidine – usually in elderly at increased doses

Paranoia May Occur with Use of the Following : Bromocriptine – not dose related Amphetamines – may occur even at low doses Indomethacin – esp in elderly patients Propanolol – may occur at any dose Asparaginase – commonly causes paranoia Sulindac

Aggression May Occur with Use of : Bromocriptine – not dose related, may persist Tranquilizers & Hypnotics – a release phenomenon Levodopa – often after dose increase Carbamazepine – esp in children & adolescents Digitalis – may be seen with higher blood levels Phenelzine

Nightmares Baclofen – usually after sudden withdrawal Ketamine – causes emotion lability, changes in body image, delirium Levodopa – often after dose increase Pentazocine Propanolol Digitalis – particularly with high drug levels Antidepressants – particularly with nighttime dosing Amantidine

Medications Can Impair Neurological Recovery Assess all medications of patients with TBI as medications may Cause sedation Produce memory dysfunction Decrease overall arousal & ability to participate in therapy

Antihypertensives Centrally acting antihypertensives, such as methyldopa, have a significantly sedating effect Clonidine is an alpha 2 agonist with central activity which may produce impaired cognition –it may also be used for the treatment of spasticity Both clonidine & prazocin (alpha 1 agonist) have been shown to reinstate deficits after sensorimotor cortex ablation (Feeney & Sutton, 1987)

Antihypertensives – Beta Blockers Lipophilic beta blockers that cross the blood – brain barrier (i.e. propanolol) are useful in the treatment of agitation, however . These agents may also produce significant sedation which interferes with the rehabilitation process

Calcium Channel Blockers A decrease in dopaminergic transmission has been found with use of calcium channel blockers in experimental models No direct effect of calcium channel blockers on motor or cognitive recovery has been established however in humans

Benzodiazepines Exert their effects on GABA A receptor; increasing the rate of chloride channel opening Rapidly cross blood – brain barrier Produce antegrade amnesia & anxiolysis Decrease new learning & memory Produce increased confusion & agitation in brain injured patients Their use in TBI patients is NOT recommended

Gastrointestinal Agents Histamine 2 receptor blockers, such as : Cimetidine Ranitidine Famotidine Nizatidine . may have sedating potential in TBI patients and in the elderly Use of PPI is suggested in lieu of H2 blockers

Metoclopramide Is commonly used to enhance GI motility It enhances gastric contraction, raises esophageal pressure, & promotes relaxation of the pylorus Has significant D2 receptor antagonist effects & can produce impaired cognitive responses Extrapyramidal side effects can be seen with use of this drug Its use in TBI patients is NOT recommended –consider use of erythromycin instead

Neuroleptics Neuroleptics block dopamine in addition to acting as cholinergic & adrenergic antagonists Use of dopaminergic antagonists is relatively contraindicated due to depletion of dopamine post brain injury Feeney has raised concerns that neuroleptics impair motor & cognitive recovery after TBI (Feeney et al, 1982)

Neuroleptics Potential side effects include : Extrapyramidal symptoms Anticholinergic side effects Lowered seizure threshold Neuroleptic malignant syndrome Detrimental effects on learning & memory

Neuroleptic Agents The majority of these agents act at the D2 receptor Rao et al, 1985 : a retrospective chart review of 26 TBI Patients in which 11 were treated with haldol revealed Significantly longer periods of post traumatic amnesia, however The acute rehabilitation outcome did not differ from those not treated with this medication

Neuroleptic Agents Patients with brain injury are more sensitive to the development of extrapyramidal side effects when treated with typical antipsychotic agents ( Rosebush & Stewart, 1989, Vincent et al, 1986, Wolf et al, 1989, Yassa et al, 1984)

Atypical Antipsychotics for TBI? There is a dearth of literature to guide treatment selection amongst the atypical antipsychotic drugs, despite extensive documentation of the ill effects of the typical antipsychotic agents .

Atypical Antipsychotics Clozapine is one of the newer agents with both dopaminergic & serotoninergic blocking properties Clozapine has action at both the D1 & D4 receptors, as well as the 5HT-1 site 2/9 patients placed on this drug for psychosis post TBI developed seizures, 7/9 showed improved aggression, fewer outbursts & fewer hallucinations (Michals et al, 1993)

Clozapine (Clozaril) Burke et al (1999) Improvement in refractory psychotic symptoms after TBI with clozapine use **Risk of seizures is increased** Risk of neutropenia and anemia warrants monitoring CBC Has greater anti-aggressive effects than other antipsychotic medications (Michals et al, 1993, Ratey, 1993)

Clozapine (Clozaril) Study N 9 study subjects :7 controls Aggressive TBI patients with psychotic symptoms or rage outbursts. Marked decrease in aggression in 2 subjects, less bizarre behavior in 1, mild improvement in agitation and hallucination in 3, indeterminate response in 3. Seizures developed in 2 study subjects Dose : Clozapine 300–750 mg/d.

