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Vincent Maida, MD Assistant Professor University of Toronto Division of Palliative Medicine William Osler Health Centre Toronto, Ontario, Canada Looking.

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Presentation on theme: "Vincent Maida, MD Assistant Professor University of Toronto Division of Palliative Medicine William Osler Health Centre Toronto, Ontario, Canada Looking."— Presentation transcript:

1 Vincent Maida, MD Assistant Professor University of Toronto Division of Palliative Medicine William Osler Health Centre Toronto, Ontario, Canada Looking at Breakthrough Nausea/Vomiting and Cancer-Related Pain The Cannabinoid Experience

2 1. Wiser W, Berger A. Oncology. 2005;19: Portenoy RK. Semin Oncol. 1995;22(suppl 3):112. Incidence of Chemotherapy-Induced Nausea and Vomiting (CINV) and Pain in Cancer Patients Approximately 70%–80% of chemotherapy patients experience nausea and vomiting 1 Approximately 70%–80% of chemotherapy patients experience nausea and vomiting 1 Patients rank nausea and vomiting as 2 of the most feared side effects of cancer treatment Patients rank nausea and vomiting as 2 of the most feared side effects of cancer treatment More than three quarters of cancer patients experience chronic pain during the course of their disease 2 More than three quarters of cancer patients experience chronic pain during the course of their disease 2

3 NCCN Practice Guidelines in Oncology–Version Antiemesis, MS-1. Consequences of Unresolved CINV Serious metabolic derangements Serious metabolic derangements Nutritional depletion and anorexia Nutritional depletion and anorexia Esophageal tears Esophageal tears Wound dehiscence Wound dehiscence Deterioration of patients’ physical and mental status Deterioration of patients’ physical and mental status Degeneration of self-care and functional ability Degeneration of self-care and functional ability Discontinuation of therapy Discontinuation of therapy Adverse sequelae of nausea and vomiting in the cancer patient

4 FLIE = Functional Living Index-Emesis; HEC = highly emetogenic chemotherapy; MEC = moderately emetogenic chemotherapy. Bloechl-Daum, B, et al. J Clin Oncol. 2006;24:4472. CINV—Decreased Quality of Life CINV—Decreased Quality of Life FLIE Questionnaire FLIE Questionnaire HEC-FLIE > MEC-FLIE P =.0049 HEC-FLIE > MEC-FLIE P =.0049 FLIE-nausea > FLIE-Vomiting P =.0097 FLIE-nausea > FLIE-Vomiting P =.0097 There is a greater negative impact on QOL from nausea than there is from vomiting There is a greater negative impact on QOL from nausea than there is from vomiting

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

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

7 NCCN Practice Guidelines in Oncology – Version Antiemesis, MS-1. NCCN Practice Guidelines Breakthrough Treatment Around-the-clock administration, rather than PRN dosing, should be considered Around-the-clock administration, rather than PRN dosing, should be considered Additional agents should be from a different drug class than initial therapy Additional agents should be from a different drug class than initial therapy –Possibilities include: dopamine antagonists, metoclopramide, butyrophenones, cannabinoids, corticosteroids, or agents such as lorazepam Nabilone (cannabinoid) has recently been approved for nausea/vomiting in patients who have not responded to conventional antiemetics Nabilone (cannabinoid) has recently been approved for nausea/vomiting in patients who have not responded to conventional antiemetics

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

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

10 Mechanism of Action of the Cannabinoids Neurotransmitter (NT) from presynaptic neuron activates the postsynaptic neuron Endogenous and Exogenous Cannabinoids Reduce Neuronal Signaling Postsynaptic Neuron Neurotransmitter Receptor Endogenous Cannabinoid Retrograde Signaling CB1 Receptor Presynaptic Neuron Inhibition of Neurotransmitter Release EXOGENOUS Cannabinoid Therapy Activated postsynaptic neuron releases endocannabinoids Endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor CB1 receptor activates a G-protein, leading to inhibition of NT release Nabilone is thought to activate CB1 receptors directly, mimicking the effects of endocannabinoids Adapted from Page 5 of Slatkin NE. J Support Oncol. 2007;5(suppl3):1. Reprinted with permission.

11 Cannabinoids—Supportive Oncology Established roles Established roles –CINV Emerging roles Emerging roles –Analgesia –Spasmolysis –Anorexia-cachexia –Sedative –Antidepressant –Antineoplastic

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

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

14 Grunberg SM, et al. Cancer. 2004;100:2261. Delayed CINV Is More Prevalent Than Acute CINV Delayed emesis is 2.5 times more prevalent than acute emesis Delayed emesis is 2.5 times more prevalent than acute emesis For moderately emetogenic chemotherapy For moderately emetogenic chemotherapy –Delayed nausea exceeds acute nausea by 16% –Delayed emesis exceeds acute emesis by 15% For highly emetogenic chemotherapy For highly emetogenic chemotherapy –Delayed nausea exceeds acute nausea by 27% –Delayed emesis exceeds acute emesis by 38%

15 Patients with Delayed Nausea/Vomiting (%) 5-HT 3 Antagonists Are Ineffective for Controlling Delayed CINV in a Substantial Proportion of Patients CarboplatinCisplatinDoxorubicin 360 patients at 18 private medical oncology groups were enrolled in the study –322 completed requirements 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 comprised standard care at each practice site Hickok JT, et al. Cancer. 2003;97:2880. Emesis Moderate nausea Severe nausea Mild nausea

16 Palonosetron Improves Outcomes, Yet CINV Persists in Most Patients No Emetic EpisodeNo Rescue MedicationNo Nausea* Endpoint % of Patients Who Failed to Achieve Endpoint (Days 1–5) *Moderate or severe Brames MJ, et al. Presented at the MASCC/ISOO 18th International Symposium; June 22-24, 2006: Toronto, Canada. Reprinted with permission.

