i am sick of feeling sick managing nausea and vomiting in the palliative patient paul daeninck wrha...
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“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
Cannabinoids in CINV
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
Cannabinoids in CINV
Tramer et al, BMJ 2001 323:16-23
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
Versus placebo (4 studies)
Versus active control (6 studies)
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
Versus placebo (4 studies)
Versus active control (14 studies)
1.6 (1.4-1.8)
2.8 (2.4-3.3)
Preference for cannabinoids NNT (95% CI)
Cannabinoids in CINV
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”
Tramer et al, BMJ 2001 323:16-23
Cannabinoids in CINV
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
Cannabinoids in CINV
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
Heir, Gary DMD, et al. IJPC 2004; 8:337-343
Topical Route: Advantages
Variations in the stratum corneum barrier
Delivery dosing may require adjustment
Rate of absorption may vary
Rash most common SE
Heir, Gary DMD, et al. IJPC 2004; 8:337-343
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
Care Beyond Cure, 2000
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
Care Beyond Cure, 2000
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
Care Beyond Cure, 2000
Rectal Administration
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
Care Beyond Cure, 2000
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
Rectal Administration
For refractory cases, use combinations that act at different receptor sites
Cerebral cortex
CTZ
GI tract
Severe or refractory nausea may benefit from corticosteroid
Care Beyond Cure, 2000
Rectal Administration
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