3/9/2015. Whosoever holds this. Whosoever holds this hammer, if s/he be worthy, shall possess the power of Thor

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1 Whosoever holds this hammer Linda Tavel, MD MBA FAAHPM Senior Medical Director Gentiva Hospice Houston Whosoever holds this hammer, if s/he be worthy, shall possess the power of Thor Mjolnir s enchantment Define the neuroleptic class of medications Identify symptoms in hospice/palliative medicine for which these medications are used Describe adverse effects of these medications as portrayed in literature Discuss safeguards and alternative measures for treatment 1

2 Dr Tavel has no conflicts of interest to disclose. Much of this talk is about off label use of neuroleptics. Mr. Jones is 96 year old man on hospice for Failure to Thrive with comorbidities of advanced cardiac disease, mild to moderate dementia (FAST 6e), mild renal insufficiency, hospitalized multiple times for dehydration and pneumonia. BMI 18.5 PPS 30%. His family complained that he was restless, confused, crying out. After evaluation, he was placed on haloperidol and escalating doses were unsuccessful in extinguishing the symptoms (up to 2 mg every 4 hours ATC). Ultimately he was changed to Chlorpromazine 25 mg po/pr tid. Two weeks later, he became jaundiced and had right upper quadrant pain.?????????????????? Ms. Braden is a 48 year old woman with breast cancer, metastatic to liver. She has significant nausea, and haloperidol 1 mg po q 6 hours prn has been prescribed. Her PPS is 40%, her pain is adequately controlled with hydromorphone 2 mg every 4 hours. Her nausea is much better, but four days later, she complains of feeling restless and wishes to get out of bed every few minutes. Her family says she is not sleeping and want a sedative for her What is going on? How do you wish to treat this? 2

3 Mrs. Oleary is an 86 year old woman with ES Dementia. Her FAST 7C, and her PPS is 40%. She has recently started risperidol 0.5 mg twice a day for her agitation and it initially worked fairly well, but now the family say she is more restless and they wish to raise the dose. With increasing the dose to 1 mg twice a day and 1 mg HS, she is stiff and can t move. She appears fearful. What do you want to know about this patient? How do you evaluate her? How do you treat this? As a class of drugs, neuroleptics affect the dopaminergic pathways plus others. Symptoms arise from either excess or inadequate levels of dopamine and depend on the portion of the brain affected. Side effects also arise from excess or inadequate levels of dopamine.. Pathway Function Symptoms Mesolimbic: reticular formation: limbic cortex Mesocortical: reticular formation: prefrontal cortex Substantia nigra: Corpus striatum Tuberoinfundibular system Thalamic dopamine Pleasure, motivation and reward Affect, executive function, concentration Extrapyramidal motor system DA inhibition of prolactin secretion Sleep and arousal High DA: Psychosis, delusions, hallucinations Low DA: Depression, apathy, anhedonia, cognitive blunting Low DA: Parkinsons, akathisia, dystonia, RLS High DA: dyskinesia Low DA: hyperprolactinemia Area postrema Emetogenesis High DA: Nausea,vomitting Therapeutic Reviews: Antipsychotics JPSM 2011:41(5):

4 Typical versus atypical antipsychotics Typical: Phenothiazines: chlorpromazine, prochlorperazine,(other antipsychotics used exclusively for schizophrenia e.g. clozapine, fluphenazine), promethazine 1/10 strength Butyrophenones: haloperidol Atypical: Aripiprazole, olanzapine, quetiapine, risperidone Drug D2 5HT2 A 5HT2C 5HT3 H1 a1 a2 AChm Aripiprazole +++* Chlorpromazine Haloperidol Prochlorperazine Olanzapine Quetiapine Risperidone Therapeutic Reviews: Antipsychotics JPSM 2011:41(5): H1 histamine: drowsiness A1 and A2 adrenergic: postural hypotension AChm muscarinic: dry mouth, constipation Atypicals have lower extrapyramidal effects through the following: 5HT2 receptor antagonism increase DA activity in nigrostriatal/mesocortical systems D2 partial agonism Lower affinity and shorter time D2 antagonism Tend to require lower doses than typicals 4

