I am Sick of Feeling Sick Managing Nausea and Vomiting in the Palliative Patient Paul Daeninck WRHA Palliative Care Program Greg Harochaw Taché Pharmacy

“I am Sick of Feeling Sick”Managing Nausea and Vomiting in the

Palliative Patient

Paul DaeninckWRHA Palliative Care Program

Greg HarochawTaché Pharmacy

DeclarationAdvisor or Paid Speaker for the following:

Valeant Pharmaceuticals

Bayer

Wyeth Pharmaceuticals

ObjectivesAt the end of this session, the attendee will be able to:

Identify the numerous GI issues causing nausea and vomiting in the palliative patient

Discuss the principles in determining the therapies for specific situations of nausea and vomiting

Recognize the complex physiology and potential for use of alternative routes in treating nausea and vomiting

GI Issues Causing Nausea/Vomiting

Medications

Radiation

Constipation

Bowel obstruction

Diarrhea

Ascites

Hemorrhage

Viscus perforation

Esophageal/gastric/ biliary duct obstruction

Liver failure

Pancreatic failure

Absorption syndromes

Infections

Electrolytes

Approach To Symptom Control

Thorough assessment history; physical examination

Discussiongoals of care, hopes, expectations, anticipated course of illness (impact on investigations & interventions)

Investigationsblood tests, X-Ray, CT, MRI, etc

Treatmentspharmacological and non-pharmacological; interventions

Ongoing reassessment/reviewOptions, goals, expectations, etc.

Symptom PrevalencePain

Fatigue/Asthenia Constipation

Dyspnea

Nausea

Vomiting

Delirium

Depression/suffering

80 - 90+%

75 - 90%

70%

60+%

50 - 60%

30%

30 - 90%

40 - 60%

Mechanisms of Nausea & Vomiting

vomiting centre: medulla

activated by stimuli from:Chemoreceptor Trigger Zone (CTZ)

area postrema, floor of 4th ventricle outside BBB (fenestrated venules)

Upper GI tract & pharynxVestibular apparatus/CerebellumHigher cortical centres

IntegrativeVomiting

Centre (IVC)

CerebralHigh CNS

Sights, SmellsMemories

ChemoreceptorTrigger Zone

ToxicCancerInfectionRadiation

DrugsChemotherapyOpioidsDigoxin, etc

BiochemicalUremiaHypercalcemia

VestibularCerebellar

OpioidsCerebellar Tumor

IncreasedIntracranial Press

Primary orMetastatic Tumor

GI TractVagal

DistensionOver-eatingGastric StasisExt. Pressure

ObstructionHigh, mid, lowConstipation

Chemical IrritantsBlood, drugs

N

a u

se

aV

o

t

G. Michael Downing

Pathogenesis of chemo- & RT-induced

emesis(CIE, RIE)

Area postrema 3rd vent

N/V Related ProblemsMedical

dehydration / electrolyte abnormalitiesesophageal tears / GI bleedaspiration pneumonia

Decreased QoLweight loss / anorexia weakness / lethargy

Psychological distress

Refusal of beneficial therapy

Principles of Therapy

Treat the underlying cause

Environmental measures

Antiemetic use: anticipate need use adequate, regular doses aim at receptor involved combinations if necessary anticipate need for alternate routes

Environmental MeasuresLimit exposure to food smells

open food trays prior to presentation

Bland foods (BRAT)

Small, frequent snacks/meals

Good oral hygene

Fresh air, calming environment

Sitting upright post meal

Avoid alcohol

Acupuncture/pressureNot as well studied

Safe in trained hands

Often used in conjunction with meds

Some evidence in CINV, delayed NV

Theory behind wrist/pressure bands

Dibble et al. Oncol Nurs Forum 2007 34:813-20

Weightman et al. BMJ 1987 295:1379

Anti-Emetic AgentsTransdermal scopolamine

Benzodiazepines

Antihistamines

Cannabinoids

Metoclopramide, Domperidone

Neuroleptics / Anti-psychotics

Corticosteroids

5-HT3 Antagonists

NK1 Antagonists (aprepitant)

IntegrativeVomiting

Centre (IVC)

CerebralHigh CNS

ChemoreceptorTrigger Zone

VestibularCerebellar

IncreasedIntracranial Press

GI TractVagal

N

a u

se

aV

o

tBenzodiazepinesCannabinoidsRelaxation

H1 AntagonistDimenhydrinateMethotrimeprazine

AnticholinergicScopolamineAtropine

Cannabinoids

Dexamethasone? VP Shunt

D2 AntagonistProchlorperazineHaloperidolMethotrimeprazineGastrokinetics

Metoclopromide5HT3 Antagonist

OndansetronGranisetron

Olanzepine?

