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Haloperidol
A Comprehensive Review and its Relevance to Hospice and Palliative Medicine
Tim Fife, D.O.
Hospice and Palliative Medicine Fellow
Grand Rapids Medical Education Partners
John Mulder, M.D.
Hospice and Palliative Medicine Fellowship Program Director
Grand Rapids Medical Education Partners
1
Introduction
2
• A retrospective review and study (n=4,252) to determine the most commonly prescribed medications in a population of
hospice patients.
• Top ten of the 100 most frequently prescribed medications in
hospice patients: 1. Acetaminophen
2. Lorazepam
3. Morphines
4. Atropine
5. Haloperidol
6. Prochlorperazine
7. Albuterol
8. Docusate
9. Bisacodyl
10. Scopalamine
Sera L, et al. Commonly Prescribed Medications in a Population of Hospice
Patients. AM J Hosp Palliat Care. 2013.
3
• European Study/Survey (n=90), whose aim was to identify a consensus of appropriate treatment for common symptoms in the end of life care for patients with cancer (based on consensus opinion).
• Four essential drugs were identified: o Morphine
o Midazolam
o Haloperidol
o Antimuscarinic
Lindqvist O, et al. Four Essential Drugs Needed for Quality Care of the Dying: A Delphi-Study Based International Expert Consensus Opinion. J Palliat Med. 2013.
4
History • Haloperidol has its origin in the research process of
central analgesic molecules derived from pethidine
(meperidine) and methadone, carried out by the
Belgian company Janssen Pharmaceutica in an
attempt to discover a new analgesic.
• Early animal studies revealed a potent tranquilizer
which exhibited antipsychotic activity as well as
analgesic qualities. In addition, it was found this
molecule produced Parkinsonism.
5
Landmarks in the history of Haloperidol:
• 1939 Otto Eisleb synthesized pethidine, a fundamental molecule in
the history of the discovery of Haloperidol
• 1953 Paul Janssen begins to carry out research
• 1958 Synthesis of R-1625 (Haloperidol) by Bert Hermans
• 1961 Johnson & Johnson acquires Janssen Pharmaceutica
• 1963 Arvid Carlsson demonstrates Haloperidol-induced changes to
dopamine levels in the brain; the “dopaminergic hypothesis of
schizophrenia” is born
• 1967 Synthesis of long-acting injectable Haloperidol (Haloperidol
deconate)
• 1969 Haloperidol patent granted in the United States
• 1976 Solomon Snyder confirms that Haloperidol is a dopamine receptor
antagonist
• 1982 Market launch of Haloperidol decanoate (Haldol®)
Cecilio LM. The consolidation of neuroleptic therapy: Janssen, the discovery of
Haloperidol and its introduction into clinical practice. Brain Res Bull. 2009.
6
7
Haloperidol (Haldol®)
8
• A butyrophenone chain which appears to be essential for D2 receptor binding
• Contains a piperdine ring and a ketone group
• The presence of the hydroxyl group enhances the binding of Haloperidol to the D2 receptor
Haloperidol Pharmacology:
Pharmacodynamics Pharmacokinetics
9
Pharmacodynamics may be simply defined as what the drug does to the body, as opposed to
pharmacokinetics, which may be defined as what the body does to the drug.
Haloperidol Pharmacodynamics
• Potent dopamine antagonist with a strong affinity
for the D2 dopamine receptor
• Weaker affinity to serotonin
• NMDA receptors, opioid (kappa, sigma, delta),
muscarinic, histamine, alpha-1 adrenergic,
substance P, and sodium channels
10
Haloperidol Pharmacodynamics
References
Stahl SM, et al. The psychopharmacology of ziprasidone: receptor-binding
properties and real-world psychiatric practice. J Clin Psychiatry. 2003.
Schotte A, et al. Risperidone compared with new and reference antipsychotic
drugs: in vitro and in vivo receptor binding. Psychopharmacology. 1996.
Whittemore ER, et al. Antagonism of N-methyl-D-aspartate receptors by sigma site
ligands: potency, subtype-selectivity and mechanisms of inhibition. J Pharmacol
Exp Ther. 1997.
Debonnel G, et al. Modulation of NMDA and dopaminergic neurotransmissions by
sigma ligands: possible implications for the treatment of psychiatric disorders. Life
Sci. 1996.