5 Haloperidol considered biggest culprit for extrapyramidal effects. RCT: overall discontinuation for side effects comparable (but EPS 8% vs. 2% atypicals) However, all treatment groups experienced: involuntary movement, akathisia, extrapyramidal symptoms so risk not zero! 5x lower risk atypicals versus haldol in first year (haldol doses were higher) Risperidone carries highest risk of EPS Common symptoms for which neuroleptics are recommended: Nausea and vomiting Delirium and agitation Tenesmus Insomnia Hiccups Breathlessness Chronic pain: headache, fibromyalgia, etc What are the minimum number of drugs to improve quality care of the dying? Delphi-Study Consensus opinion More than 80 percent clinicians agreed upon these three drugs: morphine, a benzodiazepine, and haloperidol, plus one of four antimuscarinics for respiratory tract secretions.. Four Essential Drugs..JPM 2013; 16 (1):

6 First Delphi round 35 drugs identified: Anxiety: midazolam or lorazepam Dyspnea/breathlessness: morphine Nausea/vomiting: metoclopramide or haloperidol Pain: morphine Respiratory tract secretions: hyoscine or glycopyrronium Terminal restlessness/delirium: midazolam or haloperidol Final four on Delphi round 2: Morphine, midazolam, haloperidol, glycopyrronium Four Essential Drugs..JPM 2013; 16 (1):38-43 Complex symptom that involves several sites in the brain and gi tract Treatment should follow evaluation of the underlying cause GI: metoclopramide (also a D2 blocker!) Various sites in CNS: Haloperidol, metoclopramide, chlorpromazine, prochloroperazine, olanzapine, promethazine Odansetron, mirtazapine Steroids Scopolamine others Delirium very common at end of life >85% cancer patients experience this Treatment should follow evaluation of possible reversible causes Once treatable causes addressed, medication is appropriate. Undertreated using suboptimal doses Haloperidol--most common, olanzapine, risperidone, quetiapine Median haldol daily dose in one study 2.5 mg all delirium subtypes 6

7 Painful sensation of needing to have BM. Spasms/waves of rectal pain. Causes: Malignancies of bladder, gyn, prostate, rectum Inflammatory bowel disease Radiation proctitis Treatments: laxatives, calcium channel blockers, chlorpromazine, gabapentin, amitriptyline, steroids, benzodiazepines, belladonna, anesthetic procedures Spasms of diaphragm due to: irritation of gi tract, CNS disorder, toxic-metabolic disorder, uremia, phrenic/vagus nerve involvement Evaluate and remove offending agent, correct imbalance, target treatment to cause. Therapy depends on etiology if known: H2 blockers, chlorpromazine, haloperidol, metoclopramide, gabapentin and other anticonvulsants, baclofen, ketamine, opiates if pain underlying, steroids if inflammation Sensation of being unable to breathe Evaluate for underlying causes of dyspnea, breathlessness and treat Drug of choice: opiates! If bronchodilators/steroids/oxygen already offered or determined not helpful, then benzodiazepines or chlorpromazine can also be used. 7

8 Literature review is mixed studies featured thioridazine, levomepromazine, haloperidol. Appear most effective in headache patients, and primary effect thought to be sedation and blunting affect ( neuroleptanalgesia ). In vitro/animal studies, dopamine was thought involved in regulation of nociception, but not borne out in human studies. Haloperidol found superior to placebo in migraines in one study Recent study in 735 palliative medicine patients (retrospective) 43 patients underwent opiate rotation to methadone plus haldol. Methadone atypical opiate with NMDA blocking effects. Haloperidol has antinociceptive effects, thought to potentiate analgesia via NMDA blocking pathway Pain score 5/10 baseline, 0/10 at week two. Median dose methadone 5 mg/d, haloperidol 1.5 mg/d Salpeter S, Buckley J, Buckley N, Bruera E. JPM 2015; 18 (2): % adults report insomnia: difficulty falling sleep, staying asleep, feeling rested Evaluation for treatable causes Sleep hygiene, then medications Treating insomnia: benzodiazepines, nonbenzodiazepines (zolpidem, eszopiclone), barbiturates, chloral hydrate, trazodone, mirtazapine. New practice: off-label use of antipsychotics primarily for side effects: H1 blocking, deep sleep due to serotonin receptor (5HT2A) blockade, and increasing slow-wave sleep (5HT2C) Perhaps of use in insomniac patients with concomitant psych problems but not primary RX 8

