Pathophysiology Management of Bone Abdominal Neuropathic Pain July 23 22

Pathophysiology & Management of Bone,
Abdominal & Neuropathic Pain
Attribution: Ferris, FD. Pathophysiology & Management of Bone, Abdominal and Neuropathic Pain. 2022. ISBN: 978-1-
945872-58-7. In Ferris FD, Gustin J, Humphrey L (eds). Palliative Care Interdisciplinary Curriculum. Copyright © 2022 Frank D Ferris.
PCIC ISBN: 978-0-9884318-1-2.
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programs using any part of the PCIC Curriculum, must only do so with written permission from Drs. Frank D. Ferris, Jillian Gustin or
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Acknowledgements: The Principals of the Palliative Care Interdisciplinary Curriculum gratefully acknowledge the support of Award
Number R25CA134309 from the National Cancer Institute, the Host Institutions and Private Donors. The content is solely the
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Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 1 of 43

Pathophysiology & Management of Bone,
Abdominal & Neuropathic Pain
Hi, I'm Frank Ferris, here to talk with you today about the pathophysiology and management
of bone, abdominal, and neuropathic pain, problems for many patients all around the world.
The International Association for the

Study of Pain, IASP, defines pain as an
unpleasant sensory and emotional
experience associated with actual or
potential tissue damage. Of course, it's
not only about the normal function of
the somatosensory system, but it's also
about our inputs in terms of our social,
spiritual, and psychological experience.
Margo McCaffrey makes it much easier

when she says, "Pain is whatever the
experiencing person says it is, existing
whenever that person says it does."
Will you trust your patients? I certainly
hope you will.
In this module, our goal is going to be to

talk about the pathophysiology of pain
and then based on the causes, to talk
about the strategies to control bone,
abdominal, and neuropathic pain. And
my take home is always going to be:
"Treat the pain based on the underlying
cause." The strategies will be very
different.

Pathophysiology of Pain…
Let's begin to talk about the pathophysiology of pain so we can begin to understand some of
the many different causes.
There are two types of pain. Nociceptive

pain results from the normal function of
our somatosensory system. Neuropathic
pain is the result of damage to that
system. It actually means nerve
pathology, and it's actually a disease
state. When both are happening in a
given patient, we would call it mixed
pain.
Let's start off with nociceptive pain ̶

normal function of our somatosensory
system.
When you and I started out to develop

from a zygote that single egg that was
created by our mother and our father…

…we grew a brain. We grew a spinal
cord. From that spinal cord, we
developed projections that go out into
our periphery. You and I are covered
with axons all over our body. Little nerve
endings, very specifically, that match to
a particular spot on our body.
We developed projections from those

nerves that were peripheral, with a
nerve that crosses the posterior horn of
our spinal cord, and finally, a third nerve
the climbs into our brain, particularly
ending in our thalamus.
A thalamus receives thousands of

electrical pulses per second, and you and
I learned that's normal. Each neuron is
beating bum-bum-bum every second.
Imagine the input from thousands of
neurons. And again, you think that's
normal. You've decided that that input is
your normal experience. And most of us
aren't experiencing pain from day to day.

We also developed a feedback loop that
goes from our brain, down to parts of our
spinal cord. Melzack described the gate
theory: "This is about how do we actually
begin to control the signals coming up
towards our thalamus."
Nociceptive pain is about a stimulus that

occurs somewhere on our body.
Normally, we touch ourselves, we don't
feel pain, but if it becomes extreme and
intense, it's painful.
At the end of those little axons are

nociceptors. On the surface of our body,
what we call the somatic area, which
includes our skin, muscle, and bone, we
have pressure, chemical, and
temperature receptors. Across our
peritoneum and our pleura, the lining of
our organs in our chest and our
abdominal area, only stretch receptors.
And the organs themselves don't have any nociceptors inside them.

That painful stimulus is converted by
those nociceptors into an electrical flux.
It's a sodium-potassium flux that
migrates and is transmitted along the
axons towards our spinal cord. The Aδ
fibers are the fastest, and you can see
them here illustrated in blue, the flux
going right into our spinal cord.
C fibers are slower. Again, they follow

along similar pathways, but create a
signal that amplifies the signal already
arriving at our spinal cord.
Neurotransmitters carry that signal

from the first neuron across to the
second neuron in our spinal cord, the
neurosynaptic junctions.