11
Haloperidol Pharmacokinetics
12
ABORPTION DISTRIBUTION METABOLISM ELIMINATION
Onset of action: Oral: Tmax 2-6h IM: Tmax 20 min IV: Tmax 5-15 min
Extensive protein binding with a free fraction in the plasma of 10%
Metabolized extensively in the liver by CYP3A4 -Oral – first pass metabolism Metabolites:
-Reduced Haloperidol -Haloperidol glucuronide -inactive -Pyridium: toxicity
-42% excreted renally -Glucuronide metabolites excreted in the bile
Haloperidol Pharmacokinetics
Cont’d
13
• SQ, Topical, PR – no pharmacokinetic data
available
• Duration of Action: (1-6 h) relative to route of
administration, dose [peak concentration (T-max)],
severity of clinical situation, and is a function of
distribution, metabolism, and elimination.
• Half life (t½): Oral t½ - 26h, IM t½ - 21h, IV t½ - 20h
Haloperidol Pharmacokinetics - References
Kudo S, et al. Pharmacokinetics of Haloperidol: an update. Clin
Pharmacokinet. 1999.
Holley FO, et al. Haloperidol kinetics after oral and intravenous doses. Clin
Pharmacol Ther. 1983.
Schaffer CB, et al. Bioavailability of intramuscular versus oral Haloperidol in
schizophrenic patients. J Clin Psychopharmacol. 1982.
Fang J, et al. Involvement of CYP3A4 and CYP2D6 in the metabolism of
Haloperidol. Cell Mol Neurobiol. 1997.
Subramanyam B, et al. Identification of potentially neurotoxic pyridinium
metabolite in the urine of schizophrenic patients treated with Haloperidol.
Biochem Biophys Res Commun. 1991.
Forsman A, et al. On the pharmacokinetics of Haloperidol. Nord J
Psychiatr. 1974.
14
Hepatic Disease
15
• Haloperidol is subject to hepatic blood flow,
protein binding, and intrinsic enzyme activity.
• It is thus potentially affected by liver disease and
dose modification may be necessary.
Gupta SK, et al. Effect of alosetron (a new 5-HT3 receptor antagonist) on the
pharmacokinetics of haloperidol in schizophrenic patients. J Clin Pharmacol.
1995.
Blaschke TF. Protein binding and kinetics of drugs in liver diseases. Clin Pharmacokinet. 1997.
Renal Disease
16
• No need for alteration of drug dosing in
renal insufficiency.
Prommer E. Role of Haloperidol in Palliative Medicine: An Update. AM J
Hosp Palliat Care. 2011.
• ↓ dose
Hanks G, et al. Oxford Textbook of Palliative Medicine. 2010.
Drug Interactions • Decreased levels of Haloperidol
o Carbamazepine
o Phenobarbital
o Phenytoin
• Increased levels of Haloperidol o Fluoxetine (Prozac®)
o Venlafaxine (Effexor®)
o Nefazodone (Serzone®)
o Fluvoxamine (Luvox®)
o Alprazolam (Xanax®)
Prommer E. Role of Haloperidol in Palliative Medicine: An Update. AM J Hosp
Palliat Care. 2011.
17
Adverse Effects
• Extrapyramidal Side Effects
• QT Interval Prolongation and Torsades de
Pointes
• Neuroleptic Malignant Syndrome
• Seizures
18
Extrapyramidal Side Effects (E.S.E.)
• Symptom complex resulting from a dopaminergic-cholinergic imbalance at the level of the basal ganglia.
• The high affinity of Haloperidol for the D2 receptor results in a relative increase in interneuronal acetylcholine.
• Results in: o Acute dystonia – spasm of muscles – tongue, face, neck or back
o Parkinsonism
o Neuroleptic malignant syndrome
o Akathisia
o Tardive dyskinesia
19
E.S.E. (Cont’d.)
• Double-blind randomized trial (n=244)
• Haloperidol, chlorpromazine and lorazepam
• Low-dose Haloperidol is effective in treatment of delirium with an extremely low prevalence of extrapyramidal side effects.
• Not clinically significant
Breitbart W, et al. A double-blind trial of Haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Focus. 2005.
20
E.S.E. (Cont’d.)
• Prospective blinded study (n=10)
• IV vs. PO
• Patient receiving IV Haloperidol experienced significantly less intense extrapyramidal symptoms
• Delirious patients have relatively lower levels of acetylcholine, which may lessen the severity of E.S.E.