D2 AntagonistGastrokinetics

MetoclopromideDomeperidone

PhenothiazinesMethotrimeprazine

5HT4 AgonistMetoclopromide

5HT3 AntagonistOndansetron

OctreotideDexamethasoneCannabinoids

AnticholinergicScopolamineAtropine

H1 AntagonistDimenhydrinateCyclizineMethotrimeprazine

5HT2 Antagonist Methotrimeprazine

5HT3 AntagonistOndansetron

G. Michael Downing

DOPAMINE ANTAGONISTS

ANTIMUSCARINIC

PROKINETIC

Haloperidol 0.5 - 1 mg po/sq/iv q4-12h

MTMZ 5 - 10 mg po/sl/sq q4-8h

Prochlorperazine 5 - 20 mg po/pr/iv

CPZ 25 - 50 mg po/pr/iv

Scopolamine patch (Transderm-V)

Metoclopramide 10 - 20 mg po/sq/pr q4-8h

Domperidone 10 mg po q4-8h

Antiemetics and Dosing

H1 ANTAGONISTS

SEROTONINANTAGONISTS

MISCELLANEOUS

Dimenhydrinate 25 - 100 mg po/pr q4-8h

Promethazine 25 mg po/iv q4-6h (Not sq)

Meclizine 25 mg po q6-12h

Ondansetron 8 -16 mg q 12 h po/sq/iv Granisetron 1- 2 mg q 12 h po/sq

Dexamethasone 4-16 mg po/sq/iv daily

Lorazepam 0.5 - 1 mg po/sl q4-12h

Nabilone 0.5-1 mg po/sl q8-12h

Olanzepine 2.5-10 mg OD

Antiemetics and Dosing

OlanzepineAtypical antipsychotic agent

Used in schizophrenia, delirium

Blocks multiple receptors

D1-4, 5-HT2/3/6, α1adrenergic, H1, M1-4

High affinity for serotonin vs dopaminergic

Well tolerated

Few drug interactions

OlanzepineHas been used in several case studies

Recently used in CINV and delayed NV

Good results with few problems

May also have some appetite benefits

Less expensive than 5-HT3 antagonistsNavari et al. Support Care Cancer 2007 Mar 21

Navari et al. Support Care Cancer 2005 13:529-34

Passik et al. Cancer Invest 2004 22:383-8

Passik et al. JPSM 2003 25:485-89

Srivastava et al. JPSM 2003 25:578-82

Jackson et al. J Pall Med 2003 6:251-55

Cannabinoids & Nausea

•The Nucleus of the Solitary Tract (NTS) receives information about:

Blood-borne emetics via the brainstem (BS) CTZAbdominal irritants via vagal afferents

•NTS neurons, in turn, project to a BS central pattern generator, which coordinates emesis behavior

•Higher cortical and limbic regions (governing taste, smell, sight, pain, memory and emotion) can suppress or stimulate nausea and vomiting through descending connections to the BS emetic circuitry

•Cannabinoids are thought to exert their antiemetic effects primarily via action on CB1 receptors in the NTS and higher cortical and limbic regions

Indirect, partial actions on 5-HT and DA signaling via 5-HT3 and D2 receptors are implicated

Dorsal Vagal Complex—NTSDorsal Vagal Complex—NTS

Brainstem Emetic

Circuitry

Brainstem Emetic

Circuitry

Cortex Limbic System

Cortex Limbic System

Stomach WallStomach Wall

Cannabinoids in CINV

20 pts, RCT, P vs THC, X-over

10 or 15 mg/m2 po q4h x 3, various tumours

Chemotherapy not specified

Anti-emetic effect seen in 14/20 THC vs 0/22 P (p<0.001)

