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Abstract: A prospective pilot study of the
use of inhalation marijuana as an antiemetic for cancer
chemotherapy was conducted. Fifty-six patients who had no
improvement with standart antiemetic agents were treated
and 78% demonstrated a positive response to marijuana.
Younger age and prior marijuana exposure were factors that
predicted response to treatment. Toxicity was mild and
consisted primarily of sedation and xerostomia. This
preliminary trial suggests the usefulness of inhalation
marijuana as an antiemetic agent. Because of the lack of a
randomized placebo control group, the precise role of this
agent is unclear. Further studies should include
derivatives of this substance in combination with standard
effective drugs to control chemotherapy-induced nausea and
vomiting.
A great deal of clinical information has recently been
generated concerning
the efficacy of various antiemetic agents for patients
treated with cancer
chemotherapy. (1-3). Without effective control of nausea
and vomiting,
patient compliance with potentially curative chemotherapy
programs
diminishes, compromising not only quality but quantity of
life. Effective
new chemotherapeutic agents could never be successfully
tested in clinical
trials if they possessed potent emetic side-effects.
Although a number of agents have recently been found to be
active,
including metoclopramide, (4,5) haloperidol, (6)
dexamethasone, (7) and
lorazepam, (8) the need to introduce newer agensts and
combination
antiemetic therapy may be necessary for continued control
of symptoms.
Also, complete control of nausea and vomiting during
anticancer treatment
must take into account not only the physical effects but
also the
psychological ones. Control of anxiety through behavior
modification and
relaxation is an effective antiemetic treatment of
anticipatory nausea and
vomiting. (9)
Natural and synthetic cannabinoids are known to be
effective
antiemetic agents. (10-12) Delta-9-tetrahydrocannabinol
(THC) has been
found to be superior to prochlorperazine. (13) Also,
patients who are
refractory to standart antiemetic agents have significant
reduction in
nausea and vomiting with oral THC. (14) There is little
information on
the efficacy of inhalation marijuana aside from anecdotal
reports from
patients who obtained the drug privately.
As a part of a New York State Department of Health program,
North
Shore University Hospital conducted a preliminary study of
the use of
inhalation marijuana as an antiemetic agent for cancer
chemotherapy. The
purpose of this study was to evaluate the efficacy of
inhalation marijuana
for patients refractory to standard agents, to identify
patient
characteristics to predict response, and to evaluate
toxicity and patient
acceptance of this form of treatment.
METHODS
Patients with histologically confirmed malignancies who
were actively
receiving chemotherapy were entered into the protocol.
Eligibility
criteria included: 18 years of age or older, refractoriness
to
conventional antiemetic agents, and absence of severe
cardiac or
psychiatric disease. Patients had to agree not to drive or
operate heavy
machinery or a motor vehicle for at least 12 hours after
the last dose of
marijuana. Central nervous system depressants including
alcohol were
prohibited during the administration of marijuana.
Marijuana cigarettes were supplied by the National
Institute on Drug
Abuse (NIDA) to the New York State Department of Health.
All patients
were instructed on standard smoking procedures. The patient
inhales
deeply, holds the inhalation for ten seconds, and then
exhales. After
waiting 10 to 15 seconds, the cycle is repeated. The total
dose is
completed within five minutes. A flame-proof holder was
available to
permit delivery of nearly all of the cigarette appropriate
to the patient's
dosage. The dose schedule, which was calculated to the
nearest one-fourth
cigarette; was 5 mg THC/m2, starting 6-8 hours prior to
chemotherapy and
every 4-6 hours thereafter, for a total dose of four doses
per day on each
day of chemotherapy (one cigarette= 10.8 mg THC). In order
to prevent
cigarettes from drying out and causing harsh smoke,
patients were
instructed to keep the cigarettes in the refrigerator or
humidified.
This was a nonrandomized study where patients served as
their own
controls. Patients were asked to self-rate their status by
completing a
patient evaluation form after each therapeutic episode.
Nausea was graded
on a scale from 1 (none) to 4 (severe), vomiting was graded
from 1 (none)
to 5 (10+ times), appetite was graded from 1(none) to 5
(above normal),
and physical state was graded from 1 (very weak) to 4
(above normal), and
mood was graded from 1 (very depressed to 5 (very happy).
Based on the
degree of nausea, vomiting, food intake, physical state,
and over-all mood,
patients rated the overall effectiveness of marijuana as
none, moderately
effective, and very effective.
Physician investigators were approved by the Hospital's
Patient
Qualification Review Board. Physicians utilized the
official New York
State triplicate prescription form as their research order
for medication.
Informed consent was obtained from all patients and the
procedures followed
were approved by an institutional research committee.
RESULTS
Seventy-four patients entered the study and 56 were
evaluable. Eighteen
patients who had initially agreed to be treated with
marijuana later
decided not to participate. Eighteen patients rated the
marijuana very
effective (34%) and 26 patients rated it moderately
effective (44%) for
an overall response rate of 78% (44/56). Twelve patients
(22%) noted no
benefit.