Menza M, et al. Decreased Extrapyramidal Symptoms With Intravenous Haloperidol. J Clin Psychiatry. 1987.
21
E.S.E. (Cont’d.)
• Extrapyramidal Syndrome Presenting as Dysphagia:
a case report
• Usually responds to diphenhydramine
Gonzalez F. Extrapyramidal Syndrome Presenting as Dysphagia: A Case Report.
AM J Hosp Palliat Care. 2008.
22
QT Interval Prolongation and Torsades de Pointes (TdP)
• 1997-2008
• 70 cases of QT prolongation and/or TdP
• 54 cases TdP with 80% preceded by QT prolongation
• 3 patients experienced sudden cardiac arrest
• Increased Risk:
o IV
o ↑ Doses
o High risk medically complex situations
o Pre-existing heart disease
o Electrolyte imbalance
o Antiarrhythmic agents
Prommer E. Role of Haloperidol in Palliative Medicine: An Update. AM J Hosp
Palliat Care. 2011.
23
QT Interval Prolongation and TdP References
Huffman J, et al. QTc Prolongation and the Use of Antipsychotics: A Case
Discussion. Primary Care Companion J Clin Psychiatry. 2003.
Hatta K, et al. The association between intravenous Haloperidol and prolonged
QT interval. J Clin Psychopharmacol. 2001.
Hunt N, et al. The Association Between Intravenous Haloperidol and Torsades de
Pointes. Psychosomatics. 1995.
Metzger E, et al. Prolongation of the Corrected QT and Torsades de Pointes
Cardiac Arrhythmia Associated with Intravenous Haloperidol in the Medically Ill. J
Clin Psychopharmacology. 1993.
24
Neuroleptic Malignant Syndrome • A neurologic emergency associated with neuroleptics
• D2 blockade
• FEVER – Fever, Encephalopathy, Vitals unstable, Elevated
enzymes (Increased CPK), Rigidity of muscle
• Hyperkalemia, Hypercapnia, Acidosis, DIC, Leukocytosis, tremor
• Incidence .07-2.2%
• Risks: IV, ↑ dose (rapid), Agitation, Cachexia, Dehydration
Benzer T. Neuroleptic malignant syndrome. 2002.
Bellamy CJ, et al. Neuroleptic malignant syndrome in traumatic brain injury patients treated with Haloperidol. J Trauma. 2009.
Jackson N, et al. Neuropsychiatric complications of commonly use palliative care drugs. Postgrad Med. 2008.
25
Seizures
• Lowers seizure threshold
• Among the first generation antipsychotics, it is the phenothiazine class (chlorpromazine) that carries the greatest risk (1.2%)
Pisani F, et al. Effects of psychotropic drugs on seizure threshold. Drug Saf. 2002.
Hedges D, et al. Antipsychotic medication and seizures: a review. Drugs Today. 2003.
Remick RA, et al. Antipsychotic drugs and seizures. J Clin Psychiatry. 1979.
26
Adverse Effects by System
• Cardiovascular: hypotension, hypertension, tachcardia, dysrhythmia(s), QTc prolongation-torsades de pointes, sudden death
• CNS: restlessness, anxiety, extrapyramidal reactions, dsytonic reactions, pseudoparkinsonian signs and symptoms, tardive dyskinesia, neuroleptic malignant syndrome, altered central temperature regulation, akathisia, insomnia, euphoria, agitation, drowsiness, depression, lethargy, headache, confusion, vertigo, seizures
• Dermatologic: hyperpigmentation, pruritus, rash, contact dermatitis, alopecia, photosensitivity (rare)
• Gastrointestinal: nausea, vomiting, anorexia, constipation, diarrhea, hypersalivation, dyspepsia, cholestatic jaundice, obstructive jaundice
• Genitourinary: urinary retention
• Hematologic: leukopenia
• Ocular: blurred vision
• Respiratory: laryngospasm, bronchospasm
Spectrum Health Drug Quick Reference - Haloperidol (Haldol®) 27
Clinical Indications • Delirium
• Nausea and vomiting
• Bowel Obstruction
• Hiccups
• Palliative Sedation
• Anxiety
28
Delirium
• There is a legitimate evidence base for the
treatment of delirium with Haloperidol and it is
advocated for this use by most experts
• Hyperactive, hypoactive, mixed
29
Delirium (Cont’d) • Prospective randomized trial (n=73)
• Tertiary care university hospital in Montreal, affiliated ICU
• Olanzapine vs. Haloperidol
• Clinical efficacy was similar in both treatment arms
• ↑ E.P.S. with Haloperidol (n=6) (↓ severity)
• Similar ↓ need for benzodiazepines
Skrobik YK, et al. Olanzapine vs Haloperidol: treating delirium in a critical care setting.