No patients vomited while “high”

Sallan et al, NEJM 1975 293: 795-797


30 RCTs systematically reviewed

N=1366 pts; 25 trials X-over design

Nabilone, dronabinol, levonantradol (IM)

Stemitil, domperidone, metoclopramide

Variety of tumours

Low to highly emetogenic chemotherapies

Studied first 24 h (acute efficacy)

Tramer et al, BMJ 2001 323:16-23

Oral nabilone (16)

Oral dronabinol (13)

IM levonantradol (1)

Prochlorperazine (7)

metoclopramide, alizapride

domperidone (2)

chlorpromazine, placebo (4)

prochlorperazine (6)

metoclopramide (2)

haloperidol, placebo (6)

chlorpromazine



CannabinoidControl (Placebo or Active)

Event rate (%)

Tramèr MR, et al. BMJ. 2001;323:1-8.

Control of N/V with Cannabinoids: Systematic Review

vs. Placebo vs. Active

70%

57% 59%

43%

Nausea

active control= prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, alzapride

66%

34%

57%

45%

Vomiting

vs. Placebo vs. Active

0.5 1.0 1.5 2.0 2.5

Complete Control of N/V with Cannabinoids

Nausea

NNT= number needed to treat; active control= prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, alzapride.

NNT (95% CI)

Versus placebo (4 studies)

Versus active control (7 studies)

Vomiting



8.0 (4.0-775)

6.4 (4.0-16)

3.3 (2.4-5.7)

8.0 (4.5-38)

Relative risk (95% CI) Favors cannabinoids

Tramèr MR, et al. BMJ. 2001;323:1-8

NNT = number needed to treat; active control= prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine,

haloperidol, domperidone, alzapride

Patients’ Preference for Cannabinoids

Tramèr MR, et al. BMJ. 2001;323:1-8.

0.5 1.0 2.0 4.0 6.0 8.0 10.0 Relative risk (95% CI)

Favors cannabinoids



1.6 (1.4-1.8)

2.8 (2.4-3.3)

Preference for cannabinoids NNT (95% CI)


Cannabinoids may be superior to conventional therapies in low-moderate emetogenic setting

Patient preference for cannabinoids ranged from 38-90% (placebo 4-20%)

Cannabinoids produced significantly more side effects (good & bad), more pt withdrawals

“In selected patients, cannabinoids may be useful as mood enhancing adjuvants for the control of chemotherapy related sickness”



8-THC less psychotropic, less $, stable

Less psychomimetic effects in children

Phase II trial, 8 pts (3-13 yrs)

Variety of cancers, chemotherapy

Starting dose of 5 mg/m2

Nausea and vomiting eliminated

No psychotropic effects seen

Abrahamov et al, Life Sci 1995 56:2097

Linda Parker et al, Wilfred Laurier U.

Series of studies with rats/shrews

Model for anticipatory nausea

THC or CBD >> ondansetron

THC/CBD maybe most effective

Experimental Emesis

Limebeer and Parker Neuroreport 1999

Parker et al Neuroreport 2002

Parker et al Psychopharm 2004

Limebeer et al Physiol Behav 2006


Several RCTs in chemotherapy-induced emesis (CINV)

Pre 5-HT3 antagonist era (ondansetron)

