Analgesia
1. What research has been done and what is known about the possible
medical uses of
marijuana?
A number of studies have been conducted on the antinociceptive or analgesic
effect of
tetrahydrocannabinol (THC) or marijuana in both animals and human subjects; the
results
have been conflicting. Of interest is the recent identification of cannabinoid
receptors as well as
an endogenous ligand, anandamide. There is some evidence that they are part of a
natural pain
control system distinct from the endogenous opioid system. Recognizing that some
studies have
demonstrated an antinociceptive (analgesic) effect of THC and related compounds
in rodents, it
may be useful to identify what specific kinds of pain may be relieved by
marijuana or THC.
Animal studies on the analgesic effect of marijuana have produced inconsistent
results. Whereas
one study shows that delta-9-tetrahydrocannibinol (9-THC) is equipotent to
morphine in rats
(tailflick test), and more potent than morphine in mice (hotplate test), other
studies showed that
9-THC was less potent
than morphine in both mice and rats. Cannabinoids have been shown to
be possibly analgesic in animal models of neuropathic pain.
There have been a few studies of marijuana/9-THC employing different
models of experimentally
induced pain in volunteer subjects, and these studies have also yielded
conflicting results. Raft
and colleagues (1977) found that, in oral surgery patients, premedication with
intravenous 9-THC
was less effective than diazepam or placebo in reducing two kinds of
experimentally induced
pain. Another study showed that smoked marijuana increased pain tolerance, while
others
showed either no effect or a lowering of pain threshold after oral or intravenous
dosing with 9-THC
or smoking marijuana. The current "FDA Guideline for the Clinical Evaluation of
Analgesic
Drugs" (FDA 1992) notes that "Evidence is still inadequate to establish that any
experimental
pain model will consistently and accurately predict the clinical efficacy of new
analgesics, . . . [and]
they cannot substitute for controlled trials in patients with pathologic pain
[naturally occurring
pain caused by disease or tissue injury] in producing substantial evidence of
analgesia . . ." This
is also the overwhelming consensus of investigators who conduct controlled
clinical trials of
analgesic efficacy. Therefore, the above studies contribute little information
about the analgesic
efficacy of marijuana/9-THC in patients with pain.
There appear to be no controlled analgesic studies of smoked marijuana in
patients with naturally
occurring pain. However, Noyes and his colleagues conducted two studies of oral
9-THC in
inpatients with cancer pain. Both of these studies used the same standard
single-dose analgesic
study methodology and met the criteria for well-controlled clinical trials of
analgesic efficacy,
but with small sample sizes. Both were randomized, double-blind, crossover
comparisons
employing a full-time nurse-observer, who collected hourly subjective ratings of
pain intensity
and pain relief. Observed and reported side effects were recorded, as were the
responses to an
11-item subjective effects questionnaire.
The first study in 10 cancer patients compared a placebo and 5, 10, 15, and 20
mg doses of 9-THC
over a 6-hour observation period (Noyes et al. 1975a). The slope of the
dose-response curve for
pain relief was significant, as was a pairwise comparison of pain relief after
the two lower doses
combined versus the two higher doses combined. There was also a clear
dose-response relationship
for sedation, mental clouding, and other central nervous system (CNS) related
side effects.
Because of sedation, the 20-mg dose was judged to be "of limited value for most
patients."
The second study in 36 cancer patients compared placebo, 10, and 20 mg of 9-THC and 60 and
120 mg of codeine over a 7-hour observation period (Noyes et al. 1975b).
Codeine 120 mg and
9-THC 20 mg were similar
to each other and significantly superior to placebo for the sum of the
pain intensity differences and total pain relief, while other pairwise contrasts
were not significant.
Relative potency analysis was not performed.