The first response is actually within the
context of an arc to stimulate the
muscle, and you and I know what
happens: if we hit our finger, suddenly,
we withdraw.
What I want to remind you is that
stimulus is going to be continuous in
chronic pain. No wonder people have
tight muscles and may actually respond
to a number of our complementary therapies. If they're in chronic spasm, a lot of touch,
massage, yoga can be very beneficial. It's part of the simple neurology.
The signal then moves across to the

tertiary neuron and climbs towards our
thalamus, where we begin to experience
pain...
…the perception of pain. If the signal's

only a little bit increased, then you and I
don't experience much pain, but if the
signal goes way, way up, we begin to
experience a lot of pain.

Our bodies, in response, also generate a
sympathetic response: increased heart
rate, increased blood pressure, we
begin to sweat. We may also get
nauseated, and of course, we have an
emotional response ̶ all part of the
acute pain story.
Based on how we're feeling, we also

generate signals down that modulation
pathway, and they may actually dampen
or not dampen the signals coming
towards our thalamus. If we're having a
particularly good day, we may actually
gate or close some of the signals going
towards our brain. If we're having a
lousy day or are depressed, we may
have more signals coming towards us and feel more pain.
So, nociceptive pain is really about a

stimulus that's experienced by our
nociceptors, which convert the signal or
transduce it at those receptors into an
electrical signal that passes along our
neurons, up into our brains. We perceive
pain, and we modulate it.

When there's tissue damage ̶ and of
course, if you hit your finger, you can
see the swelling that ensues, can't you?
Our body responds with inflammation.
Inflammation is associated with edema.
Part of that process is increased
prostaglandins. As the white blood cells
respond, we get more and more
prostaglandins as part of that response.
Those prostaglandins will actually

sensitize the chemical nociceptors in the
area of damage, and the pain signal is
actually going to go up, as well as
inflammation is not limited to the area
of damage. If you look at your finger,
you can see the swelling goes far beyond
the area of damage. That inflammation,
those prostaglandins will recruit
additional nociceptors in the surrounding tissues, and the pain will go up even further.
So, as we think about nociceptive pain,

remind ourselves, if it's somatic, it's on
our skin, our muscle and bone. That's
the one sensory area where neurons are
very specific. It's easy to describe and
localize, and the receptors sense
changes in pressure ̶ presence of
chemicals, changes in temperature. You
know if you put your finger on the stove,
yikes! Or something very hot, "Whoa! I
burned myself!" And you feel it very quickly.

Visceral pain, which is in our organs ̶
remember, the sensors are only
stretched on our peritoneum and our
abdomen, on our pleura and our thorax.
It's much more difficult to describe
because of the anatomy. Patients will
often say, "Oh, it's in this sort of an area,
but I'm not quite sure where."
But as the severity goes up, they'll say it
gets bigger and bigger. That's partly got to do with the anatomy of these neurons, that they
map not specifically but at multiple levels, and our brain experience is one of non-specificity.
But no matter whether it's somatic or

visceral, the reality is patients describe
nociceptive pain typically as sharp,
aching, or throbbing.
Bone Pain
So now let's talk about bone pain a very specific situation that allows us to really understand
the impact of that inflammatory response. Let's remind ourselves about Bill our gentleman
we've talked about in other modules.
He has cancer of the prostate with

multiple moaning metastases this that
you can see here on the nuclear medicine
scans. If you remember he described as
pain as a severe toothache suggesting
there's a nociceptive component as well
as their shooting pain down his
perineum, into his cold into his legs

which are cold and he's experiencing numbness suggesting he has a neuropathic component
as well.
So, what's the pathophysiology a bone

pain? Let's start out by asking ourselves.
Where are the nociceptors?
Most people would say, oh no problem.

