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Effectively Managing Nausea and Vomiting

Myra Belgeri, Pharm.D, BCGP, BCPS, FASCP

Clinical Pharmacist, Optum Hospice Pharmacy Services

October 2017

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• I have no relevant financial relationships with manufacturers of any commercial products and/or providers of commercial services discussed in this presentation.

• This discussion will include the use of medications for off-label indications.

• All medication treatments and doses discussed are only applicable to adult patients.

Disclosure

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• Review the pathophysiology and assessment of nausea and vomiting

• Develop a plan for the treatment of nausea and vomiting in hospice and palliative care

Objectives

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Mr. A is a 70 year old with recently diagnosed cholangiocarcinoma that has metastasized to the liver and peritoneum.

He is newly admitted to hospice and has been complaining of constant nausea for the past week.

Hospice nurse finds a distressed patient who is slightly jaundiced.

Patient Case – Meet Mr. A

Pathophysiology & Assessment

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• Nausea

– Unpleasant subjective feeling that one will imminently vomit

• Vomiting (emesis)

– Expulsion of gastric contents through the mouth

• May often have nausea without vomiting, or (less frequently) vice versa

– Most report nausea is more common and more disabling

• Other definitions

– Regurgitation: return of small amounts of gas or food from the stomach

– Retching: rhythmic movement of diaphragm to facilitate regurgitation into esophagus

– Dyspepsia: symptoms of the upper GI tract associated with early satiation, epigastric pain or burning, and nausea

Definitions

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• Advanced cancer patients – up to 70%

• Palliative patients with non-malignant conditions – up to 50%

• Opioid use – up to 40%

• Reported more often by women than men

• Causes substantial psychological distress

• Creates fears of starvation, dehydration, or disease progression

Prevalence

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• Gastric stasis

– Constipation, autonomic dysfunction

• Chemical disturbances

– Opioids, chemotherapy, any medication or chemical exposure

• Metabolic disturbances

– Hyperglycemia, hypercalcemia, hyponatremia, uremia

• Intestinal obstruction

– Abdominal malignancy, ileus

• Raised intracranial pressure

– CNS malignancy, trauma

• Vertigo

– Meniere’s disease, labyrinthitis, head/neck malignancy

• Anxiety

Pathophysiology

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Vomiting Center

Vestibular System

Chemoreceptor Trigger Zone

Cerebral Cortex

GI Tract

Pathogenesis of Nausea/Vomiting – The Emetogenic Pathway

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• Vestibulocochlear nerve

– Carries input from inner ear to brainstem

– Labyrinthine inputs can trigger the vomiting center

• Triggers

– Movement in the inner ear

– Opioids

– Tumors at base of skull

• Presentation

– Intermittent symptoms

– Nausea/vomiting with position changes

• When raising the head of the bed, getting out of bed

– Nausea/vomiting with movement

• Walking, wheelchair movement, riding in a car

Vestibular System

Vomiting Center

Vestibular System

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• Located outside the BBB in the CNS

– Exposed to toxins in the blood & cerebrospinal fluid

• Triggers

– Drugs (opioids, chemotherapy, SSRIs, antibiotics)

– Metabolic products (uremia, hypercalcemia)

– Comorbidities (organ failure, infection)

• Presentation

– Predominantly nausea, constant and often severe

– Aggravated by sight/smell of food

– Vomiting does not significantly relieve nausea

– Physical exam often unremarkable

Chemoreceptor Trigger Zone (CTZ)

Vomiting Center

Chemoreceptor Trigger Zone

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• Receives input from the 5 senses

• Triggers

– Anxiety, recalling past events

– Irritation or increased intracranial pressure (ICP)

• Presentation

– Anxiety

• Waves of nausea, with or without vomiting

• Nausea may be relieved by distraction

– Increased ICP

• Diurnal headache, nausea (possibly diurnal)

• Neurological signs might be present

Cerebral Cortex

Vomiting Center

Cerebral Cortex

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• Input received from peripheral pathways

– Mechanoreceptors and chemoreceptors

– GI tract, viscera, serosa

– Input directed to both the CTZ and vomiting center

• Triggers

– Impaction, obstruction (stool, metastases)

– Autonomic dysfunction (e.g., Parkinson’s)

– Medications (opioids, NSAIDs)