Risperadone Risperadone : an atypical antipsychotic acts at the D2 and 5HT - 2 receptor Schreiber et al (1998) : Successfully used risperadone to treat delusions & sleep disturbance post TBI Successfully used to treat refractory paranoid delusions & auditory hallucinations after TBI with 4 mg QD dosing (Silver et al, 2005)

Atypical Antipsychotics Olanzapine (Zyprexa) – More sedating than most antipsychotics – avoid use in TBI patients if possible Aripiprazole (Abilify) : Case Reports support the use of Aripiprazole in TBI as well. Dose 10-15 mg QD to start, maximum dose 30 mg po QD Quetiapine (Seroquel) – **one of the medications least likely to produce EPS in vulnerable patients, such as persons with TBI and Parkinsons Disease ** **Has a lower incidence of EPS than risperadone**

Quietapine (Seroquel) Study Quetiapine - 7 TBI subjects at least 3 months postinjury Pilot study open-label flexible dose schedule 84.5% reduction in Overt Aggression Scale– Modified and Clinical Global Impression Scale of Agitation and Aggression reduced from 4.14 to 2.29. Sedation reported in 3 patients. Quetiapine dose 25–300 mg/d for 6 weeks.

Ziprasidone (Geodon) Ziprasidone : Case series of 5 severe head injury patients with posttraumatic amnesia and agitation. Agitated Behavior Scale decreased from 27.2 to 18.0 with Ziprasidone 40–80 mg/d for 2 weeks.

Atypical Antipsychotics Have lower potential for extrapyramidal effects Their effect on cognitive outcome in brain injury survivors is not well described Neuroleptics should not be considered agents of first choice in the treatment of behavioral disturbance in TBI patients, but if patients are refractory to other treatments, trial of atypical antipsychotic agents should be considered

Anticonvulsants Practice Parameters of the AAN, AANS & AAPM&R : Anticonvulsant prophylaxis is warranted for only one week after closed head injury ( Brain Injury Special Interest Group, AAPM&R, 1998) The role of anticonvulsant prophylaxis in patients with penetrating head injury remains controversial

Anticonvulsants & Cognition in the TBI Patient Long term use of phenytoin has been reported to have adverse cognitive effects Phenytoin has been described to have more profound effects on cognition than tegretol (Gallassi et al, 1988) The deleterious effect of phenobarbital on cognition has been well described in the literature (Corbett et al, 1985)

Tegretol & Valproic Acid Glenn & Wrobleski have advocated use of these agents for the management of post traumatic seizures in TBI patients Controversy remains as to the relative cognitive disturbance these agents can cause Dikmen et al, 2000 : Valproic acid had no adverse effect on cognition when administered for up to 12 months to TBI survivors

Valproic Acid for Post Traumatic Seizures? Temkin, 1999 : Valproate did not demonstrate any efficacy in preventing late post traumatic seizures There was a non significant trend in his study which demonstrated higher mortality during treatment with valproate

Tegretol Smith et al, 1994 : Tegretol produces more cognitive & motor slowing than placebo in TBI patients Persinger, 2000 : 12/14 TBI patients treated with tegretol reported improvements in confusion, depression, reduction in symptoms of psychosis, improved attention & ability to focus,

Second Generation Anticonvulsants Gabapentin, lamictal, & topiramate are examples Often used as adjuvants agents for management of seizure disorder rather than monotherapy Topiramate has been shown to adversely affect cognition in healthy young adults ( Martin et al, 1999) The effects of lamictal & gabapentin on TBI patients have not yet been fully described, however Anticonvulsant polytherapy has been associated with increased adverse neuropsychiatric reactions (Reynolds & Trimble, 1985)

Opiates Can produce sedation, hallucinations, decreased attention in the TBI patient Use lowest possible doses, opt for short acting agents if possible or consider the use of opiate agonists / antagonists. “Go low and slow” with dose titration

Aminophylline Can cause : Agitation Lower seizure threshold Hallucinations Avoid its use if possible

Antiemetics Bind with dopamine receptors Have the ability to have effects similar to the antipsychotic agents Avoid their use if possible

Antidepressants Avoid those with anticholinergic activity Tricyclic antidepressants lower the seizure threshold SSRIs are the drugs of choice for the treatment of depression in the TBI patient – trazadone may also be used

Thanks for Your Attention!