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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
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

FLIE-nausea > FLIE-Vomiting P = .0097

There is a greater negative impact on
QOL from nausea than there is from
vomiting
P = .0049
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 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 1. 2007. Antiemesis, MS-1.
Cannabinoids
Botanical
Endogenous
Pharmaceutical

Marijuana

Anandamide

Nabilone

Hashish

2-AG

Dronabinol

PEA

Delta-9-THC &
cannabidiol
Cannabinoid Receptors
CB1—neuromodulation
CB2—immunomodulation

Basal ganglia

Spleen

Hippocampus

Tonsil

Cerebral cortex

Mast cells

Cerebellum

Macrophages

Spinal cord

Lymphocytes

Afferent nociceptors

Microglia
Kalant H. Pain Res Manag. 2001;6:80.
Mechanism of Action of the Cannabinoids
5
EXOGENOUS
Cannabinoid Therapy
Presynaptic
Neuron
Inhibition of
Neurotransmitter
Release
1
Neurotransmitter (NT) from
presynaptic neuron activates
the postsynaptic neuron
2
Activated postsynaptic
neuron releases
endocannabinoids
3
Endogenous CB1 ligand
diffuses back to and binds
to the presynaptic CB1
receptor
4
CB1 receptor activates a
G-protein, leading to
inhibition of NT release
5
Nabilone is thought to
activate CB1 receptors
directly, mimicking the
effects of endocannabinoids
CB1 Receptor 4
1
Postsynaptic
Neuron
2
Neurotransmitter
Receptor
Endogenous and Exogenous
Cannabinoids Reduce Neuronal Signaling
3
Endogenous
Cannabinoid
Retrograde
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
Serotonin
(5-HT3)
Substance P
(NK-1)
Dopamine
(D2)
N+V
REFLEX
GABA
Histamine
Endorphins
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.
Patients with Delayed Nausea/Vomiting (%)
5-HT3 Antagonists Are Ineffective for
Controlling Delayed CINV in a Substantial
Proportion of Patients
40
Mild nausea
Moderate nausea
Severe nausea
Emesis
38
 360
41
34
35
– 322 completed requirements
for chemotherapy cycle 1
30
20
25 24
25
25
23
21
17
19
17
15
10
10
5
0
Carboplatin
Cisplatin
Hickok JT, et al. Cancer. 2003;97:2880.
patients at 18 private
medical oncology groups
were enrolled in the study
Doxorubicin
 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
% of Patients Who Failed to Achieve
Endpoint (Days 1–5)
Palonosetron Improves Outcomes,
Yet CINV Persists in Most Patients
100
90
80
70
60
50
66
58
49
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
% of Patients in
Whom CINV Persisted
Aprepitant
60
59
56
Standard therapy
50
44*
40
35
39*
30
20*
20
10
0
Acute CINV
*P >.001 compared with standard therapy.
Poli-Bigelli S, et al. Cancer. 2003;97:3090.
Delayed CINV
Overall
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)
Cannabinoid
70
Event Rate (%)
66
60
59
57
57
45
43
40
36
20
0
vs Placebo
Nausea
vs Active
vs Placebo
Vomiting
vs Active
*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
Relative risk (95% CI)
Favors cannabinoids
10.0
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 Treatment
of Other Pain

Chronic, incapacitating back pain1
–

Multiple Sclerosis (MS) neuropathic pain2
–

Decrease in spinal pain intensity and headache with
nabilone
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 spasticityrelated 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
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)
2h
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; 2006. Marinol®
(dronabinol). Product Information. Marietta, GA: Unimed Pharmaceuticals, Inc; 2006.
Cannabinoid Metabolism
CYP450 Metabolizing
Enzymes
CYP450 Enzyme
Inhibition
CYP450 Enzyme
Induction
Nabilone
2C9*, 3A4
(aldehyde oxygenase)
None to date
None to date
Dronabinol
2C9*, 2C11, 3A4
(aldehyde oxygenase)
3A4
None to date
*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 mg
125 mg
Inhibitory Effect
on Orally
Administered
CYP3A4 Substrate*
Inhibitory Effect
on IV
Administered
CYP3A4 Substrate*
Weak
Moderate
—
Weak
*Midazolam
Majumdar AK, et al. J Clin Pharmacol. 2007;47:744.
Side Effects of Cannabinoids*
Symptom/Effect
CNS
Sedation
Somnolence
Dizziness
Euphoria/“high”
Blurred vision
Anxiety; panic
Paranoia
Psychosis
Depression
Ataxia
Asthenia
Cognitive effects
Cardiovascular
Postural hypotension
Vasodilatation (red eyes)
Tachycardia
Palpitations
Others
Dry mouth
Headache
Most Common
4
4
4
Common
4
4
4
4
4
Rare
4
4
4
4
4
4
4
4
4
4
*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 Oncology
Northwestern University
Feinberg School of Medicine
Robert H. Lurie Comprehensive Cancer Center
Chicago, 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 suspiciousappearing lesion measuring ~ 1.5 cm in
the same area noted on physical exam
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
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
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 can
be 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 wellcontrolled 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
Patients (%)
Perception vs Reality in Patients Receiving
Moderately or Highly Emetogenic
Chemotherapy
60
50
40
30
20
10
0
MD/RN prediction
Patient experience
Acute Acute Delayed Delayed
Nausea Vomiting Nausea Vomiting
60
50
40
30
20
10
0
Moderately Emetogenic
Chemotherapy
MD/RN prediction
Patient experience
Acute Acute Delayed Delayed
Nausea Vomiting Nausea Vomiting
Highly Emetogenic
Chemotherapy
Schwartzberg L. J Support Oncol. 2006;4(suppl 1):3.
Prevention of Emesis in Women on Day 1
After Chemotherapy
Results with Standard Therapy in Randomized Trials
All patients received dexamethasone and ondansetron
Patients (%)
100
80
60
AC
69
66
Cisplatin
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 Women
on Days 2 and 3
Results with Standard Therapy in Randomized Trials
Patients (%)
On Days 2 and 3: Cisplatin patients given dexamethasone 8 mg bid
AC patients given ondansetron 8 mg bid
100
80
60
AC
Cisplatin
49
47
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 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
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 chemotherapyinduced 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
Pain
All of this
Poor compliance
Anxiety,
depression
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
Cannabinoids and Pain Management
Effects Showed in
Preclinical Studies
Type of Pain
Acute
Antinociceptive
Hyperalgesia
Visceral
Significant
evidence
Significant
evidence
Significant
evidence
Anti-inflammatory
Chronic
Neuropathic
Significant evidence
Significant evidence
Significant evidence
Due to upregulation of CB1
receptors
_______________
Data from animal
studies support a
role for CB2
receptors
CB2 receptors play
important role
CB2 receptors play
important role
Allodynia
Comparison
with opioids
Due to up-regulation of CB1 receptors
Comparable
in potency
and efficacy
Greater potency and efficacy in both
inflammatory and neuropathic pain
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 Services
The Cancer Institute of New Jersey
New 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 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.
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 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)
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: 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.
Most Common Adverse Events

Nabilone1

Dronabinol2
– Drowsiness
– Euphoria (“high”)
– Vertigo
– Abdominal pain
– Dry mouth
– Nausea/vomiting
– Euphoria (“feeling
high”)
– Dizziness
– Ataxia
– Somnolence
– Headache
– Paranoid reaction
– Concentration
difficulties
– Abnormal thinking
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