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

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Presentation on theme: "I am Sick of Feeling Sick Managing Nausea and Vomiting in the Palliative Patient Paul Daeninck WRHA Palliative Care Program Greg Harochaw Taché Pharmacy."— Presentation transcript:

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

2 Declaration Advisor or Paid Speaker for the following: Valeant Pharmaceuticals Bayer Wyeth Pharmaceuticals

3 Objectives At 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

4 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

5 Approach To Symptom Control Thorough assessment history; physical examination Discussion goals of care, hopes, expectations, anticipated course of illness (impact on investigations & interventions) Investigations blood tests, X-Ray, CT, MRI, etc Treatments pharmacological and non-pharmacological; interventions Ongoing reassessment/review Options, goals, expectations, etc.

6 Symptom Prevalence Pain Fatigue/Asthenia Constipation Dyspnea Nausea Vomiting Delirium Depression/suffering % % 70% 60+% % 30% % %

7 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 & pharynx Vestibular apparatus/Cerebellum Higher cortical centres

8 Integrative Vomiting Centre (IVC) Cerebral High CNS Sights, Smells Memories Chemoreceptor Trigger Zone Toxic Cancer Infection Radiation Drugs Chemotherapy Opioids Digoxin, etc Biochemical Uremia Hypercalcemia Vestibular Cerebellar Opioids Cerebellar Tumor Increased Intracranial Press Primary or Metastatic Tumor GI Tract Vagal Distension Over-eating Gastric Stasis Ext. Pressure Obstruction High, mid, low Constipation Chemical Irritants Blood, drugs G. Michael Downing

9 Pathogenesis of chemo- & RT-induced emesis (CIE, RIE) Area postrema 3rd vent

10 N/V Related Problems Medical dehydration / electrolyte abnormalities esophageal tears / GI bleed aspiration pneumonia Decreased QoL weight loss / anorexia weakness / lethargy Psychological distress Refusal of beneficial therapy

11 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

12 Environmental Measures Limit 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

13 Acupuncture/pressure Not 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 : Weightman et al. BMJ :1379

14 Anti-Emetic Agents Transdermal scopolamine Benzodiazepines Antihistamines Cannabinoids Metoclopramide, Domperidone Neuroleptics / Anti-psychotics Corticosteroids 5-HT 3 Antagonists NK1 Antagonists (aprepitant)

15 Integrative Vomiting Centre (IVC) Cerebral High CNS Chemoreceptor Trigger Zone Vestibular Cerebellar Increased Intracranial Press GI Tract Vagal Benzodiazepines Cannabinoids Relaxation H1 Antagonist Dimenhydrinate Methotrimeprazine Anticholinergic Scopolamine Atropine Cannabinoids Dexamethasone ? VP Shunt D2 Antagonist Prochlorperazine Haloperidol Methotrimeprazine Gastrokinetics Metoclopromide 5HT3 Antagonist Ondansetron Granisetron Olanzepine? D2 Antagonist Gastrokinetics Metoclopromide Domeperidone Phenothiazines Methotrimeprazine 5HT4 Agonist Metoclopromide 5HT3 Antagonist Ondansetron Octreotide Dexamethasone Cannabinoids Anticholinergic Scopolamine Atropine H1 Antagonist Dimenhydrinate Cyclizine Methotrimeprazine 5HT2 Antagonist Methotrimeprazine 5HT3 Antagonist Ondansetron G. Michael Downing

16 DOPAMINE ANTAGONISTS ANTIMUSCARINIC PROKINETIC Haloperidol mg po/sq/iv q4-12h MTMZ mg po/sl/sq q4-8h Prochlorperazine mg po/pr/iv CPZ mg po/pr/iv Scopolamine patch (Transderm-V) Metoclopramide mg po/sq/pr q4-8h Domperidone 10 mg po q4-8h Antiemetics and Dosing

17 H1 ANTAGONISTS SEROTONIN ANTAGONISTS MISCELLANEOUS Dimenhydrinate mg po/pr q4-8h Promethazine 25 mg po/iv q4-6h (Not sq) Meclizine 25 mg po q6-12h Ondansetron 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 mg po/sl q4-12h Nabilone mg po/sl q8-12h Olanzepine mg OD Antiemetics and Dosing

18 Olanzepine Atypical antipsychotic agent Used in schizophrenia, delirium Blocks multiple receptors D 1-4, 5-HT 2/3/6, α 1 adrenergic, H 1, M 1-4 High affinity for serotonin vs dopaminergic Well tolerated Few drug interactions

19 Olanzepine Has 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-HT 3 antagonists Navari et al. Support Care Cancer 2007 Mar 21 Navari et al. Support Care Cancer : Passik et al. Cancer Invest :383-8 Passik et al. JPSM : Srivastava et al. JPSM : Jackson et al. J Pall Med :251-55