Intensive Care Med. 2004.
30
Delirium (Cont’d)
• Randomized double-blind trial (n=28)
• Korea University Medical Center
• Delirium significantly reduced in both groups
• E.P.S. (n=1), mild in Haloperidol group
Han CS, et al. A double-blind trial of Risperidone and Haloperidol for the
treatment of delirium. Psychosomatics. 2004.
31
Delirium (Cont’d) • Randomized, double-blind, placebo-controlled trial
(n=430)
• Large university hospital, Netherlands
• Low dose Haloperidol (1.5mg/d) administered prophylactically for elderly hip surgery patients
• No efficacy demonstrated in reducing post-op delirium
• Reduced severity and duration of delirium
• Reduced hospital stay (↓ cost)
Kalisvaart K. Haloperidol prophylaxis for elderly hip-surgery patients at risk for delirium: a randomized placebo-controlled study. J Am Geriatr Soc. 2005.
32
Delirium (Cont’d)
Breitbart W. Diagnosis and management of delirium in the terminally ill.
Topics in Palliative Care. 2001.
Breitbart W, et al. A double-blind trial of Haloperidol, chlorpromazine,
and lorazepam in the treatment of delirium in hospitalized AIDS patients.
Am Jour of Psychiatry. 1996.
33
Treatment of Delirium • Mild agitation – 2mg PO, IV, IM
• Moderate agitation – 5mg
• Severe agitation – 7.5-10mg
• Decrease dose by 1/3 for elderly patients
• May repeat q 30 min – patient calm yet arousable to voice
• If serious agitation persists, double dose in 30 min – may repeat
• When symptom control is achieved, 24hr dose QD, BID
Goldstein, Morrison. Evidence-Based Practice of Palliative Medicine. 2013.
34
Nausea and Vomiting
35
Glare P, et al. Treating nausea and vomiting in palliative care: a review. Clin
Interv Aging. 2011.
Nausea and Vomiting (Cont’d)
• A review of the literature which identified 3 studies which provided enough information on base line symptoms, interventions, outcome measures, and evaluation tools
• Haloperidol may be effective in patients experiencing nausea and vomiting
• No randomized controlled trials evaluating Haloperidol for nausea and vomiting
• The clinical use of Haloperidol for nausea and vomiting must be guided by clinical experience, judgment, case reports, and expert opinion
Critchley P, et al. Efficacy of Haloperidol in the treatment of nausea and vomiting in the palliative patient: a systematic review. J Pain Symptom Manage. 2001.
36
Nausea and Vomiting (Cont’d)
• 0.5mg – 1.5mg q 6-12h, up to 5mg q 12h IV/SQ
• SQ/IV = ½ PO
Tucker R, et al. Managing Nonpain Symptoms. UNIPAC 4: A Resource for Hospice
and Palliative Care Professionals. 2012.
37
Nausea and Vomiting (Cont’d)
• Retrospective study
• Trial 1 (n=23), 74% reported the use of LDH ↓ their CINV
• Trial 2 (n=10), 70% reported relief
Bleicher J, et al. Lorazepam, Diphenhydramine, and Haloperidol Transdermal Gel for Rescue From Chemotherapy-Induced Nausea/Vomiting: Results of Two Pilot Trials. J Support Oncol. 2008.
38
ABHR Gel in the Treatment of Nausea and Vomiting in
the Hospice Patient
Moon, R. Inter J of Pharma Compounding. 2006.
39
Nausea and Vomiting (Cont’d)
Haloperidol “has been extremely effective
in doses from 5-20mg/d and remains
our antiemetic of choice in most situations.”
Storey P, et al. Subcutaneous Infusions for Control of Cancer Symptoms. J Pain
and Symp Mgmt. 1990.
40
Bowel Obstruction
• May be useful as an antiemetic in the treatment of
malignant bowel obstruction
• However, has not been compared with other
antiemetics in a randomized controlled trial.
Ventafridda V, et al. The management of inoperable gastrointestinal obstruction
in terminal cancer patients. Tumori. 1990.
Ripamonti C, et al. Clinical-practice recommendations for the management of
bowel obstruction in patients with end-stage cancer. Support Care Cancer. 2001.
