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1Toronto, Ontario, Canada Looking at Breakthrough Nausea/Vomiting and Cancer-Related Pain The Cannabinoid ExperienceVincent Maida, MDAssistant ProfessorUniversity of Toronto Division of Palliative Medicine William Osler Health CentreToronto, Ontario, Canada
2Incidence of Chemotherapy-Induced Nausea and Vomiting (CINV) and Pain in Cancer Patients Approximately 70%–80% of chemotherapy patients experience nausea and vomiting1Patients rank nausea and vomiting as 2 of the most feared side effects of cancer treatmentMore than three quarters of cancer patients experience chronic pain during the course of their disease21. Wiser W, Berger A. Oncology. 2005;19:637.2. Portenoy RK. Semin Oncol. 1995;22(suppl 3):112.
3Consequences of Unresolved CINV Adverse sequelae of nausea and vomiting in the cancer patientSerious metabolic derangementsNutritional depletion and anorexiaEsophageal tearsWound dehiscenceDeterioration of patients’ physical and mental statusDegeneration of self-care and functional abilityDiscontinuation of therapyNCCN Practice Guidelines in Oncology–Version Antiemesis, MS-1.
4CINV—Decreased Quality of Life FLIE QuestionnaireHEC-FLIE > MEC-FLIE P = .0049FLIE-nausea > FLIE-Vomiting P = .0097There is a greater negative impact on QOL from nausea than there is from vomitingFLIE = Functional Living Index-Emesis; HEC = highly emetogenic chemotherapy; MEC = moderately emetogenic chemotherapy.Bloechl-Daum, B, et al. J Clin Oncol. 2006;24:4472.
5NCCN Practice Guidelines Prechemotherapy Emesis Prevention Highly emetogenic regimensDay 1: aprepitant, dexamethasone, and a 5-HT3 antagonist +/- lorazepamMay be modified on days 2–4Moderately emetogenic regimensDay 1: dexamethasone and a 5-HT3 antagonist +/- lorazepam (aprepitant added with select moderately emetogenic regimens)Modified on days 2–4Low emetogenic regimensDexamethasone, proclorperazine, or metoclopramide +/- lorazepamNCCN Practice Guidelines in Oncology – Version Antiemesis, MS-1.
6NCCN Practice Guidelines Postchemotherapy/Delayed Emesis Prevention Highly emetogenic regimensPrimary antiemetic regimen continued through period when delayed emesis may occur (ie, 2–3 days after chemotherapy cycle)Moderately emetogenic regimensDependent upon the antiemetic used before chemotherapyPalonosetron on day 1 onlyAprepitant continued on days 2 and 3 +/- dexamethasone or lorazepamDexamethasone or a 5-HT3 antagonist +/- lorazepamNCCN Practice Guidelines in Oncology – Version Antiemesis, MS-1.
7NCCN Practice Guidelines Breakthrough Treatment Around-the-clock administration, rather than PRN dosing, should be consideredAdditional agents should be from a different drug class than initial therapyPossibilities include: dopamine antagonists, metoclopramide, butyrophenones, cannabinoids, corticosteroids, or agents such as lorazepamNabilone (cannabinoid) has recently been approved for nausea/vomiting in patients who have not responded to conventional antiemeticsNCCN Practice Guidelines in Oncology – Version Antiemesis, MS-1.
9Cannabinoid Receptors CB1—neuromodulationBasal gangliaHippocampusCerebral cortexCerebellumSpinal cordAfferent nociceptorsCB2—immunomodulationSpleenTonsilMast cellsMacrophagesLymphocytesMicrogliaKalant H. Pain Res Manag. 2001;6:80.
10Mechanism of Action of the Cannabinoids 5EXOGENOUSCannabinoid TherapyNeurotransmitter (NT) from presynaptic neuron activates the postsynaptic neuron1Activated postsynaptic neuron releases endocannabinoidsPresynaptic NeuronInhibition of Neurotransmitter Release2CB1 Receptor4Endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor31Postsynaptic NeuronEndogenous Cannabinoid Retrograde SignalingCB1 receptor activates a G-protein, leading to inhibition of NT release234Neurotransmitter Receptor5Nabilone is thought to activate CB1 receptors directly, mimicking the effects of endocannabinoidsEndogenous and Exogenous Cannabinoids Reduce Neuronal SignalingAdapted from Page 5 of Slatkin NE. J Support Oncol. 2007;5(suppl3):1. Reprinted with permission.