17 20* 39* 44* Acute CINVDelayed CINVOverall % of Patients in Whom CINV Persisted Aprepitant Standard therapy *P >.001 compared with standard therapy. Poli-Bigelli S, et al. Cancer. 2003;97:3090. Aprepitant Improves Outcomes, Yet CINV Persists in Most Patients Aprepitant Improves Outcomes, Yet CINV Persists in Most Patients

18 1. Roscoe JA, et al. J Pain Symptom Manage. 2000;20: Morrow GR, et al. Support Care Cancer. 1998;6: Reesal RT, et al. Can J Psychiatr. 1990;35:80. Anticipatory Nausea and Vomiting Anticipatory nausea occurs in 29% of chemotherapy patients 1,2 Anticipatory nausea occurs in 29% of chemotherapy patients 1,2 Anticipatory vomiting occurs in 11% of chemotherapy patients 1,2 Anticipatory vomiting occurs in 11% of chemotherapy patients 1,2 Anticipatory nausea and vomiting Anticipatory nausea and vomiting –Mostly on the basis of classic or Pavlovian conditioning 3

19 1. National Cancer Institute. Available at: Accessed June 13, Tramer MR, et al. BMJ. 2001;323: NCCN Practice Guidelines in Oncology. 2005;1. Antiemesis. 4. Cesamet TM (nabilone). Product Information. San Diego, CA: Valeant Pharmaceuticals North America; Cannabinoids for the Treatment of CINV—Distinct Therapeutic Mechanism Combining agents with different mechanisms of action (MOAs) may be the optimal approach to management of CINV 1 Combining agents with different mechanisms of action (MOAs) may be the optimal approach to management of CINV 1 Cannabinoids have an MOA different from conventional antiemetics (eg, 5-HT 3 or D 2 receptor antagonists) 1-3 Cannabinoids have an MOA different from conventional antiemetics (eg, 5-HT 3 or D 2 receptor antagonists) 1-3 The antiemetic effect of cannabinoids may be due to interaction with the cannabinoid receptor system (ie, CB1 receptors found in neural tissues) 4 The antiemetic effect of cannabinoids may be due to interaction with the cannabinoid receptor system (ie, CB1 receptors found in neural tissues) 4

20 Active control = prochlorperazine, metoclopramide, chlorpromazine, haloperidol, domperidone, and alizapride. Tramer MR, et al. BMJ. 2001;323:16. *21 randomized, comparative studies of cannabinoids with placebo or other antiemetics (oral nabilone, oral dronabinol, intramuscular levonatrodol.) Cannabinoid Control (placebo or active) Event Rate (%) vs Placebovs Active vs Placebo vs Active Nausea Vomiting Control of Nausea and Vomiting Cannabinoids—A Systematic Review*

21 Relative risk (95% CI) Favors cannabinoids vs placebo (4 studies) vs active control (14 studies) Preference for cannabinoids Active control = prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, and alizapride. Tramèr MR, et al. BMJ. 2001;323:16. Patients’ Rating Preference for Cannabinoids

22 Etiology of Pain in Breast Cancer Patients Iatrogenic Iatrogenic –Postmastectomy syndrome –Chemotherapy-induced peripheral neuropathy Taxanes >> vinorelbine > capecitabine Taxanes >> vinorelbine > capecitabine Bone metastases Bone metastases Neuropathic Neuropathic –Malignant plexopathy –Malignant radiculopathy –MSCC

23 Cannabinoids—Cancer Pain European phase III study of a cannabidiol/THC buccal spray 1 European phase III study of a cannabidiol/THC buccal spray 1 N = 177 N = 177 Opioid nonresponsive pain Opioid nonresponsive pain Cannabidiol/THC spray significantly reduced pain compared with placebo (P =.014) Cannabidiol/THC spray significantly reduced pain compared with placebo (P =.014) 43% of patients showed >30% improvement in pain (P =.024) 43% of patients showed >30% improvement in pain (P =.024) 1

24 1. Pinsger M, et al. Wien Klin Wochenschr. 2006;118: Iskedjian M, et al. Curr Med Res Opin. 2007;23: Wissel J, et al. J Neurol. 2006;253:1337. Cannabinoids in the Treatment of Other Pain Chronic, incapacitating back pain 1 Chronic, incapacitating back pain 1 –Decrease in spinal pain intensity and headache with nabilone Multiple Sclerosis (MS) neuropathic pain 2 Multiple Sclerosis (MS) neuropathic pain 2 –Cannabinoids (cannabidiol/THC buccal spray, cannabidiol, and dronabinol) were significantly superior to placebo in treating neuropathic pain in MS MS spasticity-related pain 3 MS spasticity-related pain 3 –Nabilone resulted in a significant decrease in spasticity- related pain

