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 Chemical Dependency
Marijuana and Pain Management
by Michael M. Miller, M.D., Meriter Hospital NewStart
Medical Director
© 2005 Meriter Hospital
(Permission is granted to reprint this publication
without alterations for general patient use: You must
cite Meriter Hospital as the copyright holder, along
with the title and year of publication, followed with
the words "Reprinted with permission.")
FA current public policy debate that addresses a
health care issue is the question of whether the use of
marijuana 'for medical purposes' should be legalized,
and whether physicians should be able to prescribe 'medical marijuana' for their patients without threat of
arrest or loss of their medical license. Several states
(usually by ballot initiative, not by legislation) have
authorized 'medical marijuana', and the U.S. Supreme
Court will decide this year if federal drug control
activities have jurisdiction even in the face of
permissive state laws. The judicial decision is one of
state's rights: the Court will not decide if 'medical
marijuana' use should be 'legal' on a federal basis, or
even if 'medical marijuana' is a 'good thing'. But the
ballot initiatives usually win public favor because they
couch the issue as one of 'patient's rights': what kind
of draconian government would deny a person the ability
to heal their pain? In the midst of passionate arguments
(where passion often trumps reason), it would probably
be useful for health care providers—who will be drawn
into this debate, and appropriately so—to understand the
science that underlies the rhetoric.
The position of medical organizations such as the AMA
and ASAM, is that decisions about medical practice
should be evidence-driven: double-blind clinical trials
of smoked marijuana should be undertaken (with no
harassment of researchers or impediments to their
obtaining cannabis plants for their research) to
determine effectiveness and safety. And pharmaceutical
THC in the form of the orally-administered FDA-approved
medication dronabinol (Marinol), should continue to be a
Scheduled drug under the Controlled Substances Act and
should be prescribed to patients for the two current
FDA-approved indications: anorexia associated with
weight loss in patients with AIDS; and for
nausea/vomiting associated with cancer chemotherapy in
patients who have failed to respond adequately to
conventional antiemetics. Significant evidence also
exists that cannabis (plant marijuana) and its active
ingredient (THC) lower intraocular pressure in patients
with glaucoma. But a basic question is: should
cannabinoids (the various active ingredients in
marijuana that interact with specific cannabinoid
receptors in the human body) be used preferentially over
the alternatives, balancing benefits vs. risks?
Many people, including lawmakers and physicians, begin
this debate with a position that there are no
significant risks of harm from using dronabinol or
smoked marijuana. This often derives from 'experiential
data': “I know when I was younger, I knew lots of people
who smoked marijuana, even lots of it—and maybe I was
one of them—and nothing bad ever happened to them. They
turned out all right.” Such statements are certainly
true, and actually apply to most addictive drugs.
Addiction occurs only in a fraction of the people who
use drugs. Two-thirds of Americans drink alcohol, for
example, but only 10% of users will ever develop
addiction to it. For illegal drugs in general, only 20%
of users will ever develop addiction. For marijuana, the
percentage is likely closer to 5%. But the fact is that
smoked marijuana does lead to significant dysfunction in
literally millions of people (the first article in this
series addressed addiction as an outcome of chronic use,
and the second article focused on the acute effects of
THC on memory, learning, coordination, perception, and
driving skills). It is important that health care
professionals infuse into the public policy debate (and
the media debate) the reality that marijuana is not a
harmless drug for all users, and to base their arguments
on science vs. hyperbole.
In the current debate, proponents of legalization of
marijuana for 'medical purposes' often invoke
heart-rending patient anecdotes—personal stories of
persons with chronic illnesses who self-report benefits
from smoking 'pot'. For patients who have experienced
weight loss from AIDS or nausea/vomiting from cancer
chemotherapy, Marinol is of course available to them,
and their doctor can prescribe it (it's Schedule III in
all states except Oklahoma, where it is still a Schedule
II). But often the patient presents a story of chronic
pain, and begs for the ability to legally smoke
marijuana to relieve that pain. To inform that issue, we
can delve into the pathophysiology of pain and what is
known about cannabinoids and pain relief.
We all know that pain is a complex phenomenon: messages
from specialized nerve endings called pain receptors
(located throughout the body in muscles, joints, various
organs) travel along sensory nerves to the spinal cord,
and interact with other nerve cells that travel from the
spinal cord to a specific region of the brain that
receives all this information (the thalamus)—and all
this is 'subcortical', that is, this information has not
yet reached the cerebral cortex, where 'conscious
awareness' resides. It is when the signal is transferred
to yet a third pathway of nerves, from the thalamus to 'higher levels' that the individual
'feels' or
experiences pain. It is often stated that 'pain is
subjective', and there is truth to that, for the
association areas of the frontal cortex have to take the
information that comes from the thalamus and 'make
sense' of it. Data about pain ends up in a special part
of the cortex called the sensorimotor cortex, and the
source of the pain (in the left foot vs. the right
flank) can be localized. But what the pain 'means to'
the individual, is based on interactions between the
neurons in the 'sensory strip', and neurons in the
association areas, and neurons in the limbic system,
where emotional data is processed. And memory of
previous painful experiences also factors in to how we 'feel about' the objective information that has come in
from the various pain receptors throughout our bodies.