20 Cannabinoids & Nausea

21 The Nucleus of the Solitary Tract (NTS) receives information about: Blood-borne emetics via the brainstem (BS) CTZ Abdominal 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-HT 3 and D 2 receptors are implicated Dorsal Vagal ComplexNTS Brainstem Emetic Circuitry Cortex Limbic System Stomach Wall

22 Cannabinoids in CINV 20 pts, RCT, P vs THC, X-over 10 or 15 mg/m 2 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 :

23 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 :16-23

24 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 :16-23

25 Cannabinoid Control (Placebo or Active) Event rate (%) Tramèr MR, et al. BMJ. 2001;323:1-8. Control of N/V with Cannabinoids: Systematic Review vs. Placebovs. Active 70% 57% 59% 43% Nausea active control= prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, alzapride 66% 34% 57% 45% Vomiting vs. Placebo vs. Active

26 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 ( ) 6.4 (4.0-16) 3.3 ( ) 8.0 (4.5-38) Relative risk (95% CI) Favors cannabinoids Tramèr MR, et al. BMJ. 2001;323:1-8

27 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: Relative risk (95% CI) Favors cannabinoids Versus placebo (4 studies) Versus active control (14 studies) 1.6 ( ) 2.8 ( ) Preference for cannabinoids NNT (95% CI)

28 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 :16-23

29 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/m 2 Nausea and vomiting eliminated No psychotropic effects seen Abrahamov et al, Life Sci :2097

30 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

31 Cannabinoids in CINV Several RCTs in chemotherapy-induced emesis (CINV) Pre 5-HT 3 antagonist era (ondansetron) Oral or IM meds vs best treatment No comparison with 5-HT 3 antagonist No controlled trials of inhaled marijuana

32 Inhaled Marijuana Cross-over CINV study, placebo control, marijuana vs dronabinol n= 20 (15 men), 14 NSCLC 25% no vomiting, 15% no nausea 35% hallucinations or time perception changes Preference: 20% marijuana, 35% dronabinol, 45% no pref THC > marijuana therapeutic potency Levitt et al, JCO 1984 abstract C-354

33 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

34 Special Situations Constipation Obstruction

35 Symptom Prevalence Pain Fatigue/Asthenia Constipation Dyspnea Nausea Vomiting Delirium Depression/suffering 80 – 90+% % 70% 60+% % 30% % %

36 Malignancy Direct effects obstruction by tumor in wall external compression by tumor neural damage L/S spinal cord cauda equina/pelvic plexus hypercalcemia

37 Malignancy Secondary effects poor po intake dehydration weakness/inactivity confusion depression unfamiliar toilet arrangements

38 Medications Opioids Ileocecal & anal sphincter tone Peristaltic activity (SI & C) Impaired defecation reflex sensitivity to distension internal anal sphincter tone Water, electrolyte absorption (SI & C)

39 Concurrent Disease Diabetes Hypothyroidism Hypokalemia Hernia Anal fissure/stenosis Hemorrhoids Autonomic neuropathy diabetes spinal cord disease chemotherapy Parkinsons disease ALS/MS Dementia

40 Treatment Prophylaxis good symptom control activity adequate hydration recognize drug effect create a favorable environment

41 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

42 Surfactants: docusate Contact cathartics: senna, bisacodyl Osmotic laxatives: lactulose Saline osmotics: MgOH, Phosphasoda Enemas: oil, saline, soap suds, Fleet Treatment: Laxatives

43 Other Approaches Prokinetic agents: domperidone, metoclopramide Antibiotics: erythromycin Herbal preparations: mulberry, rhubarb, licorice, prune juice

44 New Agents Selective opioid antagonists Active in periphery, esp. gut Methylnaltrexone, Alvimopan Studies used IV and oral application S/E abd cramping, flatulence, nausea, dizziness


46 Common problem Associated with advanced cancers GI, ovarian, lymphoma Relapse / local spread of intrabdominal tumour Diffuse peritoneal carcinomatosis, encasement by tumour Multiple 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

47 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

48 Bowel Obstruction Standard Therapy NG tube/IV fluids (drip & suck) Bowel rest Pain control (opioids) Radiological assessment Surgical intervention

49 Bowel Obstruction Palliative Therapy Opioid analgesics, dexamethasone Promotility agents metoclopramide/domperidone Octreotide (Sandostatin ) Hyoscine butylbromide (Buscopan )

50 Somatostatin Analogues Octreotide, vapreotide, lanreotide Receptor activity brain, pituitary, pancreas, GI tract, immune cells Used in many conditions Prolongs GI transit time fluid secretion in jejunum water/electrolyte absorption decreases peristasis reduces GI blood flow Inhibits exocrine pancreatic secretion

