1. Toronto, Ontario, Canada
Looking 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 Centre
Toronto, Ontario, Canada

2. Incidence of Chemotherapy-Induced Nausea and Vomiting (CINV) and Pain in Cancer Patients
Approximately 70%–80% of chemotherapy patients experience nausea and vomiting1
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 disease2
1. Wiser W, Berger A. Oncology. 2005;19:637.
2. Portenoy RK. Semin Oncol. 1995;22(suppl 3):112.

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

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

5. NCCN Practice Guidelines Prechemotherapy Emesis Prevention
Highly emetogenic regimens
Day 1: aprepitant, dexamethasone, and a 5-HT3 antagonist +/- lorazepam
May be modified on days 2–4
Moderately emetogenic regimens
Day 1: dexamethasone and a 5-HT3 antagonist +/- lorazepam (aprepitant added with select moderately emetogenic regimens)
Modified on days 2–4
Low emetogenic regimens
Dexamethasone, proclorperazine, or metoclopramide +/- lorazepam
NCCN Practice Guidelines in Oncology – Version Antiemesis, MS-1.

6. NCCN Practice Guidelines Postchemotherapy/Delayed Emesis Prevention
Highly emetogenic regimens
Primary antiemetic regimen continued through period when delayed emesis may occur (ie, 2–3 days after chemotherapy cycle)
Moderately emetogenic regimens
Dependent upon the antiemetic used before chemotherapy
Palonosetron on day 1 only
Aprepitant continued on days 2 and 3 +/- dexamethasone or lorazepam
Dexamethasone or a 5-HT3 antagonist +/- lorazepam
NCCN Practice Guidelines in Oncology – Version Antiemesis, MS-1.

7. NCCN Practice Guidelines Breakthrough Treatment
Around-the-clock administration, rather than PRN dosing, should be considered
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
NCCN Practice Guidelines in Oncology – Version Antiemesis, MS-1.

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

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

10. Mechanism of Action of the Cannabinoids5
EXOGENOUS
Cannabinoid Therapy
Neurotransmitter (NT) from presynaptic neuron activates the postsynaptic neuron 1
Activated postsynaptic neuron releases endocannabinoids
Presynaptic Neuron
Inhibition of Neurotransmitter Release 2
CB1 Receptor 4
Endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor 3 1
Postsynaptic Neuron
Endogenous Cannabinoid Retrograde Signaling
CB1 receptor activates a G-protein, leading to inhibition of NT release 2 3 4
Neurotransmitter Receptor 5
Nabilone is thought to activate CB1 receptors directly, mimicking the effects of endocannabinoids
Endogenous and Exogenous Cannabinoids Reduce Neuronal Signaling
Adapted from Page 5 of Slatkin NE. J Support Oncol. 2007;5(suppl3):1. Reprinted with permission.

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

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

13. Diverse Neurotransmitters Mediate Emesis
Dopamine (D2)
Serotonin
(5-HT3)
Histamine
Substance P
(NK-1)
Endorphins
N + 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”
GABA
Acetylcholine
Cannabinoids
Drug classes FDA approved in CINV
Adapted from Andrews PL, Naylor RJ, Joss RA. Supportive Care Cancer. 1998;6:

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

15. Patients with Delayed Nausea/Vomiting (%)
5-HT3 Antagonists Are Ineffective for Controlling Delayed CINV in a Substantial Proportion of Patients
Mild nausea
Moderate nausea
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
Severe nausea 41 40
Emesis 38 34 35 30 25 25 24 25 23
Patients with Delayed Nausea/Vomiting (%) 21 20 19 17 17 15 10 10 5
Carboplatin
Cisplatin
Doxorubicin
Hickok JT, et al. Cancer. 2003;97:2880.

16. 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
No Emetic Episode
No Rescue Medication
No Nausea*
Endpoint
*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. Aprepitant Improves Outcomes, Yet CINV Persists in Most Patients70
Aprepitant
Standard therapy 59 60 56 50
44*
39*
% of Patients in Whom CINV Persisted 40 35 30
20* 20 10
Acute CINV
Delayed CINV
Overall
*P >.001 compared with standard therapy.
Poli-Bigelli S, et al. Cancer. 2003;97:3090.

18. Anticipatory Nausea and Vomiting
Anticipatory nausea occurs in 29% of chemotherapy patients1,2
Anticipatory vomiting occurs in 11% of chemotherapy patients1,2
Anticipatory nausea and vomiting
Mostly on the basis of classic or Pavlovian conditioning3
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.