– GI bleeding, ulceration

– GI malignancy, liver disease, bile duct obstruction

– Local radiation

Gastrointestinal (GI) Tract

Vomiting Center

GI Tract

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• Presentation

– Gastric stasis

• Epigastric pain, fullness, nausea, early satiety, reflux

• Vomiting large volumes; projectile vomiting

• Vomiting relieves the nausea

– GI irritation

• Dark, tarry stools, coffee ground emesis

• Diarrhea, nausea, occasional vomiting, altered bowel habits

Gastrointestinal (GI) Tract

Vomiting Center

GI Tract

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• Dopamine (D2)

– Triggers nausea in the CTZ; receptors stimulated by products in the bloodstream and cerebrospinal fluid

– Agonism in the GI tract slows gut motility (“dopaminergic brake”)

• Serotonin (5HT3, 5HT4)

– Released in GI tract in response to toxins; signals the CTZ and vomiting center

– 5HT4 impacts upper GI motility

• Histamine (H1, H2)

– Triggered by movement in the inner ear

– Contributes to cerebral cortex stimulations triggered by emotions or irritation

– Released in GI tract in response to toxins; signals the vomiting center

– H2 involved in gastric acid secretion

Neurotransmitters in the Emetogenic Pathway

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• Acetylcholine (ACh) and muscarinic receptors

– Released in GI tract in response to toxins; signals the vomiting center

– Contribute to cerebral cortex stimulations triggered by emotions or irritation

– Triggered by movement in the inner ear

• Neurokinin (NK1)

– Triggers nausea in the CTZ and activates vomiting center

• Gamma-amino butyric acid (GABA)

– Agonism in the CNS can subside excitatory neurons contributing to anxious state

Neurotransmitters in the Emetogenic Pathway

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Vomiting Center

H1, ACh, 5HT, NK1,

mu

Vestibular System

H1, ACh

Chemoreceptor Trigger Zone

D2, 5HT3, NK1

Cerebral Cortex

GABA, H1

GI Tract

5HT4, 5HT3, D2, H2, ACh

Neurotransmitters in the Emetogenic Pathway

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• Is the nausea and/or vomiting constant or intermittent?

• Does vomiting accompany the nausea? / Does nausea accompany the vomiting?

• Does vomiting relieve the nausea?

Timing

Associated

Symptoms

• Have there been any changes in bowel habits?

• Are you having bowel movements?

• Do you have any pain, anxiety, reflux, headache, confusion, or vision changes?

• Does the sight or smell of food trigger nausea?

• Do you become nauseated or vomit shortly after eating or drinking?

• Does movement trigger nausea or vomiting?

Triggers

Assessment

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Medications• Have you tried any treatments for your symptoms? Do they work?

• Have you been able to take any of your medications?

Assessment

Description

• Describe the quality of your emesis (amount, color, presence of undigested food, etc.)

• Describe the quality of your stool (amount, texture, color, etc.)

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Mr. A is a 70 year old with recently diagnosed cholangiocarcinoma that has metastasized to the liver and peritoneum. He is newly admitted to hospice and has been complaining of constant nausea for the past week. Hospice nurse finds a distressed patient who is slightly jaundiced.

• Constant background nausea with emesis about 30 minutes after eating

• Emesis relieves the nausea for a short period of time

• The smell of food makes the nausea worse; oral intake is poor

• Nausea not worsened by movement; patient still ambulates short distances

• Abdominal pain present constantly; started using morphine 5 mg doses with minimal relief

• Bowel movements are irregular; last BM was 2 days ago

What might be the cause (pathogenesis) of Mr. A’s nausea/vomiting?

Patient Case – Assessment

Treatment Options

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• Empiric treatment

– Use same medication for initial treatment regardless of presentation

– Less-preferred method among most hospice and palliative care practitioners

• Mechanism-based treatment

– Treatment selection guided by presentation of symptoms and knowledge of the emetogenic pathway

– Method used by most hospice and palliative care practitioners

Treatment Approach

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• Dopamine antagonists

• 5HT3 antagonists

• NK1 antagonist

• Antihistamines

• Anticholinergics

• Anxiolytics

• Corticosteroids

• Prokinetics

• Miscellaneous

Treatment Approach

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• Haloperidol (Haldol®)

– Strong D2 antagonism in the CTZ and GI tract

– Starting dose: 0.5 mg PO/SL/PR/IV/SC every 4 hours PRN

• Tablets and oral solution absorbed well SL and PR; versatile, low cost

• Low risk for side effects such as extrapyramidal symptoms at low starting dose

• Caution QT prolongation

• Prochlorperazine (Compazine®)

– Strong D2 antagonism, weak H1 antagonism

– Starting dose: 10 mg PO every 6 hours PRN or 25 mg supp PR every 12 hours PRN

• Must use tablets PO and suppositories PR; suppositories are high cost

• Antihistamine effect causes more sedation than haloperidol

Dopamine Antagonists

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• Chlorpromazine (Thorazine®)