11Cannabinoids—Supportive Oncology Established rolesCINVEmerging rolesAnalgesiaSpasmolysisAnorexia-cachexiaSedativeAntidepressantAntineoplastic
12Causes of Nausea and Vomiting in Cancer Patients Gastric stasisDrugsOpioidsChemotherapyBiochemicalHypercalcemiaUremiaRaised intracranial pressureIntestinal obstructionPainTwycross R. Palliative Care. 3rd ed, Radcliffe Medical Press. Oxford:1999:114.
13Diverse Neurotransmitters Mediate Emesis Dopamine (D2)Serotonin(5-HT3)HistamineSubstance P(NK-1)EndorphinsN + V REFLEX“In man for total control of emesis and perhaps even more for nausea, it may be necessary to block a number of different brain stem receptor sites”GABAAcetylcholineCannabinoidsDrug classes FDA approved in CINVAdapted from Andrews PL, Naylor RJ, Joss RA. Supportive Care Cancer. 1998;6:
14Delayed CINV Is More Prevalent Than Acute CINV Delayed emesis is 2.5 times more prevalent than acute emesisFor moderately emetogenic chemotherapyDelayed nausea exceeds acute nausea by 16%Delayed emesis exceeds acute emesis by 15%For highly emetogenic chemotherapyDelayed nausea exceeds acute nausea by 27%Delayed emesis exceeds acute emesis by 38%Grunberg SM, et al. Cancer. 2004;100:2261.
15Patients with Delayed Nausea/Vomiting (%) 5-HT3 Antagonists Are Ineffective for Controlling Delayed CINV in a Substantial Proportion of PatientsMild nauseaModerate nausea360 patients at 18 private medical oncology groups were enrolled in the study322 completed requirements for chemotherapy cycle 1Antiemetic regimenDay 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 siteSevere nausea4140Emesis383435302525242523Patients with Delayed Nausea/Vomiting (%)21201917171510105CarboplatinCisplatinDoxorubicinHickok JT, et al. Cancer. 2003;97:2880.
16Palonosetron Improves Outcomes, Yet CINV Persists in Most Patients 100908066705860% of Patients Who Failed to Achieve Endpoint (Days 1–5)495040302010No Emetic EpisodeNo Rescue MedicationNo Nausea*Endpoint*Moderate or severeBrames MJ, et al. Presented at the MASCC/ISOO 18th International Symposium; June 22-24, 2006: Toronto, Canada. Reprinted with permission.
17Aprepitant Improves Outcomes, Yet CINV Persists in Most Patients 70AprepitantStandard therapy5960565044*39*% of Patients in Whom CINV Persisted40353020*2010Acute CINVDelayed CINVOverall*P >.001 compared with standard therapy.Poli-Bigelli S, et al. Cancer. 2003;97:3090.
18Anticipatory Nausea and Vomiting Anticipatory nausea occurs in 29% of chemotherapy patients1,2Anticipatory vomiting occurs in 11% of chemotherapy patients1,2Anticipatory nausea and vomitingMostly on the basis of classic or Pavlovian conditioning31. 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.
19Cannabinoids for the Treatment of CINV—Distinct Therapeutic Mechanism Combining agents with different mechanisms of action (MOAs) may be the optimal approach to management of CINV1Cannabinoids have an MOA different from conventional antiemetics (eg, 5-HT3 or D2 receptor antagonists)1-3The antiemetic effect of cannabinoids may be due to interaction with the cannabinoid receptor system (ie, CB1 receptors found in neural tissues)41. National Cancer Institute. Available at: Accessed June 13, Tramer MR, et al. BMJ. 2001;323: NCCN Practice Guidelines in Oncology. 2005;1. Antiemesis. 4. CesametTM (nabilone). Product Information. San Diego, CA: Valeant Pharmaceuticals North America; 2006.
20Control of Nausea and Vomiting Cannabinoids—A Systematic Review* 80Control (placebo or active)70Cannabinoid66596057574543Event Rate (%)403620vs Placebo vs Active vs Placebo vs ActiveNauseaVomiting*21 randomized, comparative studies of cannabinoids with placebo or other antiemetics(oral nabilone, oral dronabinol, intramuscular levonatrodol.)Active control = prochlorperazine, metoclopramide, chlorpromazine, haloperidol, domperidone, and alizapride.Tramer MR, et al. BMJ. 2001;323:16.
21Patients’ Rating Preference for Cannabinoids vs placebo (4 studies)vs active control (14 studies)Relative risk (95% CI) Favors cannabinoidsActive control = prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, and alizapride. Tramèr MR, et al. BMJ. 2001;323:16.