Oral or IM meds vs best treatment

No comparison with 5-HT3 antagonist

No controlled trials of inhaled marijuana

Inhaled Marijuana

Cross-over CINV study, placebo control, marijuana vs dronabinol

n= 20 (15 men), 14 NSCLC

25% no vomiting, 15% no nausea35% hallucinations or time perception changes

Preference:20% marijuana, 35% dronabinol, 45% no pref

THC > marijuana therapeutic potencyLevitt et al, JCO 1984 abstract C-354

Inhaled Marijuana

CINV, open trial, no control

n=74, chronic users, 25% dropped out

Preference:18 (34%) v effective, 26 (44%) mod effective 12 (22%) no benefit

Side Effects:sedation 88%, dry mouth 77%, dizziness 39% 13% no A/E

Vinciguerra et al, N Y State J Med 1988, 88:525

Special SituationsConstipation

Obstruction

Symptom PrevalencePain

Fatigue/Asthenia Constipation

Dyspnea

Nausea

Vomiting

Delirium

Depression/suffering

80 – 90+%

75 - 90%

70%

60+%

50 - 60%

30%

30 - 90%

40 - 60%

MalignancyDirect effects

obstruction by tumor in wall

external compression by tumor

neural damage

L/S spinal cord

cauda equina/pelvic plexus

hypercalcemia

MalignancySecondary effects

poor po intake

dehydration

weakness/inactivity

confusion

depression

unfamiliar toilet arrangements

MedicationsOpioids

Ileocecal & anal sphincter tone

Peristaltic activity (SI & C)

Impaired defecation reflex

sensitivity to distension

internal anal sphincter tone

Water, electrolyte absorption (SI & C)

Concurrent DiseaseDiabetes

Hypothyroidism

Hypokalemia

Hernia

Anal fissure/stenosis

Hemorrhoids

Autonomic neuropathy

diabetes

spinal cord disease

chemotherapy

Parkinson’s disease

ALS/MS

Dementia

TreatmentProphylaxis

good symptom control

activity

adequate hydration

recognize drug effect

create a favorable environment

Treatment: Laxatives>80% pts on opioids need laxatives

Little research to guide choice

Softener and stimulant best first choice

May require oral/rectal routes

Enemas useful in impaction

Bulk forming agents worsen situation

Surfactants: docusate

Contact cathartics: senna, bisacodyl

Osmotic laxatives: lactulose

Saline osmotics: MgOH, Phosphasoda

Enemas: oil, saline, soap suds, Fleet

Treatment: Laxatives

Other ApproachesProkinetic agents: domperidone,

metoclopramide

Antibiotics: erythromycin

Herbal preparations: mulberry, rhubarb, licorice, prune juice

New AgentsSelective opioid antagonists

Active in periphery, esp. gut

Methylnaltrexone, Alvimopan

Studies used IV and oral application

S/E

abd cramping, flatulence, nausea, dizziness

Common problemAssociated with advanced cancers

GI, ovarian, lymphoma

Relapse / local spread of intrabdominal tumourDiffuse peritoneal carcinomatosis, encasement by

tumourMultiple partial bowel occlusions

(delaying or preventing propulsion of intestinal contents)

Symptoms of nausea/vomiting abdominal pain, distention

Bowel Obstruction

Pandha et al. Anti-Cancer Drugs, 1996; 7:5-10

Bowel Obstruction: Etiology

Mechanical obstruction causes:

secretions, gas proximal to the obstruction

distention from gas, ingested fluids, digestive secretions in turn causes secretions

Mercadante et al. JPSM 1997

distentionsecretion

Bowel ObstructionStandard Therapy

NG tube/IV fluids (“drip & suck”)

Bowel rest

Pain control (opioids)

Radiological assessment

Surgical intervention

Bowel ObstructionPalliative Therapy

Opioid analgesics, dexamethasone

Promotility agents

metoclopramide/domperidone

Octreotide (Sandostatin)

Hyoscine butylbromide (Buscopan)

Somatostatin AnaloguesOctreotide, vapreotide, lanreotideReceptor activity

brain, pituitary, pancreas, GI tract, immune cellsUsed in many conditionsProlongs GI transit time

fluid secretion in jejunum water/electrolyte absorptiondecreases peristasisreduces GI blood flow

Inhibits exocrine pancreatic secretion

Bowel Obstruction in Ovarian Cancer

13 pts, advanced ovarian cancer, inoperable GI obstruction

Octreotide dose of 300 - 600 µg/day

Octreotide controlled vomiting in all cases

Vomiting stopped in 2-3 days of starting tx

Mangili et al., Gynecologic Oncology 1996

NG drainage from 2000 to <100 ml/day

Complete relief of symptoms within 3 days (range 1-6 days)

8/13 pts D/C from hospital, continued treatment at home

Mangili et al., Gynecologic Oncology 1996

Bowel Obstruction in Ovarian Cancer

Delivery Routes for Medications

StandardOralIntravenousInhalation (nebulized)Subcutaneous

AlternativeSublingual

transmucosalmouthwashes

IntranasalTransdermal (topical)RectalVaginalIntraosseus

GH

Think “Outside the Box”

Alternative Routes of Drug Administration

Alternative delivery routestransmucosal

transdermal (topical)

rectal

Review of the science

Oral Mucosal DeliveryAdvantages:

High vascular permeability

Avoids “first pass” hepatic elimination

High potency of drug (small volumes)

Less intimidating/ “low-tech” administration

easier in home, PCH, LTC

Alternate administration route

pt NPO, difficulty swallowing, SBO, etc.