– Strong D2 antagonism, weak H1 antagonism, weak anticholinergic activity, strong alpha-adrenergic blocker

– Starting dose: 25 mg PO/IV every 6 hours PRN

• High risk for orthostatic hypotension and sedation

• Promethazine (Phenergan®)

– Strong H1 antagonism, weak D2 antagonism, moderate anticholinergic activity

– Starting dose: 12.5 mg PO/PR/IV/IM every 6 hours PRN

• Very sedating; might be most useful for stopping emesis

• Suppositories are high cost

Dopamine Antagonists

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• Ondansetron (Zofran®)

– Selective 5HT3 antagonist

• Prevention of chemotherapy-induced, radiation-induced, or post-operative nausea/vomiting

• Appropriate to continue use for 1-2 weeks beyond the related procedure

– Starting dose: 8-24 mg PO/IV prior to chemo or surgery (dose and route dependent on indication)

– May be a last-line therapy in hospice for CTZ nausea/vomiting

• Acquisition cost is high and cost at the pharmacy varies

• Caution constipation and QT prolongation

• Aprepitant (Emend®)

– Selective NK1 antagonist

• Used in combo with a 5HT3 antagonist and dexamethasone for emetogenic chemotherapy

• Appropriate to continue per dosing schedule for prevention of nausea, usually 1-3 days

5HT3 and NK1 Antagonists

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• Meclizine (Antivert®, Dramamine® Less Drowsy)

– H1 antagonism with some central anticholinergic activity

– Starting dose: 25 mg PO every 6 hours PRN

• Sedating, but possibly the least sedating of the antihistamines with antiemetic effects

• Drug of choice for vertigo; available OTC

• Anticholinergic side effects (dry mouth, confusion, constipation, urinary retention, blurred vision)

• Other antihistamines for vestibular nausea

– Hydroxyzine (Vistaril®, Atarax®)

– Promethazine (strong H1 effect)

Antihistamines

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• Scopolamine (Transderm-Scop®)

– Strong antimuscarinic (anticholinergic) and some H1 antagonism

– Dose: Apply 1 transdermal patch (1.5 mg) to hairless area behind ear every 72 hours

• Good for prophylaxis and treatment of motion sickness; blocks the vomiting center

• Do not cut patches; best if placed 4-12 hours prior to anticipated need for motion sickness

• Side effects: sedation, constipation, urinary retention, dry mouth, confusion, tachycardia

• Other anticholinergics

– Glycopyrrolate (Robinul®)

• Does not cross BBB, less sedation; most useful in full bowel obstruction

– Hyoscyamine (Levsin®)

• Short half life and need for repeated dosing complicates chronic use

• Might already be in the patient’s home for terminal secretions

Anticholinergics

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• Benzodiazepines

– e.g., lorazepam (Ativan®), alprazolam (Xanax®), diazepam (Valium®)

– GABA-A receptor agonists; GABA causes inhibition of CNS excitement

– Best for anticipatory nausea/vomiting or anxiety related causes

– Any benzodiazepine would work for this cause; choice based on patient-specific factors

• Hydroxyzine

– Antihistamine with weak anxiolytic properties

– Also anticholinergic action; caution side effects (dry mouth, constipation, urinary retention, confusion, sedation)

– Starting dose: 25 mg PO q6h PRN

• Will also have an effect on the vomiting center

Anxiolytics

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• Dexamethasone (Decadron®)

– Readily crosses BBB to provide relief of raised intracranial pressure

– Starting dose: 4 mg PO/PR/SC/IV BID in the morning and early afternoon

• Giving a dose close to bedtime can cause insomnia

• In brain malignancy, the dose may need to be titrated every few weeks

• Useful as an adjunct for other causes, such as chemotherapy induced nausea/vomiting

• Take with food to avoid GI irritation

• Other corticosteroids

– Methylprednisolone (Medrol®) may also cross the BBB

• Dexamethasone has the most evidence to support use

Corticosteroids

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• Metoclopramide (Reglan®)

– Strong D2 antagonism, moderate 5HT4 agonism, some 5HT3 antagonism in high doses

– Starting dose: 5-10 mg PO/PR/IV/IM/SC 30 minutes before meals and at bedtime

• Prokinetic effect in the upper GI tract through 5HT4 agonism and release of dopaminergic brake

• Also useful in CTZ nausea and partial bowel obstruction

• Caution EPS/TD and QT prolongation; use smallest dose for shortest period of time