22Etiology of Pain in Breast Cancer Patients IatrogenicPostmastectomy syndromeChemotherapy-induced peripheral neuropathyTaxanes >> vinorelbine > capecitabineBone metastasesNeuropathicMalignant plexopathyMalignant radiculopathyMSCC
23Cannabinoids—Cancer Pain European phase III study of a cannabidiol/THC buccal spray1N = 177Opioid nonresponsive painCannabidiol/THC spray significantly reduced pain compared with placebo (P = .014)43% of patients showed >30% improvement in pain (P = .024)1http://www.dpna.org/1sativex.htm
24Cannabinoids in the Treatment of Other Pain Chronic, incapacitating back pain1Decrease in spinal pain intensity and headache with nabiloneMultiple Sclerosis (MS) neuropathic pain2Cannabinoids (cannabidiol/THC buccal spray, cannabidiol, and dronabinol) were significantly superior to placebo in treating neuropathic pain in MSMS spasticity-related pain3Nabilone resulted in a significant decrease in spasticity-related pain1. 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.
25Rx Cannabinoids—Pharmacokinetics NabiloneDronabinolOral dosing1–2 mg 1–3 h before chemotherapy, and BID for up to 48 h afterwards5 mg/m2 1–3 h before chemotherapy, and every 2–4 h afterwards for a total of 4–6 doses/dSourceSynthetic ∆9-THC analogSynthetic ∆9-THCFormulationCrystalline powder capsuleCapsule formulated with sesame oil, among other ingredients (contraindicated in patients with a hypersensitivity to sesame oil)Onset of action60–90 min30–60 minPeak plasma concentrations (Tmax)2 h2–4 hDuration of action8–12 h4–6 h for psychoactive effectsMetabolites2 active metabolites2 active metabolites and >20 other metabolitesClearanceMajor excretory pathway is the biliary systemBiliary excretion is major route of eliminationCesamet® (nabilone). Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; Marinol® (dronabinol). Product Information. Marietta, GA: Unimed Pharmaceuticals, Inc; 2006.
26Cannabinoid Metabolism CYP450 Metabolizing EnzymesCYP450 Enzyme InhibitionCYP450 Enzyme InductionNabilone2C9*, 3A4(aldehyde oxygenase)None to dateDronabinol2C9*, 2C11, 3A43A4*Main metabolizing isoenzymeMetabolized principally through the CYP450 2C9 isoenzymeNo inhibitory or inducing effect on any of the isoenzymesCompetes with very few medications at the metabolic level, including opioidsExamples of medications metabolized by CYP3A4: antifungals, methadone, many antidepressants, HIV protease inhibitorsNahas GG, et al, eds. Marihuana and Medicine. Totowa, NJ: Humana Press; 1999:
27Aprepitant Metabolism Inhibitory Effect on Orally Administered CYP3A4 Substrate*Inhibitory Effect on IV Administered CYP3A4 Substrate*Oral aprepitant mg Weak — 125 mg Moderate Weak*MidazolamMajumdar AK, et al. J Clin Pharmacol. 2007;47:744.
28Side Effects of Cannabinoids* Symptom/EffectMost CommonCommonRareCNSSedationSomnolenceDizzinessEuphoria/“high”Blurred visionAnxiety; panicParanoiaPsychosisDepressionAtaxiaAstheniaCognitive effects4CardiovascularPostural hypotensionVasodilatation (red eyes)TachycardiaPalpitationsOthersDry mouthHeadache*If smoked, respiratory effects, such as bronchitis, chronic obstructive pulmonary disease, lung infection.Clark AJ. Pain Res Manage. 2005;10(suppl A):44A.