They are right along the periosteum?
Well, that's true. And in fact, if you do a
bone marrow or you touch the
periosteum people will scream; they're
very sensitive. But are there other
nociceptors particularly when we think
of growing metastases? They're not on
the outside of the bone. Do you
remember?
In fact, the nociceptors are throughout

the marrow. Associated closely with the
microvasculature are axons with
nociceptors throughout.

So what type of receptors are there?
Remember this is part of our surface our
somatic pain experience, which we said
was skin muscle and bone.
There are pressure chemical and

temperature receptors and remember
no stretch receptors. They're only on our
viscera.
So, when metastases are growing in the

bone medulla, remember it's a closed
space.

As the metastases grows it increases its
size. In that closed space and it goes the
pressure. So those pressure receptors
are experiencing a change and sending a
signal up to our brain saying oh there's a
threat and we experience pain.
But along with that never forget that

every solid tumor is surrounded by an
inflammatory response as our body tries
to fight that tumor. The inflammation is
associated with the edema increased
swelling more pressure.
Of course, edema also is associated with

prostaglandin production. So, we're
going to be stimulating those chemical
receptors as well and up goes the pain
response some more.

In fact, some of the tumors that grow in
or bones particularly breast
gastrointestinal and lung malignancies,
their metastases also secrete
prostaglandins. So the tumor itself may
be stimulating those chemical receptors.
Now tumors also secrete cytokines a

variety of factors that may actually
increase the osteoclast activity and lead
to bone destruction. Remember that
tumor is not only grow but they invade
and destroy this is part of that process.
So in the face of that invasion and

destruction, the destruction is not only
of the medulla the blood supply but also
of the neurons the axons in that area
and there's going to be neuropathic
pain.

Now, how are we going to treat this? A
little reminder that the pathway that
leads to the production of
prostaglandins arachidonic acid is
converted by the enzyme
cyclooxygenase and we produce
prostaglandins in our body. So, what
medications do you remember that
might inhibit cyclooxygenase?
Well, did you think of acetaminophen or

paracetamol? It can block
cyclooxygenase.
At the same time, we now know that

acetaminophen and paracetamol can
also block cannabinoid receptors which
are very prevalent in our brains the CBD
receptors. Both of which can lead to a
decreased pain experience.

As well as another class of medication.
Nonsteroidal inflammatories could be
ibuprofen could be Naprosyn could be
diclofenac a whole range of different
products that directly inhibit
cyclooxygenase both of which will lead
to less prostaglandins and less chemical
stimulation.
In fact, what we've seen is with the
addition of acetaminophen or nonsteroidals, particularly early in the development of cancers
that have bone metastases, we often get marked reduction in the pain experience by the
patient.
Now, we also know that in extreme

dexamethasone can be very helpful. It
not only inhibits cyclooxygenase but it's
also our most potent anti-inflammatory
and will reduce the edema in the tissue
surrounding the metastases, again
reducing the pressure as well as
reducing the chemical stimulation very
wonderful medication. to reduce bone
pain.
Now we know opioids can also be very

helpful because they block the
postsynaptic mμ receptors. Along with
those we know that bisphosphonates or
Denosamab, which can inhibit
osteoclasts denosumab being the most
effective ̶ can be very effective at
reducing the bone destruction and
turnover. Many of us will use zoledronic
acid once a month. Radiation therapy can also be very effective here inhibiting tuber growth
and activity possibly also ultimately reducing the inflammatory response. And it actually turns
out that if we give patients dexamethasone and the pain comes down quickly, it's predictive of
the capacity of radiation therapy to have a significant effect. Could be a single fraction. If
patients have a longer prognosis, it could be 5 or 10 or fractions. You want to consult with
your radiation therapist, and my approach is if patients get a quick response to
dexamethasone. I'm going to phone the radiation therapist pretty quickly. It can mean that I
don't need to use as many of these co analgesics or analgesics on an ongoing basis because
the patient has less pain.
So never forget that expanding

metastases can actually invade and
weaken the cortex of the bone. And then
there's a risk of fracture. If you believe
this could be happening you need to
assess the patient radiologically.
It is much easier to do a surgical

intervention before the bone breaks ̶
putting it a rod or a pin can be a single
day procedure, whereas after the
surgery may be very complex,
particularly in the area of the femur
where we can get multiple fragments.
And surgery may not even be possible in

some of these patients, particularly if
they're elderly or frail. Then we need to
immobilize them and that's a setup for
loss of functionality and maybe even
premature death.