51 Bowel Obstruction in Ovarian Cancer 13 pts, advanced ovarian cancer, inoperable GI obstruction Octreotide dose of µg/day Octreotide controlled vomiting in all cases Vomiting stopped in 2-3 days of starting tx Mangili et al., Gynecologic Oncology 1996

52 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

53 Delivery Routes for Medications Standard Oral Intravenous Inhalation (nebulized) Subcutaneous Alternative Sublingual transmucosal mouthwashes Intranasal Transdermal (topical) Rectal Vaginal Intraosseus GH

54 Think Outside the Box

55 Alternative Routes of Drug Administration Alternative delivery routes transmucosal transdermal (topical) rectal Review of the science

56 Oral Mucosal Delivery Advantages: 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.

57 Oral Mucosal Delivery Barriers: 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

58 Oral Mucosal Delivery Lorazepam Olanzapine wafers (Zyprexa Zydis ® ) Proclorperazine buccal tabs (Stemetil ® ) Mirtazapine (Remeron ® RD) Oral transmucosal drugs Highly lipophilic better than oral absorption??

59 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

60 Topical Route Oral route not desirable Mucositis Inability to swallow Nausea/vomiting Obstruction Poor taste of product Dry mouth More localized action

61 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:

62 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: Topical Route: Advantages

63 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: Topical Route: Drawbacks

64 Topical Route Mouthwash/rinses Misoprostol, Diphenhydramine, Lidocaine, Triamcinolone, Sucralfate, Dry Mouth Formulations Transdermal Route Fentanyl, Oxybutinin, Estrogen, Nitrate patches Transdermal gels Buccal spray Morphine, Fentanyl, Triamcinolone, Lidocaine Medicated lollipops Fentanyl, Nicotine, Tetracaine, Dextromethorphan, Diphenyhydramine, Nystatin

65 Topical Anti-Nauseant Gels Scopolamine 0.25mg/0.1ml Transderm V patch releases ~1mg over 72 hr ~0.1mg Q8H vs 0.25mg Apply 0.1 – 0.2ml Q8H Expiry date about 6 months

66 Topical Anti-Nauseant Gels ABHR A tivan/ B enadryl/ H aldol/ R eglan Lorazepam 2- 4 mg higher brain (cortex) Diphenhydramine mg vestibular Haloperidol 2-4 mg CTZ Metoclopramide mg/ml afferent impulses from periphery Dose 0.25ml inner wrist QID Moon RB Intl J Pharm Compound :95-8


68 Haloperidol mg po/sq/iv q4-12h MTMZ mg po/sl/sq q4-8h Metoclopramide mg po/sq/pr q4-8h Ondansetron 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 mg po/pr/sq q4-8h Scopolamine mg sq Promethazine (Not sq) Subcut Antiemetics

69 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

70 Case: Maria de J. 4 th 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

71 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

72 Rectal Route Drug absorption Limiting factors Conditions/methods of administration Care Beyond Cure: A Pharmacotherapeutic Guide to Palliative Care; Andree Neron Editor, 2000

73 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

74 Rectum vs upper GI tract: Absorption area rectal mucosa: cm² (no villi in rectum ) small intestine: 2,000,000 cm² pH Fluid content Absorption mechanisms same (passive diffusion) Formulation of drug is critical factor May have to increase dosage interval i.e. Q8H vs Q12H Rectal Drug Absorption Care Beyond Cure, 2000

75 Rectal Limiting Factors Drug insertion level 6-8cm (lower rectum) systemic circulation 15-20cm (upper rectum) portal vein hepatic first-pass effect Solutions: Aqueous & alcohol solutions are the best and most rapidly absorbed Fecal matter in rectum Defecation reflex, involuntary expulsion Care Beyond Cure, 2000

76 Rectal Administration Use liquid formulations whenever possible Use volumes <10-25 ml >80 ml risk of spontaneous expulsion Administer liquids with a small lubricated syringe Rectal canula or catheter tip syringes beneficial Cut a NG tube (#14) to 5 cm; attach to prefilled syringe reduces chance of portal vein absorption Care Beyond Cure, 2000

77 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

78 Lorazepam Use parenteral preps or tablets Bioavailability of injection > 80% Serum concentrations < ½ of IV route Metoclopramide Tablets or suspensions Phenobarbital Excellent bioavailability % Peaks at ~ 4 hours Baines, MJ BMJ 1997;315: Rectal Administration

79 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

80 Triple Suppository Metoclopramide mg Dimenhydrinate mg Prochloperazine mg Use a formulation with a single medication or combinations of up to 3 medications

81 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

82 Summary GI symptoms in palliative care varied Assessment important Tailor therapy to meet pt needs Research in area lacking Help is available WRHA Pall Care pgm: Physician on call: (24 hrs)

83 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 ® )

84 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

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