29SummaryEmesis is mediated by a variety of neurotransmitters; thus, full control may require the blocking of multiple brain receptor sitesCurrent antiemetic agents provide inadequate relief in a substantial number of cancer patientsThe mechanism of action of cannabinoids differs from that of conventional antiemetics, making it an appropriate candidate for combination with traditional agentsCannabinoids have proven to be effective antiemetic adjuvants in patients with uncontrolled nausea/vomiting and can provide additional relief in patients with severe painCannabinoids have demonstrated long-term efficacy and safety
30Case Study: Breakthrough CINV with Anthracycline-Based Therapy William J. Gradishar, MD, FACPDirector, Breast Medical Oncology Northwestern University Feinberg School of Medicine Robert H. Lurie Comprehensive Cancer Center Chicago, Illinois
31Ms. JA 44-year-old female presents with a right breast lump, which on physical examination measures ~ 1 cmA mammogram reveals a suspicious-appearing lesion measuring ~ 1.5 cm in the same area noted on physical exam
32Infiltrating 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
33Sentinel Lymph Node Negative for Tumor The sentinel lymph node was negative for tumorThe patient is referred to a medical oncologist for consideration of postoperative systemic adjuvant therapyAdditional planned breast irradiation
34Medical 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/m2 and cyclophosphamide 600 mg/m2 (AC)
35Discussion with Oncologist Risk reduction might be expected with this regimenExpected toxicitiesNeutropenia, alopecia, cardiac toxicity, mouth sores, fatigue, and nausea and vomiting
36Reassurance and Management The medical oncologist assures the patient that these symptoms can be prevented or successfully managed should they develop.
37AC Regimen and CINVThe 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
38AC Regimen and CINVWhen 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 chemotherapyOnly a fraction of patients with well-controlled emesis can decrease to 50% on days 2 and 3 following chemotherapyHesketh 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.
39Delayed SymptomsSome patients experience delayed symptoms (24 hours or more after chemotherapy), and the risk of nausea and vomiting increases during multiple cycles of therapy
40Moderately Emetogenic Chemotherapy Highly Emetogenic Chemotherapy Perception vs Reality in Patients Receiving Moderately or Highly Emetogenic ChemotherapyMD/RN predictionMD/RN predictionPatient experiencePatient experience606050504040Patients (%)303020201010Acute NauseaAcute VomitingDelayed NauseaDelayed VomitingAcute NauseaAcute VomitingDelayed NauseaDelayed VomitingModerately Emetogenic ChemotherapyHighly Emetogenic ChemotherapySchwartzberg L. J Support Oncol. 2006;4(suppl 1):3.
41Prevention of Emesis in Women on Day 1 After Chemotherapy Results with Standard Therapy in Randomized TrialsAll patients received dexamethasone and ondansetron100AC806966Cisplatin60Patients (%)4020Cisplatin group (N = 438): all received cisplatin >70 mg/m2 .Anthracycline/cyclophosphamide group (N = 424): 99% received AC.AC = doxorubicine/cyclophosphamide.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.
42Prevention of Emesis in Women on Days 2 and 3 Results with Standard Therapy in Randomized Trials On Days 2 and 3: Cisplatin patients given dexamethasone 8 mg bid AC patients given ondansetron 8 mg bid100AC80CisplatinPatients (%)6049474020Cisplatin group (N = 438): all received cisplatin >70 mg/m2 .Anthracycline/cyclophosphamide group (N = 424): 99% received AC.AC = doxorubicine/cyclophosphamide.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.
43Breakthrough CINVIn 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
44Options for Breakthrough CINV Additional agents should be from a different drug class than initial therapyPossible options include dopamine antagonists, metoclopramide, butyrophenones, cannabinoids, corticosteroids, or agents such as lorazepamNCCN Practice Guidelines in Oncology – Version Antiemesis, MS-1.
45Additional TreatmentOptions for breakthrough treatment were discussed with the patientDexamethasone + lorazepam were added to her antiemetic regimen
46Take-Home MessagesMany 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 possibleA substantial portion of patients receiving common regimens such as AC experience CINV despite recommended emetic therapyThere 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
47Case Study: Anticipatory CINV and Opioid-Refractory Pain Judith A. Luce, MDClinical Professor of Medicine, University of California, San Francisco Director, Oncology Services San Francisco General Hospital San Francisco, California
48Ms. FMs. F is a 50-year-old Honduran woman who was diagnosed with stage II breast cancer 3 years agoShe had been treated with mastectomy, chest wall radiation therapy, 6 cycles of FEC-75 chemotherapy, and tamoxifenShe came to our hospital with an enlarging mass in her sternum and severe pain
49Ms. FIncisional biopsy was performed because of a lack of information from Honduras—the mass was metastatic triple-negative breast cancerStaging revealed 2 other osseous metastases, right neck nodes, and no visceral diseaseRadiation therapy to the sternal mass was delivered, ultimately helping to reduce painPatient was started on short-acting opioids and nonsteroidal anti-inflammatory drug (NSAID) orally, but said the NSAID irritated her stomach
50Ms. FMs. 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 bedOpioids are increased, long-acting opioid prescribed, and sertralene and prochlorperazine givenChemotherapy with weekly paclitaxel and bevacizumab is begun
51Ms. FThe 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 hurtsShe is given increased opioids, lorazepam, granisetron, and the chemotherapy is switched to every 21 days
52Ms. FMs. F continues to have chemotherapy-induced nausea and vomiting for about a week after chemotherapyShe 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 prochlorperazineHer tumor has progressed
53Ms. FShe 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 kilogramsTaking chemotherapy “time out,” radiation to new bone pain
54The 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 potentialAnxiety and depressionAnorexia, complicated by selective serotonin reuptake inhibitor (SSRI)Nausea from her opioidsSevere bone pain, not well relievedPoor compliance due to discouragement
55The Perfect Storm Anorexia Chemotherapy Opioid analgesics Nausea FatiguePainAnxiety, depressionAll of thisPoor compliancePoor quality of life
56Nausea Issues for This Patient Anticipatory nausea and vomitingStill occurs in about 25% of patients in spite of new antiemeticsPrevention is key: lower incidence when initial CINV is well managedMemory? Anxiety? Lorazepam, cannabinoids may reduce incidenceTreat before chemotherapyTraining measures: visualization, acupressure?