9 Pineal gland in brain regulates the circadian rhythm in humans. Pineal responds to light signals received by retina produces melatonin which helps induces drowsiness and regulates sleep. Norepinephrine regulates synthesis and release of melatonin. Dopamine inhibits the effects of NE, so decreased melatonin, and more arousal in brain. Science Daily Accessed 3/8/15 Used to avoid movement disorders, characteristic of typical antipsychotics Over the years, several syndromes described Cardiac effects: sudden death (black box) Weight gain, insulin resistance, hyperglycemia Neuroleptic malignant syndrome Renal effects High rates of sudden death all antipsychotics: Typical 1.99 incidence-ratio vs. nonusers Atypical 2.26 incidence-ratio vs. nonusers Incidence rises with higher doses So no advantage of atypicals over typicals Mechanism: block repolarizing K+ currents and prolong QT interval An early paper found hidden cardiac issues in 13 patients who died on antipsychotics: dilated cardiomyopathy, valvular disease, His bundle disease 9

10 Olanzapine and Clozapine worst Stronger affinity for muscarinic receptors and antagonist for histamine receptors Histamine receptors influence leptin signals and muscarinic receptors affect pancreatic insulin release (hyperglycemia), orexin affected So atypicals associated with adverse metabolic changes Originally thought that the effects developed slowly over time. New data: insulin, hyperglycemic, metabolic effects in as little as 3 days on medication Uncommon, life threatening Due to dopamine blockade and unopposed sympathetic system hyperactivity. Reported in metoclopramide, haldol, prochlorperazine, droperidol, but also in olanzapine and other atypical antipsychotics: clozapine and risperidone Described in up to 2.44% typical antipsychotics, not zero in atypicals! Within two weeks of starting or increase in dose 10

11 NMS can appear suddenly or be more indolent. Autonomic hyperactivity: hyperthermia, muscle rigidity, altered consciousness, tachycardia, diaphoresis, dysarthria, dysphagia, labile BP, pathological reflexes and inhibited DTRs. Laboratory abnormalities: elevated CPK, elevated AST, elevated ALT, elevated LDH, proteinuria, hematuria, high fasting blood glucose Treatment: withdraw APs, dantrolene, support circulatory and ventilation, bromocriptine,iv fluids, rotate to lower dose antipsychotic Seizures: Dose-dependent reduction in seizure threshold Chlorpromazine and clozapine higher risk Haloperidol relatively lower risk Parkinsonism and Parkinson s disease: Due to D2 antagonism. Risk lower with quetiapine and clozapine But not zero! In Parkinson s disease, consider alternatives for anxiety/agitation/sleep such as trazodone or benzodiazepine In Parkinson s consider alternatives for nausea/vomiting such as odansetron, scopolamine (but delirium) 11

12 Stroke: Risk of CVA is higher for elderly dementia patients, with olanzapine and risperidone compared to placebo. Dystonia involuntary muscle contractions that cause slow repetitive movements or abnormal postures (torticollis) can occur in short term Tardive dyskinesia involuntary movements of tongue, lips, face, trunk and extremities (D2 antagonist meds usually long term) Akathisia consider this when increasing doses of the neuroleptic result in increasing restlessness and a need to be in constant motion (much like hyperalgesia/oin) Hyperprolactinemia galactorrhea, amenorrhea, osteoporosis, sexual dysfunction Postural hypotension: chlorpromazine, also in quetiapine and risperidone Agranulocytosis in 1% of patients on clozapine (not frequently used in palliative care) Jaundice/hepatitis in chlorpromazine, improved by discontinuation and switching to atypical All cause mortality for elderly with dementias doubled with olanzapine and all antipsychotics, particularly within first month and raising doses. 12