Oral Mucosal DeliveryBarriers:

Lipophilic Rx: needs intact mucosal cell

membrane

Hydrophilic Rx: poor absorption

Volume of dose Ideally 0.5 ml; > 1-2 ml swallowed

Excessive salvation swallowing of dose

Acceptable delivery vehicle/taste

Oral Mucosal Delivery

Lorazepam

Olanzapine wafers

(Zyprexa Zydis®)

Proclorperazine buccal tabs

(Stemetil®)

Mirtazapine (Remeron® RD)

Oral transmucosal drugs

Highly lipophilic better than oral absorption??

Haloperidol (Haldol®)Protect from light & freezing

Store below 40ºC discoloration & grayish-red precipitate

Methotrimeprazine (Nozinan®)25 mg/ml injectable

(store room temp, protect from light)

Oral Mucosal Delivery

Topical RouteOral route not desirable

Mucositis

Inability to swallow

Nausea/vomiting

Obstruction

Poor taste of product

Dry mouth

More localized action

Topical Route: Advantages

Avoids the GI tract and hepatic first-pass metabolism

Delivers to a specific site

Controls absorption rate

Provides constant dosing depot effect with anhydrous gels

Reduces systemic side effects

Heir, Gary DMD, et al. IJPC 2004; 8:337-343

Improves compliance

Allows ↑ concentration of Rx at site of application

Plasma concentrations of <10% compared to oral route


Topical Route: Advantages

Variations in the stratum corneum barrier

Delivery dosing may require adjustment

Rate of absorption may vary

Rash most common SE


Topical Route: Drawbacks

Topical RouteMouthwash/rinses

Misoprostol, Diphenhydramine, Lidocaine, Triamcinolone,

Sucralfate, Dry Mouth Formulations

Transdermal RouteFentanyl, Oxybutinin, Estrogen, Nitrate patches

Transdermal gels

Buccal sprayMorphine, Fentanyl, Triamcinolone, Lidocaine

Medicated lollipopsFentanyl, Nicotine, Tetracaine, Dextromethorphan, Diphenyhydramine, Nystatin

Topical Anti-Nauseant Gels

Scopolamine 0.25mg/0.1mlTransderm V patch releases ~1mg over 72

hr~0.1mg Q8H vs 0.25mg

Apply 0.1 – 0.2ml Q8H

Expiry date about 6 months

Topical Anti-Nauseant Gels

ABHRAtivan/Benadryl/Haldol/Reglan

Lorazepam 2- 4 mg higher brain (cortex)

Diphenhydramine 50-100 mg vestibular

Haloperidol 2-4 mg CTZ

Metoclopramide 40-80 mg/ml afferent impulses from periphery

Dose 0.25ml inner wrist QID

Moon RB Intl J Pharm Compound 2006 10:95-8

Haloperidol 0.5 - 1 mg po/sq/iv q4-12h

MTMZ 5 - 10 mg po/sl/sq q4-8h

Metoclopramide 10 - 20 mg po/sq/pr q4-8h

Ondansetron 8 -16 mg q 12 h po/sq/iv

Granisetron 1- 2 mg q 12 h po/sq

Dexamethasone 4-16 mg po/sq/iv daily

Dimenhydrinate 25 - 100 mg po/pr/sq q4-8h

Scopolamine 0.3-0.6 mg sq

Promethazine (Not sq)