41
Intractable Hiccups (IH)
• Retrospective chart review (n=240)
• 3 subjects with IH were identified
• Haloperidol (n=1), Chlorpromazine, Baclofen, and Carbamazepine proved effective
Kumar A, et al. Intractable hiccups during stroke rehabilitation. Arch Phys Med Rehabil. 1998.
42
IH (Cont’d)
• 2 case studies in which IM Haloperidol (2mg)
followed by a PO regimen (2d) was effective in
treatment of IH without recurrence
• Mention of 7 additional cases
Ives TJ, et al. Treatment of intractable hiccups with intramuscular Haloperidol. Am
J Psychiatry. 1985.
43
Anxiety
• Useful in treatment of anxiety when benzodiazepines are not sufficient for symptom control
• Psychotic symptoms accompany the anxiety
• Avoids excessive sedation
Hanks G, et al. Oxford Textbook of Palliative Medicine. 2010.
44
Palliative Sedation
• Palliative sedation is often used at end of life for
refractory symptoms such as delirium, nausea,
dyspnea, and pain
o 0.5mg – 5mg PO/SQ a 2-4h
OR
o 1-5mg IV/SQ then infusion 5-15mg/d SQ/IV
Rousseau P. Palliative sedation in the management of refractory symptoms. J
Support Oncol. 2004.
45
Palliative Sedation (Cont’d)
• National Taiwan University Hospital (n=251)
• 70 patients received palliative sedation
• 35 patients received Haloperidol
• Did not influence survival time
• Surveys of staff and families indicated Haloperidol
was an effective agent for palliative sedation
Chiu TY, et al. Sedation for refractory symptoms of terminal cancer patients in
Taiwan. J Pain Symptom Manage. 2001.
46
Innovative Uses of Haloperidol:
•Analgesic Adjunct
•Pruritus
47
Analgesic Adjunct
• Anesthesia and psychiatric literature provide well designed studies and case reports that demonstrate the efficacy of Haloperidol as well as other neuroleptics as an analgesic adjunct
• Mixed results
• Most studies appear to be in the favorable camp
• Mμ, NMDA, -1 adrenergic, substance P receptors
• Na╫ channels
• Isometric similarity to meperidine
48
Analgesic Adjunct References
Colclough G, et al. Epidural Haloperidol enhances epidural morphine
analgesia: three case reports. J Opioid Manage. 2008.
Kotake Y, et al. Additional Droperidol, not Butorphanol, augments
epidural fentanyl analgesia following anorectal surgery. J Clin Anes.
2000.
Maltbie A, et al. Analgesia and Haloperidol: a hypothesis. J Clin
Psychiatry. 1979.
Judkins KC. Haloperidol as an adjunct analgesic in the management of
post operative pain. Anaesthesia. 1982.
Hanks GW, et al. The Myth Of Haloperidol Potentiation. The Lancet. 1983.
49
Analgesic Adjunct (Cont’d)
• Well designed retrospective study
• N=240
• Patients receiving short-acting opioids
• Low-dose methadone in conjunction with
adjuvent Haloperidol resulted in excellent pain control without dose escalation or opioid-
induced hyperalgesia
Salpeter S, et al. The Use of Very-Low-Dose Methadone for Palliative Pain Control
and the Prevention of Opioid Hyperalgesia. J Palliative Med. 2013.
50
Pruritus Organic Causes of Pruritus:
• Hepatic disease
• Renal disease
• Infection o Bacterial
o Parasitic
o HIV
• Diabetes
• Carcinoid
• Malignancy
• Collagen vascular disease
“Psychologic” causes of
pruritus and self-excoriation:
• Anxiety disorder (primary
or secondary)
• Obsessive-compulsive
disorder
• Depressive disorder
(primary or secondary)
• Personality disorder
(especially borderline)
• Psychosis
• Habit
51
Pruritus
52
When there is a psychological component, or
delusional ideation, or agitation is prominent, the
author recommends considering Haloperidol
Fried R. Evaluation and treatment of “psychogenic” pruritus and self-excoriation. J
Am Acad Dermatol. 1994.
Conclusion
• Effective and essential medication for symptom
management in Hospice and Palliative patients
due to its unique pharmacodynamic profile.
• Dose: start low and go slowly
• Adverse effects: increased in medically
complex patients with high risk clinical situations
53
Questions?
54
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