Now never forget the concept of spinal
cord compression. Remember that of
those who get a compression 90% of
them present with back pain before they
get the compression. When we have
bone metastases in pain, you have an
obligation to do a complete neurological
exam on every visit, and if you even get
a reflex that's different from normal,
then you need to evaluate the patient radiologically. Will it be with a myelogram a CT or even
an MRI to assess do we actually have the risk of cord compression.
Now when we say cord compression, what do we actually mean? Well, it turns out the
pathophysiology isn't about the metastases compressing the cord. It's about the metastases
compressing the venous blood return. The blood doesn't move quickly through the spinal cord
and we end up with ischemia. Once there's a neurological deficit this can lead to death of the
spinal cord area very quickly surgical depression needs to be completed within 24 to 48 hours.
Or it's finished. If the patient has no spinal cord function at a particular level they may be left
with incontinence or even inability to walk for the rest of their lives, and we want to avoid this.
So, bone pain becomes complex doesn't it? But it's a lovely model for how do we actually think
about the impact of inflammatory pain and they inflammatory response never forget that
every solid tumor in the body is actually surrounded by an inflammatory response and the
same mechanisms could be occurring in the abdomen, in the chest or other parts of our
bodies.
Abdominal Pain
Now, let's talk about abdominal pain.
I want to remind you that the nociceptors
on our body wall, that includes our skin,
muscle, and bone, are pressure, chemical
and temperature receptors, but when we
move inside our abdomen or thorax,
there are no sensors in our organs. It's
one of the reasons why tumors can grow
in our lungs, our pancreas, our livers. We

don't know it until they expand, and the nociceptors on the linings of our organs, be it the
peritoneum or the pleura, are then stretched, and we feel uncomfortable.
And of course, you know what I mean by stretch, don't you? If you have an intense bowel
movement or a lot of gas, sometimes that stretch turns into cramps, and you're, "Ugh! I don't
like this." Fortunately, for most of us, it's transient, as the gas or the bowel movement passes.
But let's look at the story of John, a 54-

year-old gentleman diagnosed a year ago
with a hepatocellular cancer. In the last
three months, experiencing increased
abdominal distension, and along with
that a lot of bloating, diffuse abdominal
discomfort. When he's sitting or
standing, it's 5 out of 10. When he lies
down and everything moves up, it's 6 - 7
out of 10. Along with it goes intermittent
heartburn and trouble catching his breath sometimes. What do you think the cause might be?
What's common with hepatocellular cancer?
Well, very common is ascites. If the ascites
isn't too bad and earlier on, do we actually
try to treat it by keeping the fluids moving
out of our vascular space using a
continuous diuretic like spironolactone?
Do we help by restricting sodium, or if it
gets severe, to reduce the pain, do we
actually need to do a paracentesis? These
are going to be the approaches we'll use
to manage the pain associated with ascites.

A few weeks later, John's situation
progresses. More intense pain in his
right upper abdomen for the last week,
worse with movement and deep
breaths. Every breath that he feels it,
and now he's got a sharp pain in his
right shoulder.
What do you think the cause is? Do you
remember the anatomy of what nerve
goes through my diaphragm to our shoulder? The phrenic nerve. This is the result of
hepatomegaly, and now the diaphragm is being irritated. There's a lot of stretch because of
the size of the liver.
What we're going to need to do ̶

remember, around those tumors is an
inflammatory response ̶ is try to reduce
the inflammation, and for patients with
hepatomegaly with a lot of
inflammation, steroids such as
dexamethasone may be very effective.
I'm going to typically start with a pretty
high dose, 8 mg once a day. Never
forget that the half-life is 36 to 54 hours. Biologically, we don't follow the plasma half-life for
steroids, we follow the internuclear, or even the mitochondrial half-life. We can dose it once a
day, and we need, once we've established good pain control, either titrate to the lowest dose
or if we need to, even increase it a bit.
Now briefly, I want to remind you that steroids can be used for up to about three to four
months. And with patients with a limited prognosis, which is often the case with a situation
like John, we don't need to change the steroids. But if we're going to use them for a long
period, we need to be aware of the moderate effects which include enhanced Cushingoid
features, and the worrisome is actual proximal muscle wasting, particularly in the legs, that if
patients are really wasted, they can't get up out of chairs. So, if patients are going to live for
longer, we need to find an alternate solution.