19. 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 CINV1
Cannabinoids have an MOA different from conventional antiemetics (eg, 5-HT3 or D2 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
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. CesametTM (nabilone). Product Information. San Diego, CA: Valeant Pharmaceuticals North America; 2006.

20. Control of Nausea and Vomiting Cannabinoids—A Systematic Review*80
Control (placebo or active) 70
Cannabinoid 66 59 60 57 57 45 43
Event Rate (%) 40 36 20
vs Placebo vs Active vs Placebo vs Active
Nausea
Vomiting
*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.

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

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

23. Cannabinoids—Cancer Pain
European phase III study of a cannabidiol/THC buccal spray1
N = 177
Opioid nonresponsive pain
Cannabidiol/THC spray significantly reduced pain compared with placebo (P = .014)
43% of patients showed >30% improvement in pain (P = .024)
1http://

24. Cannabinoids in the Treatment of Other Pain
Chronic, incapacitating back pain1
Decrease in spinal pain intensity and headache with nabilone
Multiple Sclerosis (MS) neuropathic pain2
Cannabinoids (cannabidiol/THC buccal spray, cannabidiol, and dronabinol) were significantly superior to placebo in treating neuropathic pain in MS
MS spasticity-related pain3
Nabilone resulted in a significant decrease in spasticity-related pain
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.

25. Rx Cannabinoids—Pharmacokinetics
Nabilone
Dronabinol
Oral dosing
1–2 mg 1–3 h before chemotherapy, and BID for up to 48 h afterwards
5 mg/m2 1–3 h before chemotherapy, and every 2–4 h afterwards for a total of 4–6 doses/d
Source
Synthetic ∆9-THC analog
Synthetic ∆9-THC
Formulation
Crystalline powder capsule
Capsule formulated with sesame oil, among other ingredients (contraindicated in patients with a hypersensitivity to sesame oil)
Onset of action
60–90 min
30–60 min
Peak plasma concentrations (Tmax)
2 h
2–4 h
Duration of action
8–12 h
4–6 h for psychoactive effects
Metabolites
2 active metabolites
2 active metabolites and >20 other metabolites
Clearance
Major excretory pathway is the biliary system
Biliary excretion is major route of elimination
Cesamet® (nabilone). Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; Marinol® (dronabinol). Product Information. Marietta, GA: Unimed Pharmaceuticals, Inc; 2006.

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

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

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

29. Summary
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
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 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 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 patient is referred to a medical oncologist for consideration of postoperative systemic adjuvant therapy
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/m2 and cyclophosphamide 600 mg/m2 (AC)

35. Discussion with Oncologist
Risk reduction might be expected with this regimen
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)
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
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. Moderately Emetogenic Chemotherapy Highly Emetogenic Chemotherapy
Perception vs Reality in Patients Receiving Moderately or Highly Emetogenic Chemotherapy
MD/RN prediction
MD/RN prediction
Patient experience
Patient experience 60 60 50 50 40 40
Patients (%) 30 30 20 20 10 10
Acute Nausea
Acute Vomiting
Delayed Nausea
Delayed Vomiting
Acute Nausea
Acute Vomiting
Delayed Nausea
Delayed Vomiting
Moderately Emetogenic Chemotherapy
Highly Emetogenic Chemotherapy
Schwartzberg L. J Support Oncol. 2006;4(suppl 1):3.

41. Prevention of Emesis in Women on Day 1 After Chemotherapy Results with Standard Therapy in Randomized Trials
All patients received dexamethasone and ondansetron
100 A C 80 6 9 6 6 C i s p l a t i n 60
Patients (%) 40 20
Cisplatin 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.

42. Prevention 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 bid
100 A C 80 C i s p l a t i n
Patients (%) 60 4 9 4 7 40 20
Cisplatin 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.

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
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
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)
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
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
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

49. Ms. F
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
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

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
Opioids are increased, long-acting opioid prescribed, and sertralene and prochlorperazine given
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
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
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

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
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
Anxiety and depression
Anorexia, complicated by selective serotonin reuptake inhibitor (SSRI)
Nausea from her opioids
Severe bone pain, not well relieved
Poor compliance due to discouragement

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

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

57. 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
Fewer than half of patients with moderate to severe CINV after cycle 1 get an adjustment of regimen before cycle 21
Association of CINV with fatigue, “down time” is quite strong2
Nausea causes greater QOL impact than vomiting3
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.

