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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

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Looking at Breakthrough Nausea/Vomiting andCancer-Related PainThe Cannabinoid Experience

Vincent Maida, MD

Assistant Professor

University of TorontoDivision of Palliative MedicineWilliam Osler Health Centre

Toronto, Ontario, Canada


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.


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 1. 2007. Antiemesis, MS-1.


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 onQOL 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.


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 1. 2007. Antiemesis, MS-1.


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 1. 2007. Antiemesis, MS-1.


NCCN Practice GuidelinesBreakthrough 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 1. 2007. Antiemesis, MS-1.


Botanical

Marijuana

Hashish

Endogenous

Anandamide

2-AG

PEA

Cannabinoids

  • Pharmaceutical

  • Nabilone

  • Dronabinol

  • Delta-9-THC & cannabidiol


CB1—neuromodulation

Basal ganglia

Hippocampus

Cerebral cortex

Cerebellum

Spinal cord

Afferent nociceptors

CB2—immunomodulation

Spleen

Tonsil

Mast cells

Macrophages

Lymphocytes

Microglia

Cannabinoid Receptors

Kalant H. Pain Res Manag. 2001;6:80.


Mechanism of Action of the Cannabinoids

5

EXOGENOUS

Cannabinoid Therapy

Neurotransmitter (NT) from presynaptic neuron activates the postsynaptic neuron

1

Activated postsynaptic neuron releases endocannabinoids

2

PresynapticNeuron

Inhibition ofNeurotransmitterRelease

CB1 Receptor

4

Endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor

3

1

PostsynapticNeuron

Endogenous CannabinoidRetrograde Signaling

CB1 receptor activates a G-protein, leading to inhibition of NT release

4

3

2

NeurotransmitterReceptor

Nabilone is thought to activate CB1 receptors directly, mimicking the effects of endocannabinoids

5

Endogenous and ExogenousCannabinoids Reduce Neuronal Signaling

Adapted from Page 5 of Slatkin NE. J Support Oncol. 2007;5(suppl3):1.Reprinted with permission.


Cannabinoids—Supportive Oncology

  • Established roles

    • CINV

  • Emerging roles

    • Analgesia

    • Spasmolysis

    • Anorexia-cachexia

    • Sedative

    • Antidepressant

    • Antineoplastic


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.


Diverse Neurotransmitters Mediate Emesis

Dopamine(D2)

Serotonin

(5-HT3)

Histamine

Substance P

(NK-1)

Endorphins

N + V REFLEX

GABA

Acetylcholine

Cannabinoids

Drug classes FDA approved in CINV

Adapted from Andrews PL, Naylor RJ, Joss RA. Supportive Care Cancer. 1998;6:197-203.


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.


5-HT3 Antagonists Are Ineffective for Controlling Delayed CINV in a Substantial Proportion of Patients

  • 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

Mild nausea

Moderate nausea

Severe nausea

41

Emesis

38

40

34

35

30

25

25

24

25

23

21

Patients with Delayed Nausea/Vomiting (%)

19

20

17

17

15

10

10

5

0

Carboplatin

Cisplatin

Doxorubicin

Hickok JT, et al. Cancer. 2003;97:2880.


Palonosetron Improves Outcomes, Yet CINV Persists in Most Patients

100

90

80

66

70

58

60

% of Patients Who Failed to Achieve Endpoint (Days 1–5)

49

50

40

30

20

10

0

No Emetic Episode

No Rescue Medication

No Nausea*

Endpoint

*Moderate or severe

Brames MJ, et al. Presented at the MASCC/ISOO 18th International Symposium; June 22-24, 2006: Toronto, Canada. Reprinted with permission.


Aprepitant Improves Outcomes, Yet CINV Persists in Most Patients

70

Aprepitant

Standard therapy

59

56

60

50

44*

39*

40

35

% of Patients inWhom CINV Persisted

30

20*

20

10

0

Acute CINV

Delayed CINV

Overall

*P >.001 compared with standard therapy.

Poli-Bigelli S, et al. Cancer. 2003;97:3090.


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;20:113. 2. Morrow GR, et al. Support Care Cancer. 1998;6:244. 3. Reesal RT, et al. Can J Psychiatr. 1990;35:80.


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: http://www.meds.com/pdq/supportive_pro.html. Accessed June 13, 2007. 2. Tramer MR, et al. BMJ. 2001;323:16. 3. NCCN Practice Guidelines in Oncology. 2005;1. Antiemesis. 4. CesametTM (nabilone). Product Information. San Diego, CA: Valeant Pharmaceuticals North America; 2006.


Control of Nausea and Vomiting Cannabinoids—A Systematic Review*

80

Control (placebo or active)

70

Cannabinoid

66

59

57

57

60

45

43

Event Rate (%)

40

36

20

0

vs Placebovs Active vs Placebo vs Active

Vomiting

Nausea

*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.


Patients’ Rating Preference for Cannabinoids

Preference for cannabinoids

vs placebo (4 studies)

vs active control (14 studies)

0.5 1.0 2.0 4.0 6.0 8.0 10.0

Relative risk (95% CI)Favors cannabinoids

Active control = prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, and alizapride. Tramèr MR, et al. BMJ. 2001;323:16.


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


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://www.dpna.org/1sativex.htm


Cannabinoids in the Treatmentof 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;118:327. 2. Iskedjian M, et al. Curr Med Res Opin. 2007;23:17. 3. Wissel J, et al. J Neurol. 2006;253:1337.