Change to another patient. Rebecca, a
49-year-old woman, experiencing
fatigue and anorexia. She's had a fairly
rapid loss of five kilograms in the last
three months. She's got abdominal
discomfort, worse with eating. Later, it
turns into a gnawing ache in her lower
thoracic region, in the midline radiating
into her back. Worse when she lies
down; better when she sits up. She's developed jaundice, and a CT scan shows a mass in the
head of her pancreas and multiple small liver metastases. What do you think the cause is?
If your answer was pancreatic cancer,

you'd be correct. And never forget the
neuroanatomy in this area. The
somatosensory system comes out of our
spinal cord through a plexus called the
celiac plexus. It from there innervates
several of our organs, and what can be
most effective is a block to that celiac
plexus. We can do that early ̶ that's
going to be better to avoid tumor
invasion. If it's very bad, it needs to test or the invasive radiologist isn't going to be able to get
there, and it can be repeated. We can also supplement the pain, control with opioids as well as
steroids. They can be very effective in this patient situation.
Another patient, Mary. A 35-year-old

with metastatic ovarian cancer.
Distension, belching, anorexia. No bowel
movement over the last two weeks and
no flatus. What does that tell you?
Did you say bowel obstruction?
Absolutely, and it's complete because
there's no flatus, right? So, she's got
diffuse abdominal pain. And into her

pelvis, pressure associated with severe intermittent nausea relieved by vomiting. What's the
cause? Well, you're right, it's that complete bowel obstruction.
So traditionally, when we have

distension due to obstruction, we would
have considered putting in a nasogastric
tube to remove the fluids and
maintaining the fluid balance for the
patient with intravenous fluids.
Dexamethasone could help by reducing
the inflammation. Metoclopramide may
increase the peristalsis, and if it's not
complete, relieve the obstruction. And if necessary, we could even invite our surgeons to help
us... they could offer us ostomies that could be diverting, J or G-tubes to actually drain the
fluids from the gastrointestinal tract. But if it's really complete, and we don't want surgical
interventions, what else could we do?
It's helpful for us to remember the

normal fluid balance. If we look at this
diagram, we can see that you and I, on
average, put 8 to 12 liters of fluid into
our gastrointestinal tract each day: a
liter of saliva; our oral intake ̶ one, two,
or three liters; one or two liters from the
acid secreted in our stomachs; a small
amount from bile; a significant amount,
often two or three liters from our pancreas which is producing all those digestive enzymes; as
well as two to three liters from our small intestine.

Now, normally, our bowel takes that
fluid out. It's kind of a circulation system
where we put it in, but we also remove
it, primarily through our jejunum and
ileum. As we absorb nutrients and the
fluids, the last bit of fluid is removed
from that great desiccator, our colon,
and typically, we only have a half ̶ sorry,
a quarter to a half-liter of fluid in our
feces a day.
In the face of obstruction from ovarian

cancer which spreads throughout the
peritoneum, it may be surgically
impossible to relieve this because
there's multiple levels of metastases and
multiple levels of obstruction. And what
becomes a problem is the fluid's still
there, but we can't get it out, we can't
bypass it.
So, what are we going to think about? Well, can we actually turn off the secretion of fluids?
Today, we have access to somatostatin

or octreotide, as well as anticholinergic
medications that can actually very
effectively reduce the amount of fluid
flowing into the gastrointestinal tract,
reduce the stretch, and relieve the
patient. The pain goes away, they stop
experiencing nausea and the vomiting. I
like to use infusion of somatostatin
because the half-life is only 1.5 hours.
Some people have reported q8 hour of bolus dosing. It really doesn't work. We need to use an
infusion. If we're going to use an anticholinergic such as scopolamine or atropine, or
glycopyrrolate, the half-life is much longer. We could either do bolus dosing or infusion.