25 Cesamet ® (nabilone). Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; Marinol ® (dronabinol). Product Information. Marietta, GA: Unimed Pharmaceuticals, Inc; R x Cannabinoids—Pharmacokinetics NabiloneDronabinol Oral dosing 1–2 mg 1–3 h before chemotherapy, and BID for up to 48 h afterwards 5 mg/m 2 1–3 h before chemotherapy, and every 2–4 h afterwards for a total of 4–6 doses/d SourceSynthetic ∆ 9 -THC analogSynthetic ∆ 9 -THC FormulationCrystalline powder capsule Capsule formulated with sesame oil, among other ingredients (contraindicated in patients with a hypersensitivity to sesame oil) Onset of action60–90 min30–60 min Peak plasma concentrations (T max ) 2 h2–4 h Duration of action8–12 h4–6 h for psychoactive effects Metabolites2 active metabolites 2 active metabolites and >20 other metabolites ClearanceMajor excretory pathway is the biliary system Biliary excretion is major route of elimination

26 CYP450 Metabolizing Enzymes CYP450 Enzyme Inhibition CYP450 Enzyme Induction Nabilone2C9*, 3A4 (aldehyde oxygenase) None to date Dronabinol2C9*, 2C11, 3A4 (aldehyde oxygenase) 3A4None to date Nahas GG, et al, eds. Marihuana and Medicine. Totowa, NJ: Humana Press; 1999: Metabolized principally through the CYP450 2C9 isoenzyme Metabolized principally through the CYP450 2C9 isoenzyme No inhibitory or inducing effect on any of the isoenzymes No inhibitory or inducing effect on any of the isoenzymes Competes with very few medications at the metabolic level, including opioids Competes with very few medications at the metabolic level, including opioids Examples of medications metabolized by CYP3A4: antifungals, methadone, many antidepressants, HIV protease inhibitors Examples of medications metabolized by CYP3A4: antifungals, methadone, many antidepressants, HIV protease inhibitors *Main metabolizing isoenzyme Cannabinoid Metabolism

27 Aprepitant Metabolism Oral aprepitant 40 mgWeak— 125 mgModerateWeak *Midazolam Majumdar AK, et al. J Clin Pharmacol. 2007;47:744. Inhibitory Effect on Orally Administered CYP3A4 Substrate* Inhibitory Effect on IV Administered CYP3A4 Substrate*

28 Symptom/EffectMost CommonCommonRare CNS Sedation Somnolence Dizziness Euphoria/“high” Blurred vision Anxiety; panic Paranoia Psychosis Depression Ataxia Asthenia Cognitive effects Cardiovascular Postural hypotension Vasodilatation (red eyes) Tachycardia Palpitations Others Dry mouth Headache 4 4 Clark AJ. Pain Res Manage. 2005;10(suppl A):44A. *If smoked, respiratory effects, such as bronchitis, chronic obstructive pulmonary disease, lung infection. Side Effects of Cannabinoids*

29 Summary Emesis is mediated by a variety of neurotransmitters; thus, full control may require the blocking of multiple brain receptor sites Emesis is mediated by a variety of neurotransmitters; thus, full control may require the blocking of multiple brain receptor sites Current antiemetic agents provide inadequate relief in a substantial number of cancer patients Current antiemetic agents provide inadequate relief in a substantial number of cancer patients The mechanism of action of cannabinoids differs from that of conventional antiemetics, making it an appropriate candidate for combination with traditional agents The mechanism of action of cannabinoids differs from that of conventional antiemetics, making it an appropriate candidate for combination with traditional agents Cannabinoids have proven to be effective antiemetic adjuvants in patients with uncontrolled nausea/vomiting and can provide additional relief in patients with severe pain Cannabinoids have proven to be effective antiemetic adjuvants in patients with uncontrolled nausea/vomiting and can provide additional relief in patients with severe pain Cannabinoids have demonstrated long-term efficacy and safety Cannabinoids have demonstrated long-term efficacy and safety

30 Case Study: Breakthrough CINV with Anthracycline-Based Therapy William J. Gradishar, MD, FACP Director, Breast Medical Oncology Northwestern University Feinberg School of Medicine Robert H. Lurie Comprehensive Cancer Center Chicago, Illinois

31 Ms. J A 44-year-old female presents with a right breast lump, which on physical examination measures ~ 1 cm A 44-year-old female presents with a right breast lump, which on physical examination measures ~ 1 cm A mammogram reveals a suspicious- appearing lesion measuring ~ 1.5 cm in the same area noted on physical exam A mammogram reveals a suspicious- appearing lesion measuring ~ 1.5 cm in the same area noted on physical exam

32 Infiltrating Ductal Carcinoma ER, PR, and HER2 (-) The patient undergoes lumpectomy and sentinel lymph node biopsy, which confirms the presence of a 1.4 cm infiltrating ductal carcinoma that is ER, PR, and HER2 negative

33 Sentinel Lymph Node Negative for Tumor The sentinel lymph node was negative for tumor The sentinel lymph node was negative for tumor The patient is referred to a medical oncologist for consideration of postoperative systemic adjuvant therapy The patient is referred to a medical oncologist for consideration of postoperative systemic adjuvant therapy Additional planned breast irradiation Additional planned breast irradiation

34 Medical Oncologist Assessment The assessment of the medical oncologist is that the patient will benefit from adjuvant chemotherapy, and recommends 4 cycles of doxorubicin 60 mg/m 2 and cyclophosphamide 600 mg/m 2 (AC)

35 Discussion with Oncologist Risk reduction might be expected with this regimen Risk reduction might be expected with this regimen Expected toxicities Expected toxicities –Neutropenia, alopecia, cardiac toxicity, mouth sores, fatigue, and nausea and vomiting

36 Reassurance and Management The medical oncologist assures the patient that these symptoms can be prevented or successfully managed should they develop.