58. Pain Issues in This Patient
Fear of opioids, fear of meaning of pain
Better pain control in patients with lower scores on Pain Barriers scale1
Suggests strong role for patient education, coaching
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 PRNs2
Better pain management is 1 outcome of support interventions for stress3
Active phone coaching resulted in better pain control by about 1/34
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.

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

60. Cannabinoids and Pain Management
Use goes back to ancient times
Preclinical data for multiple types of pain mechanisms
Synergy with NSAIDS, acetaminophen, mu opiate receptors
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
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 placebo1
Side effects may be more common with THC vs sativex
1http://

61. 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 receptors
Allodynia
CB2 receptors play important role
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
Hyperalgesia
Antinociceptive
Neuropathic
Chronic
Visceral
Acute
Type of Pain
Effects Showed in Preclinical Studies
Lynch M. Pain Res Manage. 2005;10(suppl A).

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

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

64. Options for This Patient
Better pain management
Continue around-the-clock long-acting opioid, increase dose
Emphasize regular use of PRN short-acting opioid
Add cannabinoid
Trial of NSAID plus proton pump inhibitor
Home nursing for coaching, physical therapy
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 Mother of a 6-year-old son
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)
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

68. Ms. D 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

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
Dexamethasone
Ondansetron
Prochlorperazine
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
May jeopardize the stability of her disease response
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
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

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”
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

73. Common Opioid-Induced Adverse Effects
Nausea/vomiting
Approximately 25% of patients1
Usually transient2
Sedation
Between 20% and 60% of patients3
Usually at initiation of therapy or with dose increases4
Constipation
Most common side effect2
Pruritis
Between 2% and 10% of patients3
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.

74. Opioid-Induced Adverse Effects Risk Factors
Gender
Nausea/vomiting are more likely to occur in women than in men1
Race
Nausea/vomiting are more likely to occur in Caucasian-Americans than in African-Americans1
Age
Age-related reduction in renal function may lead to accumulation of opioids and their metabolites1,2
1. Cepeda MS, et al. Clin Pharmacol Ther. 2003;74: Forman WB. Clin Geriatr Med.1996;12:489.

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

76. Goals More effective, reliable control of nausea and vomiting
More effective control of neuropathic pain
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
A colleague, trained in Canada, suggested a trial of a cannabinoid adjuvant to improve the symptom cluster

78. Compelling Preclinical Data—More Evidence Is Needed
Several studies describe the potentiating effects of opioids and cannabinoids on pain1-3
Systematic review of human studies in BMJ 2001 by Campbell et al noted
“…suggestions of efficacy in spasticity and neuropathic pain”4
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.

79. 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
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
GW Pharmaceuticals, 1/4/06 (Press release)

80. Clinical Trials Under Way Nabilone
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
Cycle 1: standard antiemetic regimen
Cycle 2: standard regimen plus nabilone
Available at: Accessed May 16, 2007.

81. Cannabinoid Indications
Nabilone and dronabinol1,2
Nausea and vomiting that has not responded adequately to conventional antiemetic treatments
Dronabinol2
Appetite loss associated with weight loss in people with AIDS
1. CesametTM (nabilone) Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; Marinol® (dronabinol) Product Information. Marietta, GA: Unimed Pharmaceuticals; 2006.

82. Recommendations Educate patient on
Product nature
Potential benefits
Side effects
Risk of addiction
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. Precautions—Nabilone and Dronabinol
Use with caution in
Older patients1,2
Those with current or previous psychiatric disorders (bipolar disorder, depression, schizophrenia)1,2
Those with cardiac conditions or at risk for tachycardia or orthostatic hypotension1,2
Those with a history of seizures2
1. CesametTM (nabilone) Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; Marinol® (dronabinol) Product Information. Marietta, GA: Unimed Pharmaceuticals; 2006.

84. Most Common Adverse Events
Nabilone1
Drowsiness
Vertigo
Dry mouth
Euphoria (“feeling high”)
Ataxia
Headache
Concentration difficulties
Dronabinol2
Euphoria (“high”)
Abdominal pain
Nausea/vomiting
Dizziness
Somnolence
Paranoid reaction
Abnormal thinking
1. CesametTM (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
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