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Gout
usually attacks middle-aged men and the big toe
joint
is a favorite spot. But it can occur anywhere and
in
anyone. The accretions or urates build up and clog
the
joint, causng poor function and intense pain,
painful
enough that even the weight of a sheet on it at
night
is too much. Usually the acute attacks are far
worse,
and become less painful gouty arthritis
as
they become chronic.
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Before adequate drugs and diet suggestions came
along to help to rid the body of excess urates, people were sometimes left to to
their own devices in trying to relieve the pain of gout. One home remedy was
described in a history text from the 500’s CE called Historium Libri Decem.
In the book, the Bishop of Cahors had gout so bad that he
would stick a fireplace poker in the embers and then apply it to his foot and
shin. Man oh man, it must be some major discomfort if cauterizing your toes and
foot becomes a good idea.
The practice of cautery
(from Greek for branding iron) for gout lasted for hundreds of years, with a
17th century century surgeon from France pronouncing that he didn’t
really believe in external remedies for gout, except of course, for cautery with
a red hot poker.
The above example falls under the heading of analgesia (an = not, and gesia =
pain) by counter irritation. Counter
irritants basically substitute one pain for another. You have two competing stimuli, both of which create pain.
One is probably chronic (long-term,
comes from chronus = time); this is
pain from which the person wants relief.
The second pain is acute
(from Greek for sharp). The second pain is geared toward relieving the first
pain. Who hasn’t bitten a knuckle or lip while getting an injection or
experiencing some other pain? Is it just a distraction, a placebo, or is there
biology at work?
The concept of counter-irritation is old. Before we had
any idea how it worked or even if it worked, counter irritant uses approached
the bizarre. Heart attack and angina pectoris (pain from partially blocked
cardiac vessels) often shoot a pain down the left arm. So early physicians
decided that if counter irritants were placed on the left arm, they could
short circuit the pain as it was sent out but before it could come back to the
heart.
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Cupping
is one example of a counter irritant to relieve pain. The
little
pins on the tops of the cups are for drawing a vacuum. Dry
cupping
is shown on the left, no blood is drawn. Wet cuppin is
on
the right, where more vacuum is used and blood is suck out
of
the skin through the pores. Believe it or not,
wet cupping is more common.
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Originally used to promote healing, cups are used to quell
pain too. As far as truly scientific studies, the only thing we know about cupping and
pain relief is that the studies have been poorly conducted – better studies are
needed. But never underestimate the power of the placebo. If a patient thinks it works, then it works.
Other types of counter irritants include scarification – scratching until the
epidermis is removed. Many people with chronic itch practice this everyday of
their lives. Chemical irritants that act on the skin are called rubefacients because they turn the skin
red (through dilation of blood vessels underneath). Capsaicin, menthol,
camphor, methylsalicylate (more on this below), eucalyptus oil, all have been
tried as rubefacient counter-irritants.
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This
youngster suffers from Alagille syndrome.
It causes bile
to stockpile in his liver which
makes him itch all over, all the time. He wears a
special
suit to prevent him from scratching until he
bleeds.
The scratching is a type of counter irritant
and
will will talk more about itch and capsaicin in a
couple
of weeks. The young boy is on the
liver
transplant list.
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A study from 2009 showed you could counter a long-standing
pain in the right leg by immersing your left
foot in cold water. Painfully cold water activates TRPM8 and TRPA1. Doing this
only to the left foot reduced shock pain in the right leg by 50%. Apparently it acts to confuse pain signals at the
level of the spinal column.
So just how does counter irritation relieve pain? There are
competing ideas. Perhaps the acute pain of the irritant sparks a release of endorphins (opiate pain killer made by our own body). This seems plausible, but
chronic pain patients have very high levels of endorphins in their blood; they
just seem to not respond to them.
The hypothesis of a nerve overload is less precise, and may
actually reflect other mechanisms at work. Overload in general would mean that
a huge amount of neural input at the same time overloads the spinal nerves at
that point and results in no signals getting through. This may be how the left
foot right leg example works.
Even if some of these mechanisms contribute to
counterirritant action, additional processes are probably at work as well, namely
desensitization and habituation. You’ll be surprised how much TRPV1
heat/capsaicin sensors are involved. Capsaicin causes pain because your body
interprets it as noxious heat (TRPV1), but somehow, you can also use capsaicin
to take away pain.
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I
have used the joke before, but it keeps working. Hitting
yourself
with a hammer over and over could desensitize
pain
receptors, induce endorphin release, distract from
other
pain, confuse spinal signaling – all of which are
plausible
mechanisms for counter irritation.
The
truth is what makes it funny.