37 AC Regimen and CINV The doxorubicin/cyclophosphamide (AC) regimen is one of the most commonly recommended regimens for adjuvant therapy of breast cancer, either as a “stand alone” treatment or to be used in conjunction with a taxane (concurrently or sequentially) The doxorubicin/cyclophosphamide (AC) regimen is one of the most commonly recommended regimens for adjuvant therapy of breast cancer, either as a “stand alone” treatment or to be used in conjunction with a taxane (concurrently or sequentially) Although medical oncologists believe that AC chemotherapy is generally well tolerated by most women, the AC regimen actually falls into the “moderate risk” category (30%–90%) of chemotherapy regimens as it relates to the risk of emesis Although medical oncologists believe that AC chemotherapy is generally well tolerated by most women, the AC regimen actually falls into the “moderate risk” category (30%–90%) of chemotherapy regimens as it relates to the risk of emesis

38 AC Regimen and CINV When patients are carefully questioned regarding symptom control after receiving a chemotherapy regimen such as AC along with standard antiemetics, many (up to 70%) will indicate that emesis is controlled on day 1 after chemotherapy When patients are carefully questioned regarding symptom control after receiving a chemotherapy regimen such as AC along with standard antiemetics, many (up to 70%) will indicate that emesis is controlled on day 1 after chemotherapy Only a fraction of patients with well- controlled emesis can decrease to 50% on days 2 and 3 following chemotherapy Only a fraction of patients with well- controlled emesis can decrease to 50% on days 2 and 3 following chemotherapy Hesketh PJ, et al. J Clin Oncol. 2003;21:4112. Poli-Bigelli S, et al. Cancer. 2003;97:3090. Warr DG. J Clin Oncol. 2004;22(suppl): abstr 8007.

39 Delayed Symptoms Some patients experience delayed symptoms (24 hours or more after chemotherapy), and the risk of nausea and vomiting increases during multiple cycles of therapy

40 Schwartzberg L. J Support Oncol. 2006;4(suppl 1):3. Perception vs Reality in Patients Receiving Moderately or Highly Emetogenic Chemotherapy Acute Nausea Acute Vomiting Delayed Nausea Delayed Vomiting Patients (%) MD/RN prediction Patient experience Acute Nausea Acute Vomiting Delayed Nausea Delayed Vomiting MD/RN prediction Patient experience Moderately Emetogenic Chemotherapy Highly Emetogenic Chemotherapy

41 Cisplatin group (N = 438): all received cisplatin >70 mg/m 2. Anthracycline/cyclophosphamide group (N = 424): 99% received AC. Hesketh PJ, et al. J Clin Oncol. 2003;21:4112. Poli-Bigelli S, et al. Cancer. 2003;97:3090. Warr DG. J Clin Oncol. 2004;22(suppl): abstr AC Cisplatin All patients received dexamethasone and ondansetron AC = doxorubicine/cyclophosphamide. Prevention of Emesis in Women on Day 1 After Chemotherapy Results with Standard Therapy in Randomized Trials Patients (%)

42 49 47 On Days 2 and 3: Cisplatin patients given dexamethasone 8 mg bid AC patients given ondansetron 8 mg bid Prevention of Emesis in Women on Days 2 and 3 Results with Standard Therapy in Randomized Trials Cisplatin group (N = 438): all received cisplatin >70 mg/m 2. Anthracycline/cyclophosphamide group (N = 424): 99% received AC. Hesketh PJ, et al. J Clin Oncol. 2003;21:4112. Poli-Bigelli S, et al. Cancer. 2003;97:3090. Warr DG. J Clin Oncol. 2004;22(suppl): abstr AC = doxorubicine/cyclophosphamide. AC Cisplatin Patients (%)

43 Breakthrough CINV In this 44-year-old woman with breast cancer receiving AC adjuvant therapy, breakthrough nausea/vomiting developed despite antiemetic prophylaxis given according to the NCCN guidelines

44 Options for Breakthrough CINV Additional agents should be from a different drug class than initial therapy Additional agents should be from a different drug class than initial therapy Possible options include dopamine antagonists, metoclopramide, butyrophenones, cannabinoids, corticosteroids, or agents such as lorazepam Possible options include dopamine antagonists, metoclopramide, butyrophenones, cannabinoids, corticosteroids, or agents such as lorazepam NCCN Practice Guidelines in Oncology – Version Antiemesis, MS-1.

45 Additional Treatment Options for breakthrough treatment were discussed with the patient Options for breakthrough treatment were discussed with the patient Dexamethasone + lorazepam were added to her antiemetic regimen Dexamethasone + lorazepam were added to her antiemetic regimen

46 Take-Home Messages Many patients receive adjuvant chemotherapy, particularly those with small node negative breast cancers, for an acknowledged small potential benefit (reduction in risk of recurrence) Many patients receive adjuvant chemotherapy, particularly those with small node negative breast cancers, for an acknowledged small potential benefit (reduction in risk of recurrence) It is incumbent upon oncologists to deliver adjuvant chemotherapy with as few side effects as possible It is incumbent upon oncologists to deliver adjuvant chemotherapy with as few side effects as possible A substantial portion of patients receiving common regimens such as AC experience CINV despite recommended emetic therapy A substantial portion of patients receiving common regimens such as AC experience CINV despite recommended emetic therapy There are a variety of options available for the treatment of breakthrough CINV, these include dopamine antagonists, metoclopramide, butyrophenones, cannabinoids, corticosteroids, or agents such as lorazepam There are a variety of options available for the treatment of breakthrough CINV, these include dopamine antagonists, metoclopramide, butyrophenones, cannabinoids, corticosteroids, or agents such as lorazepam