Kinds of Pain
There are three different kinds of pain. One comes from
direct stimulation of pain receptors, due to mechanical,
thermal, or chemical injury. That could be called
'somatic pain', coming from anywhere in the body. Then
there is 'visceral pain', which comes due to
inflammation of a specific organ. Finally, there is 'neuropathic pain', which results from actual injury to
a nerve (sensory nerves from the periphery, or nerves in
the spinothalamic tract carrying information from the
spinal cord to the thalamus, can be cut, pinched,
metabolically injured by diabetes, degenerated or
demyelinated by illnesses, etc.) Treatment of pain must
be specific to the type of pain. Non-steroidal
anti-inflammatory drugs (like aspirin or NSAIDs) reduce
inflammatory pain; opioids aren't very effective for neuropathic pain.
There are an incredible series of feedback loops that
modulate the transmission of 'pain information' as it
ascends from distant parts of the body to and up the
spinal cord. Some are at the level of the dorsal horn of
the spinal cord itself, where peripheral nerves enter
the cord from specific locations in the trunk or limbs.
A major modulating loop goes from the thalamus back down
to the spinal cord, basically 'saying' something like
“hey, the thalamus has received your input, okay, just
tone it down down there.” Information is transmitted
within a nerve cell electrically (a current flows down
the cell axon), and from cell-to-cell chemically (via
the release of a neurotransmitter chemical from one cell
that interacts with a specialized area on the membrane
of the other cell, the 'receptor' for that chemical).
Drugs that treat pain (and for many other conditions) 'work' because they impact this chemical relay of
information. And the last 30 years have shown us that
external chemicals (in pills) 'work' because they have a
specific site of action in the body, which is a receptor
for an internal chemical that does the same thing that
the medication is doing. Thus, the major pain killers
are opioid analgesics, and we now know huge amounts
about the endogenous opioid systems of endorphins and
enkephalins: opioids 'work' because they affect opioid
receptors in the nervous system. There are 5 major types
of opioid receptors, and now it is known that there are
3 major types of cannabinoid receptors: CB1, CB2, and
CB3. And pharmaceutical research firms have created both
agonists and antagonists for each of them, and are busy
finding out how they might eventually help patients.
It has been determined that CB1 receptors are present in
their highest density in areas that control cognitive,
motor, sensory, and emotional functions—which makes
sense given marijuana's effects. Thus, they are located
in the cerebral cortex and association areas (affecting
concentration and memory), in the cerebellum and basal
ganglia (affecting coordination), in the thalamus and periaqueductal grey matter of the cerebrum (the
'pain
centers'), in the amygdala and other limbic system
structures (affecting emotion and 'reward'), in the
hypothalamus and brainstem (affecting pulse, body
temperature, appetite, sleep-wake cycles and hormones),
in the spinal cord, and also in peripheral organs (the
spleen, on white blood cells, and in the testes). The
hippocampus (a major 'memory center'), the coordination
areas, and the pain areas are most prominent. It is now
known that the reason marijuana produces loss of motor
control is by promoting muscle relaxation, muscle
weakness, and lack of coordination by the action of THC
on CB1 receptors in the cerebellum and basal ganglia,
resulting in inhibition of release of GABA, glutamate,
and other neurotransmitters. Marinol works by acting on
CB1 receptors in the vomiting center of the medulla in
the brainstem, and CB1 receptors affecting appetite in
the hypothalamus.
In the early 1990's, scientists discovered not only CB1
and CB2, but also some endogenous compounds that act on
them. Best known is anandamide: infusing THC or
anandamide through micropipettes into brain areas rich
in CB1 receptors will produce comparable effects. Also,
infusing anandamide into injured soft tissues in a lab
animal will provide pain relief. It's also been shown
that when pain centers (such as the periaqueductal grey
area of the midbrain are stimulated by electrodes, there
is increased released of anandamide in those areas,
mimicking the effects of a painful stimulus arriving in
the midbrain from some peripheral site of injury.
Biologists have also discovered that endogenous
cannabinoids are inactiviated by a re-uptake process,
through which they are removed from the synapse and
pulled back into the presynaptic cell by a specific
transporter system involving a specific carrier protein,
called AMT; then, once inside the presynaptic neuron,
anandamide is hydrolyzed by a specific enzyme called
FAAH. Thus, phamacologists know of many potential sites
of action for new drugs that could act on the endogenous
cannabinoid system: drugs to work on AMT or FAAH, for
example.
