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