47 Case Study: Anticipatory CINV and Opioid-Refractory Pain Judith A. Luce, MD Clinical Professor of Medicine, University of California, San Francisco Director, Oncology Services San Francisco General Hospital San Francisco, California

48 Ms. F Ms. F is a 50-year-old Honduran woman who was diagnosed with stage II breast cancer 3 years ago Ms. F is a 50-year-old Honduran woman who was diagnosed with stage II breast cancer 3 years ago She had been treated with mastectomy, chest wall radiation therapy, 6 cycles of FEC-75 chemotherapy, and tamoxifen She had been treated with mastectomy, chest wall radiation therapy, 6 cycles of FEC-75 chemotherapy, and tamoxifen She came to our hospital with an enlarging mass in her sternum and severe pain She came to our hospital with an enlarging mass in her sternum and severe pain

49 Ms. F Incisional biopsy was performed because of a lack of information from Honduras—the mass was metastatic triple-negative breast cancer Incisional biopsy was performed because of a lack of information from Honduras—the mass was metastatic triple-negative breast cancer Staging revealed 2 other osseous metastases, right neck nodes, and no visceral disease Staging revealed 2 other osseous metastases, right neck nodes, and no visceral disease Radiation therapy to the sternal mass was delivered, ultimately helping to reduce pain Radiation therapy to the sternal mass was delivered, ultimately helping to reduce pain Patient was started on short-acting opioids and nonsteroidal anti-inflammatory drug (NSAID) orally, but said the NSAID irritated her stomach Patient was started on short-acting opioids and nonsteroidal anti-inflammatory drug (NSAID) orally, but said the NSAID irritated her stomach

50 Ms. F Ms. F returns to clinic having lost 2 kilograms, complaining of insomnia, anorexia, terrible pain, nausea, and fatigue. She is tearful and depressed. She spends most of her time on the sofa or in bed Ms. F returns to clinic having lost 2 kilograms, complaining of insomnia, anorexia, terrible pain, nausea, and fatigue. She is tearful and depressed. She spends most of her time on the sofa or in bed Opioids are increased, long-acting opioid prescribed, and sertralene and prochlorperazine given Opioids are increased, long-acting opioid prescribed, and sertralene and prochlorperazine given Chemotherapy with weekly paclitaxel and bevacizumab is begun Chemotherapy with weekly paclitaxel and bevacizumab is begun

51 Ms. F The patient is much worse at her next visit. She has had nearly continuous nausea and vomiting on weekly chemotherapy, still has poorly controlled pain, anorexia, and insomnia. She says she had bad nausea after her original chemotherapy also. She complains about “all the pills” but does say that the radiation has helped her pain a lot. Now another bone hurts The patient is much worse at her next visit. She has had nearly continuous nausea and vomiting on weekly chemotherapy, still has poorly controlled pain, anorexia, and insomnia. She says she had bad nausea after her original chemotherapy also. She complains about “all the pills” but does say that the radiation has helped her pain a lot. Now another bone hurts She is given increased opioids, lorazepam, granisetron, and the chemotherapy is switched to every 21 days She is given increased opioids, lorazepam, granisetron, and the chemotherapy is switched to every 21 days

52 Ms. F Ms. F continues to have chemotherapy- induced nausea and vomiting for about a week after chemotherapy Ms. F continues to have chemotherapy- induced nausea and vomiting for about a week after chemotherapy She now notes that taking the short-acting opioid makes her more nauseated, but she doesn’t feel any immediate relief from the long-acting drug. She notes “no help” from sertralene and lorazepam, so she stopped them. She has sleepiness from the prochlorperazine She now notes that taking the short-acting opioid makes her more nauseated, but she doesn’t feel any immediate relief from the long-acting drug. She notes “no help” from sertralene and lorazepam, so she stopped them. She has sleepiness from the prochlorperazine Her tumor has progressed Her tumor has progressed

53 Ms. F She remains weepy, discouraged, and the only medications she takes regularly are the short- and long-acting opioids, but she takes the PRN only about twice a day. She has lost 4 more kilograms She remains weepy, discouraged, and the only medications she takes regularly are the short- and long-acting opioids, but she takes the PRN only about twice a day. She has lost 4 more kilograms Taking chemotherapy “time out,” radiation to new bone pain Taking chemotherapy “time out,” radiation to new bone pain

54 The Perfect Storm This patient has Chemotherapy-induced nausea and vomiting (CINV), with a major contribution from anticipatory NV, since her regimen is of relatively low emetogenic potential Chemotherapy-induced nausea and vomiting (CINV), with a major contribution from anticipatory NV, since her regimen is of relatively low emetogenic potential Anxiety and depression Anxiety and depression Anorexia, complicated by selective serotonin reuptake inhibitor (SSRI) Anorexia, complicated by selective serotonin reuptake inhibitor (SSRI) Nausea from her opioids Nausea from her opioids Severe bone pain, not well relieved Severe bone pain, not well relieved Poor compliance due to discouragement Poor compliance due to discouragement

55 The Perfect Storm Poor quality of life Opioid analgesics Chemotherapy Nausea Pain Anxiety, depression Fatigue All of this Poor compliance Anorexia

56 Nausea Issues for This Patient Anticipatory nausea and vomiting Still occurs in about 25% of patients in spite of new antiemetics Still occurs in about 25% of patients in spite of new antiemetics Prevention is key: lower incidence when initial CINV is well managed Prevention is key: lower incidence when initial CINV is well managed Memory? Anxiety? Lorazepam, cannabinoids may reduce incidence Memory? Anxiety? Lorazepam, cannabinoids may reduce incidence Treat before chemotherapy Treat before chemotherapy Training measures: visualization, acupressure? Training measures: visualization, acupressure?