57Nausea Issues for This Patient CINV with delayed nauseaAbout half of all patients experience moderate to severe delayed nausea and vomiting even in this era of better agentsFewer than half of patients with moderate to severe CINV after cycle 1 get an adjustment of regimen before cycle 21Association of CINV with fatigue, “down time” is quite strong2Nausea causes greater QOL impact than vomiting31. 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.
58Pain Issues in This Patient Fear of opioids, fear of meaning of painBetter pain control in patients with lower scores on Pain Barriers scale1Suggests strong role for patient education, coachingCompliance with regimenCancer patients with an average of 8 hours of pain/day complied better with long-acting around-the-clock meds, only 25% with PRNs2Better pain management is 1 outcome of support interventions for stress3Active phone coaching resulted in better pain control by about 1/341. 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.
59Pain Management Adjuncts Antianxiety drugs, usually benzodiazepinesNeuroleptics with neuropathic pain activityAnti-inflammatory agentsAntidepressants: many possibilitiesCannabinoidsTopical agents: lidocaine, capsaicinPhysical measures: splints, physical therapy, massage, acupuncture, topical physical agentsPsychosocial measures: active coaching regimen, relaxation/meditation, group support
60Cannabinoids and Pain Management Use goes back to ancient timesPreclinical data for multiple types of pain mechanismsSynergy with NSAIDS, acetaminophen, mu opiate receptorsClear clinical efficacy in neuropathic pain, including multiple sclerosis and rheumatoid arthritis (RA)Modulation of inflammation may also help pain—efficacy in RA, postoperative painCancer pain studies are fewerMostly older studies, small, but randomizedBest was European Sativex study: 43% of patients achieved ≥30% reduction in pain vs placebo1Side effects may be more common with THC vs sativex1http://www.dpna.org/1sativex.htm
61Cannabinoids and Pain Management Greater potency and efficacy in both inflammatory and neuropathic painComparable in potency and efficacyComparison with opioidsDue to up-regulation of CB1 receptorsAllodyniaCB2 receptors play important roleCB2 receptors play important roleSignificant evidenceAnti-inflammatoryDue to up-regulation of CB1 receptors _______________Data from animal studies support a role for CB2 receptorsHyperalgesiaAntinociceptiveNeuropathicChronicVisceralAcuteType of PainEffects Showed in Preclinical StudiesLynch M. Pain Res Manage. 2005;10(suppl A).