That cannabis can relieve pain has been known for
centuries. Marijuana was used for surgical anesthesia in
China almost 5000 years ago; for pain during childbirth
in ancient Israel; and for various ailments by the
famous Roman physician Galen. In the early 20th century,
before modern medical schools and pharmaceuticals,
cannabinoid extracts were considered to be among the
most effective options for treatment of migraine. We now
know the science of how cannabinoids are effective for
pain.
Research has shown that, after chronic injury to a nerve
(producing the special kind of pain called 'neuropathic
pain'), there is a decrease in the number of opioid
receptors in the dorsal horn of the spinal cord at the
level of the injury. This is an example of modulation:
it's like the body says 'OK, I've heard enough already!”
But there is not a decrease in the number of CB1
receptors in the dorsal horn. So information from that
nerve registers on the same number of cannabinoid
receptors—and if the 'signal' could be diminished, the
idea is that the pain would be less. What actually
happens is that after chronic nerve injury, there is an upregulation in the CB1 receptors in the thalamus: when
CB1 receptors in the thalamus (the 'central pain
center') are activated, they send signals down the
modulating nerve tracts back down to the spinal cord,
where GABA (the inhibitory neurotransmitter) is
released, decreasing the activity of the dorsal horn
cells that are about to send more 'pain information' up
to the thalamus. The hope of researchers is to see if
specific CB1 agonists will act on these upregulated
receptors in the thalamus and send lots of inhibitory
signaling down the cord to eventually reduce the
subjective experience of pain.
There are actually two different types of nerve fibers
that carry information in the spinothalamic tract. The
large-diameter fibers, called C fibers, contain more CB1
receptors and fewer mu-type opioid receptors; the
small-diameter fibers, called A-d fibers, contain more
mu opioid receptors and fewer CB1 cannabinoid receptors.
It is the C fibers that are more involved in
transmission of information in cases of neuropathic
pain, and thus there is another reason to wonder if
cannabinoids may be especially useful in the treatment
of neuropathic pain.
A fascinating finding is that CB2 receptors are located
not in the nervous system but mainly in immune tissues:
the spleen, tonsils, and on monocytes, B lymphocytes and
T lymphocytes. Anandamide is almost functionally
inactive at CB2 receptors, but another endogenous
chemical has been found that works there. Pharmaceutical
companies are working feverishly to find compounds that
act through the natural cannabinoid receptor system to
reduce the effects of inflammation.
It is known that CB1 receptor activitation on
presynaptic neurons in the medulla blocks serotonin and
norepinephrine release and thus reduces nausea. CB1
activity also decreases GABA-mediated inhibition of
norepinephrine in spinal cord neurons, and also
decreases GABA-medicated inhibition of endogenous
opioids that act on both mu and kappa opioid receptors.
So some of the pain-relieving effects of cannabinoids
does have to do with interactions with the internal
opioid system. However, most of the data now shows that
the pain-reducing actions of THC are not only
dose-related, but also independent of the endogenous
opioid system.
So that's the science. Now to the practical
applications. THC and other cannabinoids in marijuana do
have pain-killing properties, and that there is a clear
dose-response relationship. The problem is that the
potency of these compounds to relieve pain is quite low.
A 10 mg. dose of pharmaceutical THC is equipotent with
60 mg of codeine. A 'joint' of marijuana delivers about
5 mg. of THC, or the equivalent of one “Tylenol #3”
tablet. Marinol comes in 5 mg., 10 mg., and 25 mg.
strengths. But clinical studied have shown than when
patients have severe, chronic pain (such as from
cancer), when they push the dose of THC to try to attain
relief, they experience unwanted motor (coordination),
cognitive (memory) or emotional effects (anxiety,
dissociation symptoms, even perceptual changes), and
they find the drug to be unpleasant or dysphoric.
Given the recent discoveries about CB receptors,
there is hope that pharmaceutical researchers will
extract novel cannabinoids from marijuana or synthesize
new CB-receptor agonists or antagonists that will more
more potent pain killers than THC, or that will produce
effective analgesia without mental or motor side
effects. And to avoid the dangers of smoking a drug,
researchers already have in the pipeline novel drug
administration systems, such as THC inhalers. But for
now, all this brings us back to the political
argument. Is smoked marijuana sufficiently safe and
effective that it should be reduced from a Schedule I
agents (not for therapeutic use) to a Schedule II or III
agent (like oral Marinol capsules). It does have
beneficial effects, but not much, quantitatively,
compared to alternative agents in well-designed clinical
trials. Is it safe? Well, the dangers of a smoked
product (not to mention difficulties determining dosage
when the smoked method is used) compared to an oral
product, are obvious. And the epidemiology of cannabis
abuse and dependence is clear: people's lives are
definitely side-tracked by compulsive, repetitive,
out-of-control use of marijuana.
Hopefully our policy makers will leave medical practice
to the health care professionals and await the results
of clinical trials with smoked marijuana, and understand
the 'medical marijuana' issue for what it is: a
sociopolitical process to add respectability to
marijuana smoking and make it appear to be conventional
and approvable.
10/11/2005
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