• Other prokinetic

– Erythromycin 250 mg PO TID before meals

• Gastric motilin agonist

• May have a place in therapy for those unable to take metoclopramide

• Macrolide antibiotic; caution risk of QT prolongation

• Limit use to 4 weeks or less due to drop in efficacy and risk of tachyphylaxis

Prokinetics

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• Olanzapine (Zyprexa®)

– Affinity for many receptors in the emetic pathway: D2, various 5HT, H1, Ach

• Studied in chemotherapy-induced nausea/vomiting

• Case reports available for palliative care population

– Starting dose for palliative care: 5 mg PO at bedtime

• Less risk for EPS than with strong dopamine antagonists

• Side effects: sedation, dry mouth, constipation, weight gain, hyperglycemia

• May exert action on several portions of the emetogenic pathway

• Good option for nausea/vomiting refractory to other therapies

• Acid suppression agents

– Proton pump inhibitors (omeprazole, lansoprazole)

– H2 antagonists (ranitidine, famotidine)

Miscellaneous Therapies

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• Cannabinoids

– CB1 cannabinoid receptors are found throughout the CNS, brainstem, GI tract and rest of the body

– CB1 receptor agonists such as Δ9-THC from the cannabis plant have an effect on nausea and vomiting

– Two FDA-approved cannabinoids: dronabinol (Marinol®) and nabilone (Cesamet®)

• Not more effective than traditional antiemetics; high cost

• Only approved for chemotherapy-induced nausea/vomiting

• Current knowledge of role in mechanisms of N/V outside chemotherapy is limited

• Schedule III controlled substance; potential for dependence

• Lowers seizure threshold; may cause hypotension and syncope

Miscellaneous Therapies

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• Multiple emetogenic pathways involved

– Chemoreceptor trigger zone

– Gastroparesis and constipation

– Sensitization of the vestibular nerve

• Generally occurs with opioid initiation or dose escalation

– Tolerance develops after 3-5 days of continued use

• Treatment

– OINV is largely mediated through D2 receptors

– Schedule a D2 antagonist around the clock for several days, then taper and d/c

• Haloperidol is a good choice with demonstrated efficacy and minimal sedation

• Metoclopramide has also demonstrated efficacy

• Other dopamine antagonists may be limited in use due to side effects and worsening sedation

– Could also attempt to lower opioid dose by 10-20%, but may compromise pain control

Opioid-Induced Nausea/Vomiting (OINV)

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People develop tolerance to the nauseating effects of opioids

typically within 3-5 days of use.

If the opioid dose cannot be reduced without compromising pain control,

schedule haloperidol 0.5 mg PO every 8 hours for 7 days

then taper and discontinue.

Take Note!

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Antihistamines

Anticholinergics

Dopamine agonists

Selective 5HT3

antagonists

Selective NK1

antagonist

Anxiolytics

Corticosteroids

Prokinetics

Treatment Approach – Mechanism-based

Vestibular

H1, ACh

Chemoreceptor

Trigger Zone

D2, 5HT3, NK1

Cerebral Cortex

GABA, H1

GI Tract

5HT4, 5HT3,

D2, H2, ACh

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Mr. A is a 70 year old with recently diagnosed cholangiocarcinoma that has metastasized to the liver and peritoneum. He has been determined to have nausea related to gastric stasis and CTZ based on the following:

• Emesis 30 minutes after eating; temporarily relieves the nausea

• New opioid use – morphine started for abdominal pain

• Bowel movements are irregular with last BM 2 days ago

• Nausea is constant and worsened by the smell of food

What would be the best treatment for Mr. Armstrong’s symptoms?

Patient Case – Treatment

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• When first selection is not working, do we add or remove?

– Multifactorial symptom, may be best to add

– Choose a medication with a different mechanism of action

– Also first consider titration of the initial agent if partial response

• Beware polypharmacy

– Prokinetics + anticholinergics = counter-intuitive

• e.g., avoid promethazine with metoclopramide

– Multiple dopamine antagonists = high risk for EPS

• e.g., haloperidol with metoclopramide

– Multiple QT prolonging medications = arrhythmia risk

• e.g., haloperidol, ondansetron

Treatment Tips

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• Major antiemetic drug-disease interactions

– Seizures

• Most antiemetics can lower seizure threshold; use with caution

– Parkinson’s disease

• Caution EPS and worsening Parkinson’s symptoms with dopamine antagonists

• Best options: promethazine, ondansetron

– Dementia with Lewy bodies

• High risk of neuroleptic malignant syndrome with potent dopamine antagonists

• Reported mostly with typical (first-generation) antipsychotics such as haloperidol and chlorpromazine

• Best options: promethazine, ondansetron

Treatment Tips

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• When empiric treatment approach is necessary…

– Sudden onset of vomiting at 3am and patient needs immediate relief!