63Options for This Patient Better nausea managementContinue prochlorperazine, 5HT3Addition of cannabinoidRegular schedule of administrationMedi-set and home nursing coachingConsider, with new chemotherapy: aprepitant, steroid taper
64Options for This Patient Better pain managementContinue around-the-clock long-acting opioid, increase doseEmphasize regular use of PRN short-acting opioidAdd cannabinoidTrial of NSAID plus proton pump inhibitorHome nursing for coaching, physical therapyReferral to acupuncture and massageChange SSRI to either quetiapine or olanzapineContinue PRN lorazepam
65Case Study: Noncompliance as a Result of CINV and Pain Kristen Fessele, RN, MSN, AOCNAssociate Director, Human Research Services The Cancer Institute of New Jersey New Brunswick, New Jersey
66Ms. D Ms. D is 38 years old Mother of a 6-year-old son Originally diagnosed with infiltrating ductal carcinoma of the right breast at age 33ER/PR negativeHer2/neu amplified by fluorescence in situ hybridization (FISH)
67Ms. DReceived 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 vomitingDeveloped herpes zoster to the left upper chest (C3 dermatome) in cycle 6; continues to experience poorly controlled postherpetic neuralgia
68Ms. D Relapsed with a solitary pulmonary metastasis 7 months ago Receives paclitaxel, cisplatin and trastuzumab with a 75% decrease in size of lesionHas 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 includingDexamethasoneOndansetronProchlorperazineIncreasing 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 planMay jeopardize the stability of her disease responseOverall 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 patternGabapentin, used specifically for her neuropathic pain (as well as for hot flashes due to chemotherapy-induced premature menopause), also induces unacceptable sedation in this patientTopical lidocaine application provides some, but incomplete, relief of postherpetic neuralgia
72Pain ManagementMs. 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 reliefShe has also tried gabapentin at varying (but suboptimal) doses and schedules without good effect, as she finds it too sedating to fully escalate
73Common Opioid-Induced Adverse Effects Nausea/vomitingApproximately 25% of patients1Usually transient2SedationBetween 20% and 60% of patients3Usually at initiation of therapy or with dose increases4ConstipationMost common side effect2PruritisBetween 2% and 10% of patients31. 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.
74Opioid-Induced Adverse Effects Risk Factors GenderNausea/vomiting are more likely to occur in women than in men1RaceNausea/vomiting are more likely to occur in Caucasian-Americans than in African-Americans1AgeAge-related reduction in renal function may lead to accumulation of opioids and their metabolites1,21. Cepeda MS, et al. Clin Pharmacol Ther. 2003;74: Forman WB. Clin Geriatr Med.1996;12:489.
75Approaches for Managing Opioid-Induced Adverse Effects Dose reduction of opioidSymptomatic management of adverse effectOpioid rotationSwitching route of systemic administrationCherny N, et al. J Clin Oncol. 2001;19:2542.
76Goals More effective, reliable control of nausea and vomiting More effective control of neuropathic painIncreased compliance with treatment plan to allow continued response to chemotherapy regimen
77Tumor Board Presentation During discussion of challenging management cases at weekly tumor board, Ms. D was reviewedA colleague, trained in Canada, suggested a trial of a cannabinoid adjuvant to improve the symptom cluster
78Compelling Preclinical Data—More Evidence Is Needed Several studies describe the potentiating effects of opioids and cannabinoids on pain1-3Systematic review of human studies in BMJ 2001 by Campbell et al noted“…suggestions of efficacy in spasticity and neuropathic pain”41. 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.
79Clinical 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 sclerosisFDA 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 painGW Pharmaceuticals, 1/4/06 (Press release)
80Clinical Trials Under Way Nabilone Phase IV multicenter trial of nabilone in patients with diabetic peripheral neuropathyAverage, worst pain; pain at night scoresOther QOL measuresPhase IV multicenter trial of nabilone in patients receiving initial chemotherapyCycle 1: standard antiemetic regimenCycle 2: standard regimen plus nabiloneAvailable at: Accessed May 16, 2007.
81Cannabinoid Indications Nabilone and dronabinol1,2Nausea and vomiting that has not responded adequately to conventional antiemetic treatmentsDronabinol2Appetite loss associated with weight loss in people with AIDS1. CesametTM (nabilone) Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; Marinol® (dronabinol) Product Information. Marietta, GA: Unimed Pharmaceuticals; 2006.
82Recommendations Educate patient on Product naturePotential benefitsSide effectsRisk of addictionDevelop a treatment plan incorporating these goalsReduction in painIncreased functional abilitiesImproved sleep qualityIncreased quality of lifeReduction in the use of other medications
83Precautions—Nabilone and Dronabinol Use with caution inOlder patients1,2Those with current or previous psychiatric disorders (bipolar disorder, depression, schizophrenia)1,2Those with cardiac conditions or at risk for tachycardia or orthostatic hypotension1,2Those with a history of seizures21. CesametTM (nabilone) Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; Marinol® (dronabinol) Product Information. Marietta, GA: Unimed Pharmaceuticals; 2006.
85Patient 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.
86ConclusionsAdditional options for symptom management are beneficial, especially for patients with metastatic disease and multiple sources of distressCannabinoids may prove to be a helpful adjunct to standard antiemetic regimens and to opioids for pain managementClinical studies are under way to evaluate if cannabinoids may help to reduce the dose of opioids needed