TABLE I. Patient Characteristics (Percent)
Responders Nonresponders P
Value
(N=44) (N=12)
Female 64 75
NS*
Mean age (yr) 41 51
(median) (40) (54)
Breast cancer 36 33
NS
Lymphoma 34 25
NS
Prior radiation therapy 30 8
NS
Prior THC 29 20
NS
Prior Marijuana 52 17
0.06
Euphoria 60 36
NS
(high)
Smoker 53 38
NS
*NS= not significant
Standard deviation= 11.9
Standard deviation= 15.6
Characteristics of responding and nonresponding patients
are listed in
Table I. While no statistically significant differences
were noted between
responders and nonresponders with regard to sex, type of
diagnosis, prior
radiation therapy, prior oral THC treatment, incidence of
euphoria, or
smoking history, it is important to remember that the
sample sizes were
small, making interpretation of differences difficult.
Patients who
responded to marijuana cigarettes were more likely to be
younger, median
age 40 vs 54 for nonresponders, and had prior marijuana
exposure, 52% vs
17% (p= 0.06).
The most common diagnoses for this group of patients were
breast
cancer, lymphoma, lung cancer, colon cancer, ovarian
cancer, testicular
cancer, sarcoma, acute leukemia, and myeloma. The most
common emetic
chemotherapeutic agents were cyclophosphamide, doxorubicin,
cis-platinum,
procarbazine, methotrexate, dacartazine, and streptozocin,
given either
singly or in combination. Four of seven patients treated
with cis-platinum
responded favorably to marijuana cigarettes.
Toxic side effects included sedation in 88%, dry mouth in
77%,
dizziness in 39%, and confusion in 13%. Anxiety, headache,
and fantasizing
were also seen but were less common. There was no toxicity
in 13% of
patients (Table II).
TABLE II. Percent Toxicity
Sedation 88
Dry Mouth 77
Dizziness 39
Confusion 13
Anxiety 11
Headache 11
Fantasizing 11
None 13
DISCUSSION
The results of this prospective study suggest that
inhalation
marijuana is active in controlling nausea and vomiting
resulting from
chemotherapy. Marijuana benefited patients who were treated
with a wide
range of chemotherapeutic agents including drugs which have
considerable
emetogenic potential. A prior report by Chang et al (15)
documented
effectiveness of oral THC and inhaled marijuana against
high-dose
methotrexate, which normally has mild gastrointestinal
toxicity. While
most experience indicates that THC is generally ineffective
against
cis-platinum-induced emesis, benefit was seen in a small
number of patients
treated in our program with this agent.
Since this was a single arm, nonrandomized, outpatient
program, this
study lacks a controlled placebo group. Nevertheless, the
patients acted
as their own controls, having previously failed standard
antinausea
medications. They evaluated marijuana based on their
subjective rating of
the severity of nausea, vomiting, appetite and food intake,
mood, and
physical state after chemotherapy treatment. A
placebo-controlled,
randomized inpatient study which quantitates all emetic
episodes would
obviously provide objective and precise information. (16)
Failure to respond to oral THC does not preclude benefit
from inhaled
marijuana. Twenty-nine percent of patients who failed oral
THC responded
to the cigarette form. This is not unexpected, since only
5-10% of orally
administered THC is absorbed, whereas inhaled marijuana has
a five-to
tenfold greater bioavailability. (17) Clearly, oral THC is
an effective
treatment for chemotherapy-induced emesis. Most studies
have demonstrated
THC to be better than placebo and comparable to
prochlorperazine. (18)
The major obstacle related to the oral and inhaled
cannabinoids is the
route of administration. Patients with anticipatory
vomiting do not retain
the oral THC. Because of its poor water solubility,
parenteral
adminstration of cannabinoids has been difficult. The only
cannabinoid
available for parenteral use, levonantradol, is currently
being
investigated and has documented activity comparable to THC.
(19) Perhaps
intranasal or transdermal forms of THC will be developed
and found to be
clinically useful.
Patient characteristcs were evaluated to identify factors
which would
predict response to marijuana. There were no significant
differences
between responders and nonresponders with regard to sex,
diagnosis, prior
radiation therapy, prior THC ingestion, induced euphoria,
and history of
cigarette smoking. The only factors that approached
significance were
young age and prior marijuana intake. Unlike the experience
with oral THC,
experiencing a euphoric high was not a prerequisite to
obtaining the
antiemetic effect with marijuana. (20)
The mechanism of the antiemetic action of cannabinoids is
unknown.
Inhibition of prostaglandin and cyclic adenosine
monophosphate has been
suggested. Its major action is more likely related to its
effect on the
brain, as marijuana causes central nervous system
depression and impairment
of brain function. At the cellular level, cannabinoids
interfere with the
synthesis of nucleic acids and chromosome proteins. (21)
Some of the problems encountered in this study which could
influence
interpretation of the results were the low patient accrual
and the fact
that nearly 25% of patients who initially consented refused
to receive
treatment. Reasons for patients' refusal to participate
included physician
and patient bias against smoking, harshness of smoke from
the cigarettes,
and preference for oral THC capsules. The major objection
was related to
the social stigma attached to the use of marijuana. Many
patients rejected
the idea of "smoking pot" at home and exposing their
children to the
implications of this type of medication. Should this
therapy become
available in a different vehicle of administration, patient
acceptance
would significantly improve.
Our results demonstrate that inhalation marijuana is an
effective
therapy for the treatment of nausea and vomiting due to
cancer
chemotherapy. A randomized, controlled trial would,
however, be necessary
to accurately define the exact role of this drug. Toxic
effects are well
tolerated and the availability of a parenteral form would
improve patient
utilization of this agent. Future antiemetic protocols
should include the
active ingredient of marijuana in combination with current
effective
agents.
Acknowledgments. The authors thank Rosemarie Galderisi and
Annie
Middleton for their assistance.
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