And remember, if the patient is
experiencing a lot of stretch from
peristalsis and a lot of cramping, the
opioids may be very effective here. But
we don't like the slowing effect of
opioids in normal patients, and we get
constipation, in this particular case,
codeine, loperamide, diphenoxylate,
associated with atropine or even
morphine, can markedly reduce the peristalsis and stop the cramping.
Neuropathic Pain
Now, let's talk about one of the most problematic pains that a patient can experience:
neuropathic pain.
The International Association for the

Study of Pain defines it as pain arising as
a direct consequence of a lesion or
disease affecting the somatosensory
system. This is a disease process, not
just a symptom. Although the patient
experiences it, it's about pathology in
the nervous system itself.
There can be many different causes. Is it

coming from compression or
transection? Infiltration, which can occur
from a tumor? Is it actually ischemia
because the blood supply to that
particular axon or even the whole nerve
has been damaged, or as we described,
even the spinal cord? Or is it metabolic
changes, like we might see with
diabetes? Typically, the patient uses words like burning, electrical, shooting, stabbing, tingling,

often associated with numbness. And many times, the patient will even say, "The pain seems
to be much worse than any kind of observable injury." And it is, because the injury is inside us.
As I mentioned, many causes. Is it

coming from the chemotherapy that you
and I use? Is it coming from
compression of the nerves such as
sciatica, spinal cord compression, or
metastases? Could it be that the nerve
itself has been affected? HIV can
actually infiltrate the nerve and damage
it, as well as herpes ̶ both simplex and
the zoster can be problematic. Cancer
can actually invade and destroy, as we described in our bone metastases, destroying the
whole structure of the medulla. Ischemia can come. Is it actually a venous circulation
problem? Is it the edema that's coming from venous stasis, which is actually leading to
compression and destruction of the nerve? Or is it actually a primary arterial where we
actually block the blood supply to the nerve itself?
Diabetes is one of the classics, which is really about lipid infiltration of the vascular structure,
which leads to slow or even no blood flow, and ultimately death, because of ischemia to that
part of the axon. Or is it transection, simple amputation of a limb? Let's imagine, a below-knee
or above-knee amputation. We destroy the axon. We don't destroy the nerve itself. Do you
remember where the nerve body is? It's right up paravertebrally. So the nerve is still alive, but
the axon has been severed, and it's now going to become very erratic in its electrical
conduction.
So, unlike nociceptive pain, where there is

an observable injury and inflammatory
response, and hopefully repair, and the
pain goes away, when we get neuropathic
pain, there's damage to the nerve itself. It
could be peripheral damage, it could be
central damage. It may even be damaged
to the sympathetic system.
This is not going to go away. You and I may
learn and adapt to it, so if there's an increased input, we may learn it's our new normal. But

these patients are going to have a very different experience, probably for the rest of their
lives.
Pathophysiology - Peripheral mechanisms…

Let's begin to understand some of the pathophysiology at different parts of our
somatosensory system. Let's think first of all, what can happen in terms of damage in the
periphery?
We could have changes right at the ends

of those axons. The transduction
process starts to really become
dysfunctional. Why?
Well, it could be in the face of damage

that there's excitability of the
membranes, and they're not only
producing bum-bum-bum, but now it's
bup-bup-bup bup, bup, bup, bup, bup-
bup-bup bup...
If you actually look at these nerves as
they're coming towards our spinal cord,
and all these axons are joining together,
it's like a fancy electrical telephone cable, isn't it? Multiple wires, each of them with an
insulator around it. In our bodies, it's Schwann cells and myelin that insulate one axon from
the other. If because of the damage demyelination occurs, suddenly, two nerves are sitting on
top of each other, and if this one's excited, guess what, not only does a signal go up this nerve,
but a signal goes up this nerve. So that bup-bup-bup-bup-bup gets amplified, and our brain
experiences multiple more inputs.
In the face of damage out at that periphery, we actually regenerate part of our axons. We can
end up with neuromas, these sort of net mesh of axons. Many different nociceptors at the
ends of them in different places. There can be new projections into uninjured areas, and we
end up with an expanded receptive field. So, a stimulus in that area is misinterpreted, and we
get many more signals.
We can also get, if we move along that