– Might be the only place in therapy for compounded multi-ingredient products

• ABHR suppositories – hits D2, H1, ACh, GABA, 5HT4

• Provides symptom relief until a thorough assessment can be performed

• Topical products unlikely to provide relief

• Hospice medication of choice for empiric treatment: haloperidol

– Covers most common causes of nausea/vomiting in terminal patients

– Versatile medication

• Highly lipophilic, absorbed well via rectal and sublingual routes

• Not sedating in low doses; low cost

Treatment Tips

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Mr. A is a 70 year old with recently diagnosed cholangiocarcinoma that has metastasized to the liver and peritoneum.

• He started using metoclopramide 10 mg by mouth before meals and at bedtime last week for nausea and vomiting related to gastric stasis.

• He also started senna/docusate 8.6/50 mg 2 tablets at bedtime for constipation due to morphine use. He is now happy to report daily bowel movements and no more episodes of vomiting.

• However, he still reports constant, mild to moderate nausea that is worsened by the smell of food. He is troubled by being unable to enjoy some of his favorite meals. He has an expired bottle of promethazine tablets in the home and is asking if he can use those for the nausea.

What is the best plan for treatment?

Patient Case – Refractory Symptoms

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• Have a working knowledge of the emetogenic pathway

– Understand that nausea and vomiting are multifactorial conditions

– Know how symptom presentation is linked to underlying cause/pathway

• Patient assessment is key!

– Have a mental or actual checklist of assessment items

• Use knowledge of the emetogenic pathway to select mechanism-based treatments

– Assessing the patient and moving to mechanism-based treatments can quickly manage the symptom and lessen adverse drug effects

Key Points

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Questions?

Myra Belgeri, Pharm.D, BCGP, BCPS, FASCP

mbelgeri@hospiscript.com

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1. Glare PA, Dunwoodie D, Clark K, et al. Treatment of nausea and vomiting in terminally ill cancer patients. Drugs 2008; 68(18): 2575-2590.

2. Wood GJ, Shega JW, Lynch B, et al. Management of intractable nausea and vomiting in patients at the end of life. JAMA 2007; 298(10): 1196-1207.

3. Collis E, Mather H. Nausea and vomiting in palliative care. BMJ 2015; 351: 1-11.

4. Neoh K, Adkinson L, Montgomery V, et al. Management of nausea and vomiting in palliative care. Br J Hosp Med 2014; 75(7): 391-396.

5. Singh P, Yoon SS, Kuo B. Nausea: a review of pathophysiology and therapeutics. Ther AdvGastroenterol 2016; 9(1): 98-112.

6. Tornblom H, Abrahamsson H. Chronic nausea and vomiting: insights into underlying mechanisms. Neurogastroenterol Motil 2016; 28: 613-619.

7. Prommer E. Role of haloperidol in palliative medicine: an update. Am J Hosp Palliat Med 2012; 29(4): 295-301.

8. Camilleri M, Parkman HP, Shafi MA, et al. Clinical guideline: management of gastroparesis. Am J Gastroenterol 2013; 108: 18-37.

References

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9. Chu CC, Hsing CH, Shieh JP, et al. The cellular mechanisms of the antiemetic action of dexamethasone and related glucocorticoids against vomiting. Eur J Pharmacol 2014; 722: 48-54.

10. Kim JS, Sung HY. Gastrointestinal autonomic dysfunction in patients with Parkinson’s disease. J Mov Disord 2015; 8(2): 76-82.

11. MacKintosh D. Olanzapine in the management of difficult to control nausea and vomiting in a palliative care population: a case series. J Palliat Med 2016; 19(1): 87-90.

12. Ang SK, Shoemaker LK, Davis MP. Nausea and vomiting in advanced cancer. Am J Hosp PalliatMed 2010; 27(3): 219-225.

13. Gordon P, LeGrand SB, Walsh D. Nausea and vomiting in advanced cancer. Eur J Pharmacol 2014; 722: 187-191.

14. Sharkey KA, Darmani NA, Parker LA. Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system. Eur J Pharmacol 2014; 722: 134-146.

15. Smith HS, Laufer A. Opioid induced nausea and vomiting. Eur J Pharmacol 2014; 722: 67-78.

References