Subcut Antiemetics

Case: Maria de J.35 y o, mother of 3, works in textiles

Lower abdominal pain, nausea

Investigations reveal ovarian mass, resection: adenocarcinoma

Chemo with platinum/paclitaxel, nausea with first 2 cycles, N/V subsequently

Admitted for IV hydration, pt wants to stop tx

gh

Case: Maria de J.4th cycle delayed x 1 week, P & S clinic

Full assessment reveals anticipatory nausea, constipation on AXR

Oral and PR laxatives given, BZD prechemo

No vomiting, still nauseated, avoids po route

Refuses hospital stay

gh

Case: Maria de J.Use of triple suppository advised (tid –

qid) dexamethasone 2 mg

metoclopramide 10 mg

diphenhydramine 25 mg

Nausea controlled for final 2 cycles, no hydration necessary

Rectal RouteDrug absorption

Limiting factors

Conditions/methods of administration

Care Beyond Cure: A Pharmacotherapeutic Guide to Palliative Care; Andree Neron Editor, 2000

First 6-8cm of rectum drain directly into systemic circulation

Drugs admin by this route: no hepatic first-pass effect

Rx high hepatic extraction may in bioavailability; variable due to:

Patient

Absorption site

Drug formulation, penetration of mucosa

Rectal Drug Absorption

Care Beyond Cure, 2000

Rectum vs upper GI tract:Absorption area rectal mucosa: 200-400 cm² (no villi in rectum)

small intestine: 2,000,000 cm²

pHFluid content

Absorption mechanisms same (passive diffusion)

Formulation of drug is critical factorMay have to increase dosage interval i.e. Q8H vs Q12H

Rectal Drug Absorption


Rectal Limiting FactorsDrug insertion level

6-8cm (lower rectum) systemic circulation15-20cm (upper rectum)

portal vein hepatic first-pass effect

Solutions:Aqueous & alcohol solutions are the best and

most rapidly absorbed

Fecal matter in rectumDefecation reflex, involuntary expulsion


Rectal Administration

Use liquid formulations whenever possibleUse volumes <10-25 ml>80 ml ↑ risk of spontaneous expulsion

Administer liquids with a small lubricated syringeRectal canula or catheter tip syringes beneficial Cut a NG tube (#14) to 5 cm; attach to prefilled

syringereduces chance of portal vein absorption



Administer capsules and tablets directly into the rectum

Compounding pharmacy: “designer” rectal suppositories Administration a lot easier

Hepatic absorption usually not a problem with the use of suppositories


LorazepamUse parenteral preps or tabletsBioavailability of injection > 80%Serum concentrations < ½ of IV route

MetoclopramideTablets or suspensions

PhenobarbitalExcellent bioavailability 90-100%Peaks at ~ 4 hours

Baines, MJ BMJ 1997;315:1148-1150


For refractory cases, use combinations that act at different receptor sites

Cerebral cortex

CTZ

GI tract

Severe or refractory nausea may benefit from corticosteroid



Triple SuppositoryMetoclopramide 10 - 20mg

Dimenhydrinate 25 - 75mg

Prochloperazine 10 - 25mg

Use a formulation with a single medication or combinations of up to 3 medications

Other Antinauseant Suppositories

Dimenhydrinate 75mg/Metoclopramide 15mg/Prochloperazine 10mg

Dimenhydrinate 25mg/Metoclopramide 10mg/ Prochloperazine 15mg

Metoclopramide 10mg/Haloperidol 1mg

Dimenhydrinate 25mg/ Metoclopramide 20mg/ Prochloperazine 10mg/ Dexamethasone 2mg

SummaryGI symptoms in palliative care varied

Assessment important

Tailor therapy to meet pt needs

Research in area lacking

Help is available

WRHA Pall Care pgm: 237-2400

Physician on call: 237-2053 (24 hrs)

Case example

Young woman, chronic pain

Compression of C6 root, migraine, constant, rated 8/10

Attempted pain control using methadone, not tolerated

Lost to F/U until Jan 07, returned on meperidine (Demerol®)

Case example

GP requested IV anti-nauseants

Good effect but cumbersome

Topical compound (/ml, in PLO):metoclopramide 20 mg

dimenhydrinate 25 mg

Benefit, but required adjustment to (/ml):dimenhydrinate 100 mg

haloperidol 4 mg

metoclopramide 80 mg

Documents

I am Sick of Feeling Sick Managing Nausea and Vomiting in the Palliative Patient Paul Daeninck WRHA Palliative Care Program Greg Harochaw Taché Pharmacy