axon, sensitization at the other end of
that nerve before we get it actually
producing neurotransmitters. What can
happen?
Well, in the face of a lot of electrical

inputs, it turns out we can get increased
expression of sodium channels, many
more sodium channels than we had
before.
So we can also get increased expression

of calcium channels. These are voltage-
gated channels, which in the face of
stimulation, the charge changes, calcium
enters and releases more
neurotransmitters. So now we've got
more electrical stimulation through the
neural synapsis of the subsequent
neurons ̶ increased substance P,
glutamate, and other neurotransmitters.

Pathophysiology - Central mechanisms…
So now let's move beyond that peripheral axon into the spinal cord and think about the
central mechanisms that may be causing pain.
We call this central sensitization. It's on

the other side of the neurosynaptic
junctions.
It turns out we have receptors that have

only relatively recently been discovered
called NMDA receptors, or N-methyl-D-
aspartate. These are normally inactive in
our bodies, and they're blocked by
magnesium.
But in the face of increased

neurotransmitters, particularly the
glutamate and glycine, again, there are
changes to the charge in that receptor.
The magnesium is released, the channel
̶ opens and becomes active. This leads
to decreased opioid responsiveness ̶
although we may have been using
morphine, it doesn't have as much of an
effect as it had before ̶ as well as we get to pathognomonic phenomenon, allodynia and
hyperalgesia, and let's talk about those.

So if I actually draw a curve of what
happens if I, in a particular part on my
body, increase the stimulus, this graphic
shows us that as the stimulus intensity
goes up, while I may have only thought of
it as a normal sort of pressure, suddenly, I
start to experience pain, and with
increasing stimulus, the pain gets more
intense.
In the face of injury, that curve moves to

the left. A given stimulus produces
much more pain.
Hyperalgesia is more pain from a given

stimulus. It's about increased sensitivity
to that stimulus.

Allodynia, on the other hand, is pain in
response to a stimulus that wouldn't
previously have been painful. The best
example I can give you is the patient in
bed. They've had bed sheets on their feet
for all their lives, and now, they're saying
to us, "Please, don't put anything on my
feet, they're so painful."
Or maybe it's the woman who has chest
wall disease from her breast cancer, and she can't stand clothing on her body. Clothes and
bedsheets weren't previously painful. Now they can be excruciating. This is central
sensitization.
Management of Neuropathic Pain…

Now let's think about how we're going to manage the pain that comes from either central or
peripheral sensitization, and the damage that goes along with neuropathic pain. What I want
to say from the outset is there's very little research in this area.
The ideas that we're going to be talking

about have mostly been extrapolated
from non-cancer pain situations,
particularly diabetic peripheral
neuropathy ̶ and you'll be seeing DPN
on the slides ̶ as well as post-herpetic
neuralgi ̶ and you'll be seeing PHN on
the slides.
There are actually very few randomized
controlled trials including in these areas, very few comparative trials, and what ends up
happening is based on what we think is going on in the patients, particular patients'
pathophysiology. We then make a choice of where to start. Fortunately, common patterns
lead to good interventions if we follow particular strategies.

So, let's begin to think about John, a 62-
year-old gentleman, presenting with
cough and weight loss and discovered to
have a non-small cell cancer of the lung
in his right upper lung. He gets some
chemotherapy, cisplatinum-based, and
ultimately develops peripheral
neuropathy, both in his stocking area, in
his legs, as well as gloves, along his
hands and arms. He describes it as 4 out of 10, and he's experiencing hyperalgesia. Anything
that touches him in that area is more painful now than it would have been before. So, what do
we know?
We know that chemotherapy,

particularly the platins, the taxanes and
vinca-alkaloids can actually affect the
neurons. Not only the cell body, the
axonal transport system, but they can
damage the myelin sheath and even the
glial support structure. These
medications can lead to burning in the
periphery, that is protracted and may go
on forever.
Gabapentinoids
It turns out, if we have chemotherapy-
induced peripheral neuropathy or even
the peripheral neuropathy that comes
from the vascular damage associated
with diabetes, the gabapentinoids are a
very good choice.