Rx Cannabinoids—Pharmacokinetics

Cesamet® (nabilone). Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; 2006. Marinol® (dronabinol). Product Information. Marietta, GA: Unimed Pharmaceuticals, Inc; 2006.


Cannabinoid Metabolism

*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: 74-116.


Aprepitant Metabolism

Oral aprepitant 40 mgWeak—125 mgModerateWeak

Inhibitory Effecton OrallyAdministeredCYP3A4 Substrate*

Inhibitory Effecton IVAdministeredCYP3A4 Substrate*

*Midazolam

Majumdar AK, et al. J Clin Pharmacol. 2007;47:744.


Side Effects of Cannabinoids*

*If smoked, respiratory effects, such as bronchitis, chronic obstructive pulmonary disease, lung infection.

Clark AJ. Pain Res Manage. 2005;10(suppl A):44A.


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


Case Study: Breakthrough CINV with Anthracycline-Based Therapy

William J. Gradishar, MD, FACP

Director, Breast Medical OncologyNorthwestern UniversityFeinberg School of MedicineRobert H. Lurie Comprehensive Cancer CenterChicago, Illinois


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


Infiltrating Ductal CarcinomaER, 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


Sentinel Lymph Node Negativefor 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


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)


Discussion with Oncologist

  • Risk reduction might be expected with this regimen

  • Expected toxicities

    • Neutropenia, alopecia, cardiac toxicity, mouth sores, fatigue, and nausea and vomiting


Reassurance and Management

The medical oncologist assures the patient that these symptoms canbe prevented or successfully managed should they develop.


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


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.


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


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

0

0

AcuteNausea

AcuteVomiting

DelayedNausea

DelayedVomiting

AcuteNausea

AcuteVomiting

DelayedNausea

DelayedVomiting

Moderately EmetogenicChemotherapy

Highly EmetogenicChemotherapy

Schwartzberg L. J Support Oncol. 2006;4(suppl 1):3.


Prevention of Emesis in Women on Day 1 After ChemotherapyResults 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

0

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.


Prevention of Emesis in Womenon Days 2 and 3Results 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

60

Patients (%)

4

9

4

7

40

20

0

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.


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


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 1. 2007. Antiemesis, MS-1.


Additional Treatment

  • Options for breakthrough treatment were discussed with the patient

  • Dexamethasone + lorazepam were added to her antiemetic regimen


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


Case Study: Anticipatory CINVand Opioid-Refractory Pain

Judith A. Luce, MD

Clinical Professor of Medicine, University of California, San Francisco Director, Oncology ServicesSan Francisco General HospitalSan Francisco, California


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


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


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


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


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


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


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


The Perfect Storm

Anorexia

Chemotherapy

Opioid analgesics

Nausea

Fatigue

Anxiety, depression

Pain

All of this

Poor compliance

Poor quality of life


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?


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:E40. 2. Dibble SL, et al. Oncol Nurs Forum. 2004;31:E1. 3. Bloechl-Daum B, et al. J Clin Oncol. 2006;24:4472.


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;99:385. 2. Miaskowski C, et al. J Pain. 2002;3:12. 3. Antoni MH, et al. Am J Psychiatry. 2006;163:1791.


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


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://www.dpna.org/1sativex.htm


Effects Showed in Preclinical Studies

Type of Pain

Acute

Visceral

Chronic

Neuropathic

Antinociceptive

Significant evidence

Significant evidence

Significant evidence

Hyperalgesia

Significant evidence

Significant evidence

Due to up-regulation of CB1 receptors_______________

Data from animal studies support a role for CB2 receptors

Anti-inflammatory

Significant evidence

CB2 receptors play important role

CB2 receptors play important role

Allodynia

Due to up-regulation of CB1 receptors

Comparison with opioids

Comparable in potency and efficacy

Greater potency and efficacy in both inflammatory and neuropathic pain

Cannabinoids and Pain Management

Lynch M. Pain Res Manage. 2005;10(suppl A).


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


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


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


Case Study: Noncompliance as a Result of CINV and Pain

Kristen Fessele, RN, MSN, AOCN

Associate Director, Human Research ServicesThe Cancer Institute of New JerseyNew Brunswick, New Jersey


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)


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


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


“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


“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


“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


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


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;74:102. 2. Swegle JM, Logemann C. Am Fam Physician. 2006;74:1347. 3. Cherny N, et al. J Clin Oncol. 2001;19:2542. 4. McNicol E, et al. J Pain. 2003;4:231.


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;74:102. 2. Forman WB. Clin Geriatr Med.1996;12:489.


Approaches for ManagingOpioid-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.


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


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


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;74:1317. 2. Manzanares J, et al. Trends Pharmacol Sci. 1999;20:287. 3. Reche I, et al. Eur J Pharmacol. 1996;318:11. 4. Campbell F. BMJ. 2001;323:13.


Clinical Trials Under WaySativex

  • 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)


Clinical Trials Under WayNabilone

  • 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: http://clinicaltrials.gov/ct/action/GetStudy. Accessed May 16, 2007.


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; 2006. 2. Marinol® (dronabinol) Product Information. Marietta, GA: Unimed Pharmaceuticals; 2006.


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


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; 2006. 2. Marinol® (dronabinol) Product Information. Marietta, GA: Unimed Pharmaceuticals; 2006.


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

Most Common Adverse Events

1. CesametTM (nabilone) Product Information. Costa Mesa, CA: Valeant Pharmaceuticals; 2006. 2. Marinol® (dronabinol) Product Information. Marietta, GA: Unimed Pharmaceuticals; 2006.


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.


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


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