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In simple terms, desensitization of the TRPV1 channels means
that while some activation causes pain, continued activation depletes the
neuron of the molecules need to create or transmit the signal, and the pain
neuron can’t fire any longer. If it can’t fire, there’s no pain – analgesia.
There are two kinds of desensitization, homologous means
that continued use of one agonist on a receptor makes that receptor less able
to respond to that agonist. Heterologous desensitization is when other agonists
work on receptors in another part of the tissue.
The heterologous type of desensitization sounds an awful lot
like the example above where really cold water on one foot reduces pain in the
other foot. So this could be one of the mechanisms of counter irritants.
On the other hand, consider the old example of placing a
frog in hot water (video here) – it jumps out due to TRPV1 heat/pain signaling.
But if you place a frog in warm water and then heat it slowly, the frog won’t
jump out. It will sit there until it’s a frog leg dinner. This is habituation (tolerance) and perhaps homologous
desensitization as well. Perhaps capsaicin pain creams
act by habituation and counter
irritation, nothing says they can’t do both.
Another desensitization/habituation model uses
resiniferatoxin injected into the covering of the brain (epidura) to stop
neuropathic pain. Remember that resinferitoxin is a strong capsaicin-like
molecule, with a score of 108.8 billion Scoville units. It is such a strong
agonist that it alone can desensitize TRPV1 in short order - so much that it is
termed an anti-nociceptive agonist.
Even more amazing, a Sept. 2012 study used two agonists of
TRPV1, capsaicin and MRS1477. Use one or the other and you get hyperalgesia.
But administer both at the same time and you get analgesia. In this case, they
are hoping that this will be an alternative to opiates in cancer-mediated pain.
This all sounds great – TRPV1 is on small (C type) and some
larger (Adelta) pain fibers, and wearing them out can reduce pain. But wouldn’t it just be easier to block them with an antagonist (something that binds but
doesn’t activate)? Well, there’s a problem with that – TRPV1 does more than just
signal pain.
If you block TRPV1 activity to produce analgesia, you also block its heat-sensing role. Now your body won’t know when it is getting hotter
and won’t cool itself down. You end up with hyperthermia and that can kill you.
This has been a consistent problem with TRPV1 agonists as analgesics, including
if resinferitoxin is given orally – but who would want 108.8 billion SHU in
their mouth?
It is the oral TRPV1 antagonists that seem to bring the
hyperthermia when trying to treat osteoarthritis. The hyperthermia has been
attributed to the action of TRPV1 antagonists in the GI tract. New work shows that activity of TRPV1 is increased (and the expression) in the joint
during osteoarthritis, but no increase in expression or activity in the spinal
column. Injection of a TRPV1 antagonist into the joint to stop the pain signals
from the joint without the hyperthermia.
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Wint-O-Green
Life Savers are famous for emiting light
when
chewed. This is called triboluminescence
and also
occurs
when you rub quartz together or pull tape from
a
roll. The mechanism is through energy release by
mechanical
breaking of crystals or bonds. In the case
of
life savers, sugar dried to crystal will undergo
triboluminescence,
but the light is often in the UV
range.
But the oil of wintergreen chemistry converts
the
UV to visible light. And now you know.
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Some chemicals may be both agonistic and antagonistic for
TRPV1. A new paper states that methyl
salicylate (oil of wintergreen) activates TRPV1, so it induces a warm
feeling, but it also blocks TRPV1 activation by capsaicin, acid, anandamide, and
perhaps inflammatory mediators. This means that it can be analgesic, which is
why it's the main ingredient in BenGay.
However, the same paper indicates that analgesic activity of
methyl salicylate might be due to its TRPV1-independent activity on a different
system, the same pain generating system blocked by aspirin (cyclooxygenase). Arguing against this - BenGay is amazingly painful when loaded into a teammate’s underwear or jock. Take my word for it.
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Acupuncture
is a source of constant argument in science.
Does
it really do something or is it all placebo. Recent
(2012-2014)
papers are starting to show that it does have
specific
physiologic actions. Here is shown the
electroacupuncture.
In medical terms, this is equivalent to
TENS
(transcutaneous electrical nerve stimulation). In TENS,
the
current is passed through the area that is being
affected,
but in acupuncture, a remote area may be used,
according
to acupuncture charts.
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Next week, capsaicin receptors are also used in some other
systems, not just heat and pain. Who would have guessed that eating chili
peppers could stop but also cause cancer?
Because
pain is involved, I am including demonstration links only for triboluminescence.
For
more information, see:
Counter
irritants –
Gout
–
Acupuncture
–
Methyl
salicylate triboluminescence –