57 1. Dibble SL, et al. Oncol Nurs Forum. 2003;30:E Dibble SL, et al. Oncol Nurs Forum. 2004;31:E1. 3. Bloechl-Daum B, et al. J Clin Oncol. 2006;24:4472. Nausea Issues for This Patient CINV with delayed nausea About half of all patients experience moderate to severe delayed nausea and vomiting even in this era of better agents About half of all patients experience moderate to severe delayed nausea and vomiting even in this era of better agents Fewer than half of patients with moderate to severe CINV after cycle 1 get an adjustment of regimen before cycle 2 1 Fewer than half of patients with moderate to severe CINV after cycle 1 get an adjustment of regimen before cycle 2 1 Association of CINV with fatigue, “down time” is quite strong 2 Association of CINV with fatigue, “down time” is quite strong 2 Nausea causes greater QOL impact than vomiting 3 Nausea causes greater QOL impact than vomiting 3

58 1. Gunnarsdottir S, et al. Pain. 2002;99: Miaskowski C, et al. J Pain. 2002;3: Antoni MH, et al. Am J Psychiatry. 2006;163:1791. Pain Issues in This Patient Fear of opioids, fear of meaning of pain Fear of opioids, fear of meaning of pain –Better pain control in patients with lower scores on Pain Barriers scale 1 –Suggests strong role for patient education, coaching Compliance with regimen Compliance with regimen –Cancer patients with an average of 8 hours of pain/day complied better with long-acting around-the-clock meds, only 25% with PRNs 2 –Better pain management is 1 outcome of support interventions for stress 3 –Active phone coaching resulted in better pain control by about 1/3 4

59 Pain Management Adjuncts Antianxiety drugs, usually benzodiazepines Antianxiety drugs, usually benzodiazepines Neuroleptics with neuropathic pain activity Neuroleptics with neuropathic pain activity Anti-inflammatory agents Anti-inflammatory agents Antidepressants: many possibilities Antidepressants: many possibilities Cannabinoids Cannabinoids Topical agents: lidocaine, capsaicin Topical agents: lidocaine, capsaicin Physical measures: splints, physical therapy, massage, acupuncture, topical physical agents Physical measures: splints, physical therapy, massage, acupuncture, topical physical agents Psychosocial measures: active coaching regimen, relaxation/meditation, group support Psychosocial measures: active coaching regimen, relaxation/meditation, group support

60 Cannabinoids and Pain Management Use goes back to ancient times Use goes back to ancient times Preclinical data for multiple types of pain mechanisms Preclinical data for multiple types of pain mechanisms Synergy with NSAIDS, acetaminophen, mu opiate receptors Synergy with NSAIDS, acetaminophen, mu opiate receptors Clear clinical efficacy in neuropathic pain, including multiple sclerosis and rheumatoid arthritis (RA) Clear clinical efficacy in neuropathic pain, including multiple sclerosis and rheumatoid arthritis (RA) Modulation of inflammation may also help pain—efficacy in RA, postoperative pain Modulation of inflammation may also help pain—efficacy in RA, postoperative pain Cancer pain studies are fewer Cancer pain studies are fewer –Mostly older studies, small, but randomized –Best was European Sativex study: 43% of patients achieved ≥30% reduction in pain vs placebo 1 –Side effects may be more common with THC vs sativex 1

61 Lynch M. Pain Res Manage. 2005;10(suppl A). Cannabinoids and Pain Management Greater potency and efficacy in both inflammatory and neuropathic pain Comparable in potency and efficacy Comparison with opioids Due to up-regulation of CB1 receptorsAllodynia CB2 receptors play important role Significant evidence Anti-inflammatory Due to up- regulation of CB1 receptors _______________ Data from animal studies support a role for CB2 receptors Significant evidence Hyperalgesia Significant evidence Antinociceptive NeuropathicChronicVisceralAcute Type of Pain Effects Showed in Preclinical Studies

62 Cross-Reacting Pharmacotherapy Nausea medications Phenothiazines, butyrophenones: sedation, potentially desirable CNS effects Phenothiazines, butyrophenones: sedation, potentially desirable CNS effects Cannabinoids: anxiolytic; synergy with opioids, anti-inflammatory agents; orexigenic Cannabinoids: anxiolytic; synergy with opioids, anti-inflammatory agents; orexigenic NK1 antagonists, 5HT3 antagonists NK1 antagonists, 5HT3 antagonists Benzodiazepines: lorazepam reduces anxiety and anticipatory nausea/vomiting; improves sleep Benzodiazepines: lorazepam reduces anxiety and anticipatory nausea/vomiting; improves sleep Steroids: orexigenic, anti-inflammatory, mood Steroids: orexigenic, anti-inflammatory, mood

63 Options for This Patient Better nausea management Continue prochlorperazine, 5HT3 Continue prochlorperazine, 5HT3 Addition of cannabinoid Addition of cannabinoid Regular schedule of administration Regular schedule of administration Medi-set and home nursing coaching Medi-set and home nursing coaching Consider, with new chemotherapy: aprepitant, steroid taper Consider, with new chemotherapy: aprepitant, steroid taper