The time-effect curves for both doses of codeine and for 9-THC, 10 mg, peaked at the
third
hour. As in the first study, the 20 mg dose of 9-THC peaked at the fifth
hour, which probably
reflects the delayed absorption of oral THC. "Patients receiving 20 mg of THC
were heavily
sedated and even at 10 mg reported considerable drowsiness. Other dose limiting
side effects
included dizziness, ataxia and blurred vision" (Noyes et al. 1975b).
Mental clouding, thinking
impairment, disconnected thought, disorientation, slurred speech, and impaired
memory were
much more prominent after both doses of 9-THC than after codeine
administration, and patients
expressed particular concern over their "loss of control" over thought and
action. Five patients
experienced very unpleasant psychic effects after 9-THC; three patients said
they felt as if they
were dying, one patient experienced depressed mood, and one patient suffered
paranoid ideation.
In two patients, the adverse mood effects persisted 3 or 4 days.
These studies indicate that 9-THC has some analgesic
activity in humans. They also indicate
that there is, at best, a very narrow therapeutic window between doses that
produce useful
analgesia and those that produce unacceptable adverse CNS effects.
2. What are the major unanswered scientific questions?
Since oral 9-THC has
some analgesic activity, it is highly likely that smoked marijuana has
some analgesic activity in some kinds of clinical pain. Because 9-THC from smoked marijuana
is absorbed directly into the pulmonary circulation, this route of administration
results in a 9-THC
blood level curve much more like that produced by an intravenous injection than
that after oral
administration. It is therefore likely that smoked marijuana potentially allows
a more precise
titration to effect than oral administration of 9-THC with its delayed, poor,
and erratic
bioavailability. Theoretically, smoked marijuana or inhaled THC potentially has
some of the
characteristics of a patient-controlled analgesia (PCA) pump. It is therefore
possible that some
pain patients could use smoked marijuana to titrate themselves into the
therapeutic window of
adequate pain relief while avoiding unacceptable adverse effects. Although the
above scenario is
pharmacologically reasonable, only properly designed controlled clinical
analgesic studies can
determine if it actually works and is practically useful. For example, it is
also possible that the
minimum blood level of 9-THC that produces useful
analgesia also usually produces a level of
sedation, mental clouding, and thinking impairment that is unacceptable to most
patients.
There are currently available a great variety of both opioid and nonsteroidal
anti-inflammatory
drug (NSAID) analgesics in various dosage formulations suitable for many routes
of administration.
Adroit use of these can manage most acute pain and even chronic cancer pain
satisfactorily. If
marijuana is to be a useful analgesic, healthcare providers need to know how it
compares in
efficacy and safety to at least a few of the standard analgesics that would be
used in managing a
particular kind of pain.
3. What are the diseases or conditions for which marijuana might have
potential as a treatment
and which merit further study?
Neuropathic pain represents a treatment problem for which currently available analgesics are, at best, marginally effective. Since 9-THC is not acting by the same mechanism as either opioids or NSAIDs, it may be useful in this inadequately treated type of pain. Evaluation of cannabinoids in the management of neuropathic pain, including HIV-associated neuropathy, should be undertaken. A few animal studies support this idea. Another potentially useful role for marijuana/9-THC might be as an adjuvant when added to a regimen of standard analgesics.
References
FDA Guideline for the Clinical Evaluation of Analgesic Drugs. DHHS Pub. No. 93-3093. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Food and Drug Administration, 1992.
Noyes, R., Jr.; Brunk, S.F.; Baram, D.A.; and Canter, A. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol 15(2-3):139-143, February-March, 1975a.
Noyes, R., Jr.; Brunk, S.F.; Avery, D.A.H.; and Canter, A.C. The analgesic properties of delta-9-tetrahydrocannabinol. Clin Pharmacol Ther 18(1):84-89, July, 1975b.
Raft, D.; Gregg, J.; Ghia, J.; and Harris, L. Effects of intravenous tetrahydrocannabinol on experimental and surgical pain. Clin Pharmacol Ther 21(1):26-33, 1977.
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