NAUSEA 101: OR WHY ZOFRAN IS NOT

ONE SIZE FITS ALLSara Warzecka MD The Carolinas Center

Hospice and Palliative Care Conference September 9, 2019

NO FINANCIAL DISCLOSURES

OBJECTIVES

➤ What is nausea? ➤ Biochemical mechanisms of nausea

(receptor-based thinking) ➤ Anti-emetic pharmacology ➤ Cases ➤ Extras ➤ Conclusion

WHAT IS NAUSEA?

“No one dies of nausea but it can seriously sap the will to live.” - Yann Martel

http://quotesgram.com/sick-quotes-about-friends/

NAUSEA AS SEEN BY THE BODY

NAUSEA INPUT POINTS➤ Areas of input to the vomiting center (nucleus of tractus solitarius) in

the medulla

➤ Chemoreceptor trigger zone (CTZ)- area postrema (outside BBB) - D2, NK-1 (5-HT3)

➤ The “sampling port” at the base of the fourth ventricle to detect substances that do not belong in the blood

➤ Central nervous system

➤ Cortex, meninges, thalamus, hypothalamus

➤ Vestibular system - ACh and H1

➤ GI Tract and viscera (via the vagus nerve)- mechanoreceptors, chemoreceptors, 5-HT3, peripheral D-2 in GI tract

➤ Midbrain ICP receptors

V-O-M-I-T-I-N-G CAUSES➤ V - Vestibular - labrynthitis, motion sickness

➤ O - Obstruction

➤ M - Motility - autonomic, ascites, gastroparesis

➤ I - Inflammation/Infection - chemo - release of serotonin (5-HT3) from gut lining, radiation therapy

➤ T - Toxins - uremia, hyperCa, hypoNa, antibiotics, anticholinergics

➤ I - Intracranial - primary cerebral lesions, metastases, elevated ICP

➤ N - Nerves - anxiety/depression, anticipatory nausea

➤ G - Gums - mucositis, thrush, oropharyngeal secretions

V-O-M-I-T-I-N-G RECEPTORS➤ V - Vestibular - ACh, H1 ➤ O - Obstruction - mechanoreceptors, chemoreceptors, 5-HT3

(ACh, H1)

➤ M - Motility Dysfunction - D2 peripheral, 5-HT4 (ACh, H1)

➤ I - Inflammation/Infection - 5-HT3, NK-1 (ACh, H1) ➤ T - Toxins - D2, chemoreceptors, 5-HT3 ➤ I - Intracranial - multiple

➤ N - Nerves (psych)- multiple

➤ G - Gums/mouth/oropharynx - multiple

ASSESSMENT➤ Symptoms: nausea, vomiting, retching, reflux, early satiety,

anorexia, bloating

➤ Duration/frequency - continuous vs intermittent

➤ Intensity - keeping fluids down?

➤ Aggravating/relieving factors

➤ Timing - relationship to eating? medication?

➤ Associated symptoms

➤ Drug/medication history

➤ Physical exam (focused)

➤ Labs and radiology

TREATMENT - ANTI-EMETICS PHARMACOLOGY

➤ PURE Antagonists:

➤ Haldol - D2

➤ Diphenhydramine - H1 ➤ Scopolamine and hyoscyamine - ACh ➤ Ondansetron and mirtazapine - 5-HT3

➤ Arepitant - NK1

ANTI-EMETICS PHARMACOLOGY➤ MIXED Antagonists

➤ Metoclopramide (Reglan)- D2 periph > D2 central > 5-HT3

➤ Prochlorperazine (Compazine)- D2 >>> H1 > ACh

➤ Promethazine (Phenergan)- H1 > ACh > D2(weak)

➤ Olanzapine (Zyprexa)- 5-HT2 > D2 > H1 > alpha-1 ➤ Chlorpromazine (Thorazine) - D2 > H1 > ACh >

alpha-1

MEDS BY VOMITING➤ V - Vestibular - Scopolamine patch, promethazine, meclizine

➤ O - Obstruction - Senna/metoclopramide if not complete, glucocorticoids, octreotide

➤ M - Motility Dysfunction - Metoclopramide

➤ I - Inflammation/Infection - Promethazine, ondansetron, prochlorperazine

➤ T - Toxins - Haloperidol, metoclopramide, prochlorperazine, olanzapine (ondansetron)

➤ I - Intracranial - Glucocorticoids

➤ N - Nerves - Lorazepam ➤ G - Gums/mouth/oropharynx - Treat underlying condition

CHEMOTHERAPY INDUCED NAUSEA AND VOMITING (CINV)➤ Incidence 19-58%

➤ Risk factors for CINV:

➤ Lower education, childcare responsibilities, poorer functional status, depression, sleep disturbance, evening fatigue, intrusive thoughts

➤ Response to release of 5-HT3, substance P, and cholecystokinin from the GI tract

➤ Mediated by:

➤ 5-HT3 and NK-1 receptors on the vagus nerve ➤ Various receptors in the CTZ

CINV PHASES

➤ Acute CINV - minutes to hours of admin - peak 5-6hrs - resolution by 24 hours

➤ Delayed CINV - >24 hours - peak 48-72hrs ➤ Anticipatory emesis - precedes chemo admin due to prior

negative experiences

CINV TREATMENT➤ Prophylactic regimens based on emetogenicity of chemo

➤ Strong evidence for use of glucocorticoids with first generation 5-HT3 receptor antagonists for prophylaxis of acute CINV

➤ NK-1 receptor antagonist - for acute and delayed CINV ➤ aprepitant/fosaprepitant (Emend), rolapitant (Varubi)

➤ High dose reglan - 20mg vs 24hr infusion of 40-60mg

➤ Consider olanzapine in refractory CINV

➤ Non-pharmacologic (lacking evidence) ➤ Acupuncture/pressure ➤ Guided imagery/hypnosis ➤ TENS unit

TETRAHYDROCANNABINOL➤ Dronabinol - synthetic cannabinoid ➤ FDA approved for treatment of CINV

➤ In patient failing conventional antiemetics

➤ 5mg/m2 2hrs prior to chemo and q4hrs after

➤ No head to head studies ➤ Side effects ➤ Users claim smoking works better

DIABETIC GASTROPARESIS➤ Mechanism - impaired vagal control

➤ Other contributors: impairment of inhibitory nitric oxide containing nerves, underlying smooth muscle dysfunction

➤ High glucose levels causing gastric dysrhythmias ➤ Prokinetic agents

➤ Reglan 10-20mg q6-8hrs

➤ Erythromycin 40-250mg q8hrs ➤ Eliminate factors that delay gastric emptying:

➤ anticholinergic agents, antihistamines, TCAs, CCBs, opioids

➤ PPIs and sucralfate ➤ More rare: interferon, levodopa

➤ Fiber supplements, insoluble fiber, high fats, tobacco, alcohol

TARDIVE DYSKINESIA

➤ Anti-dopaminergic meds are still anti-dopaminergic!

➤ Annual rate with typical antipsychotics 3-8%

➤ Lower rate with atypical due to weaker affinity for D2 ➤ Increased risk at higher doses

➤ Risk factors

➤ Elderly (RR 5-6x), female

➤ Longer duration of use

➤ Conditions: dementia, diabetes

OPIOID-INDUCED NAUSEA➤ Mechanism of nausea:

➤ CTZ-mediated

➤ Direct vestibular stimulation

➤ Constipation (afferent cholinergic pathways)

➤ Anecdotally codeine/morphine may be worse

➤ Tolerance develops in 3-7 days

➤ Treatment

➤ Prochlorperazine (Compazine)- D2 >>> H1 > ACh

➤ 5mg q8hrs prn

➤ Small study showing no benefit in prophylaxis

NON-PHARMACOLOGIC THERAPIES➤ Small frequent meals ➤ Low fat/fiber

➤ Short-term liquid diet

➤ Ginger

➤ Rehydration ➤ Mind-body therapies:

➤ Hypnosis, acupressure, acupuncture

VOMITING OUTSIDE THE BOX➤ Study of isopropyl alcohol:

➤ Patients in ED presenting for n/v randomized to alcohol swab or ondansetron (w/wo oral or swab placebos)

➤ Improved nausea scored for use of inhaled isopropyl alcohol with or without ondansetron

*Other studies indicate post-op efficacy

INEFFECTIVE TREATMENT

➤ Previous treatment with compounded Ativan, Haldol, and Benadryl (ABH) topical proved ineffective

➤ Not absorbed systemically to therapeutic levels

*Appears in Choosing Wisely society recommendations from AAHPM

NAUSEA CASES➤ Cause (Differential) ➤ Mechanism of nausea ➤ Propose treatment options

➤ Specific to patient

➤ General for cause

CASE #1➤ NC is a 62 yo F w/ h/o DMII for 14 years who started insulin

therapy two years ago now presents with worsening nausea for the last month. She notes being unable to finish a normal meal and feeling sick to her stomach shortly after eating. On recollecting, she thinks she has likely been suffering from some nausea for the better part of a year. But she also states the last few days she has been vomiting apart from eating and her husband and grandson have been sick with similar complaints as well.

CASE #1 DISCUSSION➤ Diabetic gastroparesis

➤ M - Motility Dysfunction - D2 peripheral, 5-HT4 (ACh, H1)

➤ Metoclopramide (Reglan) - 10mg PO 30min qac and qhs (max)

➤ Acute gastroenteritis ➤ I - Inflammation/Infection - 5-HT3, NK-1 (ACh, H1)

➤ Ondansetron - 8mg PO q8hrs prn (ODT)

➤ Other options: promethazine, prochlorperazine

CASE #2

➤ CA is a 75 yo M w/ h/o COPD and metastatic lung cancer currently undergoing chemotherapy with cisplatin/gemcitabine. He comes to you as his PCP to discuss better options for treating his nausea that shows up 3-4 days after he receives chemotherapy and nearly any time he goes to his oncologist’s office.