64 Options for This Patient Better pain management Continue around-the-clock long-acting opioid, increase dose Continue around-the-clock long-acting opioid, increase dose Emphasize regular use of PRN short-acting opioid Emphasize regular use of PRN short-acting opioid Add cannabinoid Add cannabinoid Trial of NSAID plus proton pump inhibitor Trial of NSAID plus proton pump inhibitor Home nursing for coaching, physical therapy Home nursing for coaching, physical therapy Referral to acupuncture and massage Referral to acupuncture and massage –Change SSRI to either quetiapine or olanzapine –Continue PRN lorazepam

65 Case Study: Noncompliance as a Result of CINV and Pain Kristen Fessele, RN, MSN, AOCN Associate Director, Human Research Services The Cancer Institute of New Jersey New Brunswick, New Jersey

66 Ms. D Ms. D is 38 years old Ms. D is 38 years old Mother of a 6-year-old son Mother of a 6-year-old son Originally diagnosed with infiltrating ductal carcinoma of the right breast at age 33 Originally diagnosed with infiltrating ductal carcinoma of the right breast at age 33 –ER/PR negative –Her2/neu amplified by fluorescence in situ hybridization (FISH)

67 Ms. D Received doxorubicin + cyclophosphamide followed by paclitaxel (trastuzumab was not given adjuvantly outside clinical trials at that time) Received doxorubicin + cyclophosphamide followed by paclitaxel (trastuzumab was not given adjuvantly outside clinical trials at that time) Had difficulties with postchemotherapy nausea and vomiting, as well as anticipatory vomiting Had difficulties with postchemotherapy nausea and vomiting, as well as anticipatory vomiting Developed herpes zoster to the left upper chest (C3 dermatome) in cycle 6; continues to experience poorly controlled postherpetic neuralgia Developed herpes zoster to the left upper chest (C3 dermatome) in cycle 6; continues to experience poorly controlled postherpetic neuralgia

68 Ms. D Relapsed with a solitary pulmonary metastasis 7 months ago Relapsed with a solitary pulmonary metastasis 7 months ago –Receives paclitaxel, cisplatin and trastuzumab with a 75% decrease in size of lesion Has recently “forgotten” several lab appointments, and this week did not appear for her treatment appointment Has recently “forgotten” several lab appointments, and this week did not appear for her treatment appointment

69 “I can’t take this anymore, and nothing you’ve given me is really helping!” Complaining of: Poorly controlled nausea after chemotherapy despite use of 5-day antiemetic regimen posttreatment including Poorly controlled nausea after chemotherapy despite use of 5-day antiemetic regimen posttreatment including –Dexamethasone –Ondansetron –Prochlorperazine Increasing frequency and intensity of postherpetic neuralgia Increasing frequency and intensity of postherpetic neuralgia

70 “I dread chemo all week because I know I’m going to feel even worse afterwards…” Patient’s fear of nausea and vomiting is causing her to become noncompliant with her chemotherapy plan Patient’s fear of nausea and vomiting is causing her to become noncompliant with her chemotherapy plan –May jeopardize the stability of her disease response Overall symptom burden is draining her coping reserve Overall symptom burden is draining her coping reserve

71 “I hate this –if I take all those pills, I’m too sleepy to do anything, and if I don’t, I can’t sleep, and I’m tired anyway…” Ms. D has not acclimated to opiate-induced sedation as most patients do, possibly due to her inconsistent dosing pattern Ms. D has not acclimated to opiate-induced sedation as most patients do, possibly due to her inconsistent dosing pattern Gabapentin, used specifically for her neuropathic pain (as well as for hot flashes due to chemotherapy-induced premature menopause), also induces unacceptable sedation in this patient Gabapentin, used specifically for her neuropathic pain (as well as for hot flashes due to chemotherapy-induced premature menopause), also induces unacceptable sedation in this patient Topical lidocaine application provides some, but incomplete, relief of postherpetic neuralgia Topical lidocaine application provides some, but incomplete, relief of postherpetic neuralgia

72 Pain Management Ms. D has used oxycodone 5 mg with acetaminophen 325 mg, 1–2 tablets once or twice daily to make her postherpetic neuralgia pain “almost bearable” Ms. D has used oxycodone 5 mg with acetaminophen 325 mg, 1–2 tablets once or twice daily to make her postherpetic neuralgia pain “almost bearable” Lidocaine patches offer some relief Lidocaine patches offer some relief She has also tried gabapentin at varying (but suboptimal) doses and schedules without good effect, as she finds it too sedating to fully escalate She has also tried gabapentin at varying (but suboptimal) doses and schedules without good effect, as she finds it too sedating to fully escalate

73 1. Cepeda MS, et al. Clin Pharmacol Ther. 2003;74: Swegle JM, Logemann C. Am Fam Physician. 2006;74: Cherny N, et al. J Clin Oncol. 2001;19: McNicol E, et al. J Pain. 2003;4:231. Common Opioid-Induced Adverse Effects Nausea/vomiting Nausea/vomiting –Approximately 25% of patients 1 –Usually transient 2 Sedation Sedation –Between 20% and 60% of patients 3 –Usually at initiation of therapy or with dose increases 4 Constipation Constipation –Most common side effect 2 Pruritis Pruritis –Between 2% and 10% of patients 3

74 1. Cepeda MS, et al. Clin Pharmacol Ther. 2003;74: Forman WB. Clin Geriatr Med.1996;12:489. Opioid-Induced Adverse Effects Risk Factors Gender Gender –Nausea/vomiting are more likely to occur in women than in men 1 Race Race –Nausea/vomiting are more likely to occur in Caucasian-Americans than in African-Americans 1 Age Age –Age-related reduction in renal function may lead to accumulation of opioids and their metabolites 1,2