13 Atypical antipsychotics are also linked to acute kidney injury Hypotension, acute urinary retention and neuroleptic malignant syndrome (rhabdomyolysis) can impact renal function Pneumonia, acute myocardial infarction, ventricular arrhythmia also impact kidney injury Caution advised in elderly Atypical Antipsychotic Drugs and the Risk for AKI AIM 2014; 161: Pharmacogenetics of Antipsychotics: Antipsychotics metabolized by cytochrome enzymes: CYP1A2, CYP2D6, CYP3A4, CYP2C19 Smoking induces CYP1A2 CYPs are polymorphic More than 80 variations on CYP2D6!! Poor metabolizers Intermediate metabolizers Ultrametabolizers And--variants on DRD2 and DRD3 (DA receptors) Drug-drug interactions: Neuroleptics/anticholinergics Increased anticholinergic effects Neuroleptic/dopamine antagonists Increased risk of extrapyramidal motor effects Tricyclic antidepressants/neuroleptics Risk of Ventricular tachycardia especially in poor metabolizers CYP2D6 Anticonvulsants/neuroleptics Cardiac drugs/neuroleptics QT prolongation Hypotension 13

14 Haldol can be effective with an average dose 2.1 mg in 24 hours Relatively few (1 in 15) stopped that medication due to harms (akathisia, somnolence, urinary retention, rigidity, tardive dyskinesia, worsening depression, postural hypotension) More than half continued the med beyond 10 days Pharmacovigiliance in Hospice/Palliative Care:Net Effect Haloperidol JPM 2013; 16(1): Low doses of neuroleptics can be effective, but might not prevent delirium recall Doses equivalent to Haldol 2.5 mg per day, higher in agitated and mixed delirium The average Haloperidol daily dose did not correlate with delirium recall or distress for patients and family, BUT with nurses and physicians distress related to the patients symptoms Who are we treating??????? Neuroleptic Dose in the Management of Delirium in patients with Advanced Cancer JPSM 2010; 39: Mr. Jones is 92 year old man on hospice for Failure to Thrive..with comorbidities of advanced cardiac disease, mild to moderate dementia (FAST 6e), mild renal insufficiency, hospitalized multiple times for dehydration and pneumonia. BMI 18.5 PPS 30%. His family complained that he was restless, confused, crying out. After evaluation, he was placed on haloperidol and escalating doses were unsuccessful in extinguishing the symptoms (up to 2 mg every 4 hours ATC). Ultimately he was changed to Chlorpromazine 25 mg po/pr tid. Two weeks later, he became jaundiced and had right upper quadrant pain.?????????????????? 14

15 Ms. Braden is a 48 year old woman with breast cancer, metastatic to liver. She has significant nausea, and haloperidol 1 mg po q 6 hours prn has been prescribed. Her PPS is 40%, her pain is adequately controlled with hydromorphone 2 mg every 4 hours. Her nausea is much better, but four days later, she complains of feeling restless and wishes to get out of bed every few minutes. Her family says she is not sleeping and want a sedative for her What is going on? How do you wish to treat this? Mrs. Oleary is an 86 year old woman with ES Dementia. Her FAST 7C, and her PPS is 40%. She has recently started risperidol 0.5 mg twice a day for her agitation and it initially worked fairly well, but now the family say she is more restless and they wish to raise the dose. With increasing the dose to 1 mg twice a day and 1 mg HS, she is stiff and can t move. She appears fearful. What do you want to know about this patient? How do you evaluate her? How do you treat this? Whosoever holds this hammer, if s/he be worthy, shall possess the power of Thor Mjolnir s enchantment 15

16 Continue to use neuroleptic medications, but: Assess carefully for underlying reversible causes of symptoms Utilize nonpharmacological management when possible Use the most effective drug at the lowest doses Consider alternative medications Go for the two-fer technique Streamline medications to reduce drugdrug interactions, med errors, and pill burden Watch carefully for adverse effects of the neuroleptics: Movement disorders Neuroleptic Malignant Syndrome Akathisia Cardiac and renal effects These medications are still indicated at the end of life! Our goal: relieve suffering Every day is precious 16

17 Questions? Comments? Interesting Cases? 17