CASE #2 DISCUSSION➤ Delayed chemotherapy-induced nausea and vomiting (CINV)

➤ T - Toxins (CTZ)- D2, chemoreceptors, 5-HT3

➤ I - Inflammation/Infection - 5-HT3, NK-1 (ACh, H1)

➤ Metoclopramide (Reglan)- 10mg TID x3 days

➤ Olanzapine - 10mg PO daily x3 days

➤ Anticipatory nausea

➤ N - Nerves (psych)- multiple

➤ Benzodiazepines prior to treatment - starting low dose

➤ Hypnosis, biofeedback, guided imagery, relaxation training

CASE #3➤ MT is a 46yo M w/ HTN, bipolar disorder and chronic back

pain on opioid therapy managed by a pain specialist who comes in with complaints of nausea and vomiting. He notes significant cramping abdominal pain that improves with emesis, which is quite large. He feels unable to keep most food down. However, he is passing gas. He is able to tell you that his pain medications were switched one week ago and he is having to take more breakthrough doses, but he is not sure which medication he is on.

CASE #3 DISCUSSION➤ Opioid-induced nausea and vomiting

➤ T - Toxins - D2, chemoreceptors, 5-HT3

➤ V - Vestibular - ACh, H1

➤ Treatment vs opioid rotation

➤ Prochlorperazine (Compazine) - 5-10mg PO q6-8hrs prn

➤ Obstipation

➤ O - Obstruction - mechanoreceptors, chemoreceptors, 5-HT3 (ACh, H1)

➤ Senna, metoclopramide, glucocorticoids - treat the etiology

➤ Ondansetron - 4-8mg PO q8hrs prn

CASE #4

➤ CO is a 66yo F with ESRD of unclear etiology who is undocumented and requires emergent dialysis. She comes in to see you today due to sudden onset of constant nausea with intermittent vomiting. One of your partners started her on low dose amitriptyline for insomnia early this week and it has now been one week since she was last dialyzed.

CASE #4 DISCUSSION➤ Uremia and new medication (anti-cholinergic)

➤ T - Toxins - D2, chemoreceptors, 5-HT3

➤ Metoclopramide (Reglan)- 5mg bid (max 10mg on HD)

➤ Haldol - 0.5-2mg PO q4hrs PRN (no renal dosing)

➤ Alternatives: prochlorperazine (renal dosing not defined), ondansetron or olanzapine (no renal dosing),

➤ Discontinue amitriptyline and… ➤ Dialyze!

QUESTIONS?

REFERENCES➤ Felton M, Weinberg R, Pruskowski J. Olanzapine for Nausea, Delirium, Anxiety, Insomnia, and Cachexia. Fast Facts.

April 2016.

➤ Hallenbeck, J. The Causes of Nausea and Vomiting (V.O.M.I.T.). Fast Facts. May 2015.

➤ Nausea: a review of pathophysiology and therapeutics. Therapy Adv Gastroenterol. 2016 Jan; 9(1): 98-112.

➤ Pallin D. Inhaled isopropyl alcohol superior to oral ondansetron as an antiemetic. Ann Emerg Med. 2018.

➤ Perkins P, Dorman S. Haloperidol for the treatment of nausea and vomiting in palliative care patients. Cochrane Database Syst Rev. 2009; (2):CD006271.

➤ Singh K, et al. Risk Factors Associated With Chemotherapy-Induced Nausea in the Week Before the Next Cycle and Impact of Nausea on Quality of Life Outcomes. J Pain Symptom Manage. 2018;56(3):352-362.

➤ Smith TJ, Ritter JK, Poklis JL, Fletcher D, Coyne PJ, Dodson P, Parker G. ABH gel is not absorbed from the skin of normal volunteers. J Pain Symptom Manage. 2012;43(5):961-966.

➤ Shakil A, Church RJ, Rao SS. Gastrointestinal complications of diabetes.”Am Family Physician. 2008 Jun 15; 77(12):1697-702.

➤ Tageja N, Groninger H. Chemotherapy-Induced Nausea and Vomiting. Fast Facts. September 2015.

➤ Tsukuura H, Miyazaki M, Morita T, et al. Efficacy of prophylactic treatment for oxycodone-induced nausea and vomiting among patients with cancer pain (POINT): a randomized, placebo-controlled, double-blind trial [published online ahead of print October 16, 2017]. Oncologist. doi: 10.1634/theoncologist.2017-0225

➤ Weissman DE. Opioids and Nausea. Fast Facts. May 2015.

➤ Wilner SL, Arnold R. Cannabinoids in the Treatment of Symptoms in Cancer and AIDS. Fast Facts. June 2015.