75 Cherny N, et al. J Clin Oncol. 2001;19:2542. Approaches for Managing Opioid-Induced Adverse Effects Dose reduction of opioid Dose reduction of opioid Symptomatic management of adverse effect Symptomatic management of adverse effect Opioid rotation Opioid rotation Switching route of systemic administration Switching route of systemic administration

76 Goals More effective, reliable control of nausea and vomiting More effective, reliable control of nausea and vomiting More effective control of neuropathic pain More effective control of neuropathic pain Increased compliance with treatment plan to allow continued response to chemotherapy regimen Increased compliance with treatment plan to allow continued response to chemotherapy regimen

77 Tumor Board Presentation During discussion of challenging management cases at weekly tumor board, Ms. D was reviewed During discussion of challenging management cases at weekly tumor board, Ms. D was reviewed A colleague, trained in Canada, suggested a trial of a cannabinoid adjuvant to improve the symptom cluster A colleague, trained in Canada, suggested a trial of a cannabinoid adjuvant to improve the symptom cluster

78 1. Cichewicz DL. Life Sci. 2004;74: Manzanares J, et al. Trends Pharmacol Sci. 1999;20: Reche I, et al. Eur J Pharmacol. 1996;318: Campbell F. BMJ. 2001;323:13. Compelling Preclinical Data—More Evidence Is Needed Several studies describe the potentiating effects of opioids and cannabinoids on pain 1-3 Several studies describe the potentiating effects of opioids and cannabinoids on pain 1-3 Systematic review of human studies in BMJ 2001 by Campbell et al noted Systematic review of human studies in BMJ 2001 by Campbell et al noted –“…suggestions of efficacy in spasticity and neuropathic pain” 4

79 GW Pharmaceuticals, 1/4/06 (Press release) Clinical Trials Under Way Sativex A biologically derived compound of tetrahydrocannabinol (THC) and cannbidiol (CBD), administered as an oromucosal spray, is used in the United Kingdom for neuropathic pain and spasticity associated with multiple sclerosis A biologically derived compound of tetrahydrocannabinol (THC) and cannbidiol (CBD), administered as an oromucosal spray, is used in the United Kingdom for neuropathic pain and spasticity associated with multiple sclerosis –FDA approved IND status for Cannabis sativa L. extract in 2006, allowing start of phase III trial in the United States to evaluate effect of this compound on patients with cancer experiencing chronic pain

80 Available at: Accessed May 16, Clinical Trials Under Way Nabilone Phase IV multicenter trial of nabilone in patients with diabetic peripheral neuropathy Phase IV multicenter trial of nabilone in patients with diabetic peripheral neuropathy –Average, worst pain; pain at night scores –Other QOL measures Phase IV multicenter trial of nabilone in patients receiving initial chemotherapy Phase IV multicenter trial of nabilone in patients receiving initial chemotherapy –Cycle 1: standard antiemetic regimen –Cycle 2: standard regimen plus nabilone

81 1. Cesamet TM (nabilone) Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; Marinol ® (dronabinol) Product Information. Marietta, GA: Unimed Pharmaceuticals; Cannabinoid Indications Nabilone and dronabinol 1,2 Nabilone and dronabinol 1,2 –Nausea and vomiting that has not responded adequately to conventional antiemetic treatments Dronabinol 2 Dronabinol 2 –Appetite loss associated with weight loss in people with AIDS

82 Recommendations Educate patient on Educate patient on –Product nature –Potential benefits –Side effects –Risk of addiction Develop a treatment plan incorporating these goals Develop a treatment plan incorporating these goals –Reduction in pain –Increased functional abilities –Improved sleep quality –Increased quality of life –Reduction in the use of other medications

83 1. Cesamet TM (nabilone) Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; Marinol ® (dronabinol) Product Information. Marietta, GA: Unimed Pharmaceuticals; Precautions—Nabilone and Dronabinol Use with caution in Use with caution in –Older patients 1,2 –Those with current or previous psychiatric disorders (bipolar disorder, depression, schizophrenia) 1,2 –Those with cardiac conditions or at risk for tachycardia or orthostatic hypotension 1,2 –Those with a history of seizures 2

84 Most Common Adverse Events Nabilone 1 Nabilone 1 –Drowsiness –Vertigo –Dry mouth –Euphoria (“feeling high”) –Ataxia –Headache –Concentration difficulties Dronabinol 2 –Euphoria (“high”) –Abdominal pain –Nausea/vomiting –Dizziness –Somnolence –Paranoid reaction –Abnormal thinking 1. Cesamet TM (nabilone) Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; Marinol ® (dronabinol) Product Information. Marietta, GA: Unimed Pharmaceuticals; 2006.

85 Patient Update/Summary Nabilone was added to Ms. D’s antiemetic regimen on her most recent cycle. She reports good improvement in her nausea control, and no episodes of vomiting. She is continuing use of a pain diary to track dosing of breakthrough opioids, and reports an overall improvement in symptom burden.

86 Conclusions Additional options for symptom management are beneficial, especially for patients with metastatic disease and multiple sources of distress Additional options for symptom management are beneficial, especially for patients with metastatic disease and multiple sources of distress Cannabinoids may prove to be a helpful adjunct to standard antiemetic regimens and to opioids for pain management Cannabinoids may prove to be a helpful adjunct to standard antiemetic regimens and to opioids for pain management –Clinical studies are under way to evaluate if cannabinoids may help to reduce the dose of opioids needed


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