Taking a gander at Leap forward Sickness/Spewing and Tumor Related Torment The Cannabinoid Experience.

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Taking a gander at Leap forward Sickness/Spewing and Growth Related Agony The Cannabinoid Experience Vincent Maida, MD Aide Teacher College of Toronto Division of Palliative Prescription William Osler Wellbeing Center Toronto, Ontario, Canada
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Taking a gander at Breakthrough Nausea/Vomiting and Cancer-Related Pain The Cannabinoid Experience Vincent Maida, MD Assistant Professor University of Toronto Division of Palliative Medicine William Osler Health Center Toronto, Ontario, Canada

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Incidence of Chemotherapy-Induced Nausea and Vomiting (CINV) and Pain in Cancer Patients Approximately 70%–80% of chemotherapy patients experience sickness and retching 1 Patients rank queasiness and heaving as 2 of the most dreaded reactions of malignancy treatment More than seventy five percent of tumor patients experience ceaseless agony over the span of their malady 2 1. More astute W, Berger A. Oncology . 2005;19:637. 2. Portenoy RK. Semin Oncol . 1995;22(suppl 3):112.

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Consequences of Unresolved CINV Adverse sequelae of queasiness and regurgitating in the disease tolerant Serious metabolic disturbances Nutritional consumption and anorexia Esophageal tears Wound dehiscence Deterioration of patients’ physical and mental status Degeneration of self-consideration and utilitarian capacity Discontinuation of treatment NCCN Practice Guidelines in Oncology–Version 1. 2007. Antiemesis, MS-1.

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CINV—Decreased Quality of Life FLIE Questionnaire HEC-FLIE > MEC-FLIE P = .0049 FLIE-sickness > FLIE-Vomiting P = .0097 There is a more prominent negative effect on QOL from queasiness than there is from regurgitating FLIE = Functional Living Index-Emesis; HEC = exceedingly emetogenic chemotherapy; MEC = modestly emetogenic chemotherapy. Bloechl-Daum, B, et al. J Clin Oncol . 2006;24:4472.

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NCCN Practice Guidelines Prechemotherapy Emesis Prevention Highly emetogenic regimens Day 1: aprepitant, dexamethasone, and a 5-HT 3 enemy +/ - lorazepam May be adjusted on days 2–4 Moderately emetogenic regimens Day 1: dexamethasone and a 5-HT 3 opponent +/ - lorazepam (aprepitant included with select respectably emetogenic regimens) Modified on days 2–4 Low emetogenic regimens Dexamethasone, proclorperazine, or metoclopramide +/ - lorazepam NCCN Practice Guidelines in Oncology – Version 1. 2007. Antiemesis, MS-1.

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NCCN Practice Guidelines Postchemotherapy/Delayed Emesis Prevention Highly emetogenic regimens Primary antiemetic regimen proceeded through period when postponed emesis may happen (ie, 2–3 days after chemotherapy cycle) Moderately emetogenic regimens Dependent upon the antiemetic utilized before chemotherapy Palonosetron on day 1 just Aprepitant proceeded on days 2 and 3 +/ - dexamethasone or lorazepam Dexamethasone or a 5-HT 3 adversary +/ - lorazepam NCCN Practice Guidelines in Oncology – Version 1. 2007. Antiemesis, MS-1.

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NCCN Practice Guidelines Breakthrough Treatment Around-the-clock organization, as opposed to PRN dosing, ought to be viewed as Additional operators ought to be from an alternate medication class than starting treatment Possibilities include: dopamine rivals, metoclopramide, butyrophenones, cannabinoids, corticosteroids, or specialists, for example, lorazepam Nabilone (cannabinoid) has as of late been endorsed for sickness/retching in patients who have not reacted to ordinary antiemetics NCCN Practice Guidelines in Oncology – Version 1. 2007. Antiemesis, MS-1.

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Botanical Marijuana Hashish Endogenous Anandamide 2-AG PEA Cannabinoids Pharmaceutical Nabilone Dronabinol Delta-9-THC & cannabidiol

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CB1—neuromodulation Basal ganglia Hippocampus Cerebral cortex Cerebellum Spinal string Afferent nociceptors CB2—immunomodulation Spleen Tonsil Mast cells Macrophages Lymphocytes Microglia Cannabinoid Receptors Kalant H. Torment Res Manag . 2001;6:80.

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Mechanism of Action of the Cannabinoids 5 EXOGENOUS Cannabinoid Therapy Neurotransmitter (NT) from presynaptic neuron enacts the postsynaptic neuron 1 Activated postsynaptic neuron discharges endocannabinoids 2 Presynaptic Neuron Inhibition of Neurotransmitter Release CB1 Receptor 4 Endogenous CB1 ligand diffuses back to and ties to the presynaptic CB1 receptor 3 1 Postsynaptic Neuron Endogenous Cannabinoid Retrograde Signaling CB1 receptor initiates a G-protein, prompting restraint of NT discharge 4 3 2 Neurotransmitter Receptor Nabilone is thought to actuate CB1 receptors specifically, imitating the impacts of endocannabinoids 5 Endogenous and Exogenous Cannabinoids Reduce Neuronal Signaling Adapted from Page 5 of Slatkin NE. J Support Oncol . 2007;5(suppl3):1. Reproduced with consent.

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Cannabinoids—Supportive Oncology Established parts CINV Emerging parts Analgesia Spasmolysis Anorexia-cachexia Sedative Antidepressant Antineoplastic

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Causes of Nausea and Vomiting in Cancer Patients Gastric stasis Drugs Opioids Chemotherapy Biochemical Hypercalcemia Uremia Raised intracranial weight Intestinal check Pain Twycross R. Palliative Care. 3 rd ed, Radcliffe Medical Press. Oxford:1999:114.

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Diverse Neurotransmitters Mediate Emesis Dopamine (D 2 ) Serotonin (5-HT 3 ) Histamine Substance P (NK-1) Endorphins N + V REFLEX GABA Acetylcholine Cannabinoids Drug classes FDA affirmed in CINV Adapted from Andrews PL, Naylor RJ, Joss RA. Strong Care Cancer . 1998;6:197-203.

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Delayed CINV Is More Prevalent Than Acute CINV Delayed emesis is 2.5 times more pervasive than intense emesis For modestly emetogenic chemotherapy Delayed sickness surpasses intense queasiness by 16% Delayed emesis surpasses intense emesis by 15% For profoundly emetogenic chemotherapy Delayed sickness surpasses intense queasiness by 27% Delayed emesis surpasses intense emesis by 38% Grunberg SM, et al. Malignancy . 2004;100:2261.

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5-HT 3 Antagonists Are Ineffective for Controlling Delayed CINV in a Substantial Proportion of Patients 360 patients at 18 private therapeutic oncology gatherings were enlisted in the study 322 finished prerequisites for chemotherapy cycle 1 Antiemetic regimen Day 1 30-min prechemotherapy: ondansetron (24 mg PO or 20 mg IV) + dexamethasone (12 mg PO or 10 mg IV) Remaining days of chemotherapy: regimen that involved standard consideration at every practice site Mild queasiness Moderate sickness Severe queasiness 41 Emesis 38 40 34 35 30 25 24 25 23 21 Patients with Delayed Nausea/Vomiting (%) 19 20 17 15 10 5 0 Carboplatin Cisplatin Doxorubicin Hickok JT, et al. Disease . 2003;97:2880.

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Palonosetron Improves Outcomes, Yet CINV Persists in Most Patients 100 90 80 66 70 58 60 % of Patients Who Failed to Achieve Endpoint (Days 1–5) 49 50 40 30 20 10 0 No Emetic Episode No Rescue Medication No Nausea* Endpoint *Moderate or serious Brames MJ, et al. Exhibited at the MASCC/ISOO eighteenth International Symposium; June 22-24, 2006: Toronto, Canada. Republished with authorization.

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Aprepitant Improves Outcomes, Yet CINV Persists in Most Patients 70 Aprepitant Standard treatment 59 56 60 50 44* 39* 40 35 % of Patients in Whom CINV Persisted 30 20* 20 10 0 Acute CINV Delayed CINV Overall * P >.001 contrasted and standard treatment. Poli-Bigelli S, et al. Disease . 2003;97:3090.

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Anticipatory Nausea and Vomiting Anticipatory queasiness happens in 29% of chemotherapy patients 1,2 Anticipatory spewing happens in 11% of chemotherapy patients 1,2 Anticipatory sickness and retching Mostly on the premise of exemplary or Pavlovian molding 3 1. Roscoe JA, et al. J Pain Symptom Manage. 2000;20:113. 2. Morrow GR, et al. Bolster Care Cancer. 1998;6:244. 3. Reesal RT, et al. Can J Psychiatr . 1990;35:80.

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Cannabinoids for the Treatment of CINV—Distinct Therapeutic Mechanism Combining specialists with distinctive instruments of activity (MOAs) may be the ideal way to deal with administration of CINV 1 Cannabinoids have a MOA not the same as ordinary antiemetics (eg, 5-HT 3 or D 2 receptor adversaries) 1-3 The antiemetic impact of cannabinoids may be because of association with the cannabinoid receptor framework (ie, CB1 receptors found in neural tissues) 4 1. National Cancer Institute. Accessible at: http://www.meds.com/pdq/supportive_pro.html. Gotten to June 13, 2007. 2. Tramer MR, et al. BMJ . 2001;323:16. 3. NCCN Practice Guidelines in Oncology. 2005;1. Antiemesis. 4. Cesamet TM (nabilone). Item Information. San Diego, CA: Valeant Pharmaceuticals North America; 2006.

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Control of Nausea and Vomiting Cannabinoids—A Systematic Review* 80 Control (placebo or dynamic) 70 Cannabinoid 66 59 57 60 45 43 Event Rate (%) 40 36 20 0 vs Placebo vs Active versus Placebo vs Active Vomiting Nausea *21 randomized, near investigations of cannabinoids with placebo or different antiemetics (oral nabilone, oral dronabinol, intramuscular levonatrodol.) Active control = prochlorperazine, metoclopramide, chlorpromazine, haloperidol, domperidone, and alizapride. Tramer MR, et al. BMJ . 2001;323:16.

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Patients’ Rating Preference for Cannabinoids Preference for cannabinoids versus placebo (4 thinks about) versus dynamic control (14 studies) 0.5 1.0 2.0 4.0 6.0 8.0 10.0 Relative danger (95% CI) Favors cannabinoids Active control = prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, and alizapride. Tramã¨r MR, et al. BMJ . 2001;323:16.

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Etiology of Pain in Breast Cancer Patients Iatrogenic Postmastectomy disorder Chemotherapy-actuated fringe neuropathy Taxanes >> vinorelbine > capecitabine Bone metastases Neuropathic Malignant plexopathy Malignant radiculopathy MSCC

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Cannabinoids—Cancer Pain European stage III investigation of a cannabidiol/THC buccal shower 1 N = 177 Opioid nonresponsive agony Cannabidiol/THC splash altogether lessened torment contrasted and placebo ( P = .014) 43% of patients indicated >30% change in torment ( P = .024) 1 http://www.dpna.org/1sativex.htm

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Cannabinoids in the Treatment of Other Pain Chronic, debilitating back torment 1 Decrease in

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