They work at those calcium channels to
block them so we don't get nearly as
much neurotransmitter produced, and
there are actually some positive
randomized controlled trials.
Both of gabapentin and pregabalin, you
can see the results here. They've been
effective for both of them in diabetic
peripheral neuropathy, post-traumatic
neuralgia. We can see in cancer pain, the gabapentin's been useful, and even in fibromyalgia,
the pregabalin has been helpful.
If we were to compare these with an

older analgesic, the tricyclics, they're
not as favorable in terms of the
response, but they are better in terms
of their safety. They're not hepatically
metabolized, there's no drug
interactions, and the side effects are
well tolerated.
Many people like to think about using

pregabalin. Certainly, it's easier to titrate,
faster onset, better in terms of reducing
anxiety and improving sleep, but the
problem is it's still expensive.

So I actually like to start for many
patients who can't afford the pregabalin
with gabapentin. We start with low
dose, often at bedtime, titrate by
increasing it every eight hours, and
often need to get up into the higher
range. We can go as high as 3600 - 5400
mg every 24 hours.
No doubt, pregabalin is very effective. If

the gabapentin hasn't worked, the
pregabalin might, and you can see the
dosing here on the slide, much lower
doses potentially helping the patient get
good pain control even in the face of
their peripheral neuropathy.
Let's focus on the action of

antidepressants that we mentioned in
the last section.

They actually work on the modulation
pathway, and they actually affect
noradrenaline and serotonin.
Amitriptyline, which has been around
for years was our first choice, and that
was what was available. We saw it was
very effective, even in low dose.
Subsequently, we see, have less side
effects. And we've now got SNRIs such
as duloxetine and venlafaxine, which could be very effective in this type of neuropathic pain,
as well as the SSRIs ̶ maybe less effective but also less side effects.
So, what about those side effects? Well,

the first generation can be very
problematic as we increase the dose.
Very significant anticholinergic effects
causing nausea and a variety of other
unpleasant experiences for the patient:
dry mouth, etc.
Second generation aren't as potent in
terms of their side effects, and you can
see the SSRIs and SNRIs are better. The problem with them is, particularly in males, they can
cause very unwanted sexual dysfunction. So, where does that leave us?
We like to land in the middle if we're

going to use tricyclic antidepressants,
and I must admit, I don't use them very
often these days. I'll start off with either
the second generation, desipramine,
nortriptyline, imipramine, or I'll even
start with duloxetine or venlafaxine.
And for both of the latter, we actually
have positive clinical trials.
So, what about the dosing? With the tricyclics, we typically use much less of a dose for
analgesia than we do for depression.

We often start at 10 - 25 mg at bedtime.
Because of the half-life, which is up to
24 hours, we can only increase the dose
after five half-lives, once we get a
steady state, and that's going to be
every three to five days. So, it's going to
take us a while to get into the
therapeutic range for many of our
patients.
We could increase the dose above 100 mg at bedtime, but at that point, we start to need to
measure blood levels to assess for risk of toxicity. There's no doubt, if there's no risk, we can
continue to actually increase the dose, and some patients are relatively rapid metabolizers and
will tolerate a higher dose. So, think about tricyclic antidepressants, but maybe there are other
alternatives.
Anticonvulsants
We've talked about the management of peripheral neuropathy.
Now, let's talk about the management of

that shooting pain that tends to go down
people's legs. Whether it's a disc or
sciatica, it's that sharp, electrical stabbing
pain.

Anticonvulsants might be very effective
for this type of pain because
anticonvulsants, just like they change
the excitation in our brains, can actually
change the excitation of those
peripheral neurons, reduce the sodium-
potassium flux, and dampen that pain
experience. There's actually very limited
data, so it's really trial and error.
Historically, many people have used carbamazepine, sodium valproate. I've tried phenytoin,
but I didn't think it was very effective. But today, I'm more inclined to use the newer
generation anticonvulsants because they have less side effects. There's actually no clear data
about their effectiveness, but anecdotally, I've seen several of them are more effective at
reducing that shooting pain, and with less side effects.
If you're going to use carbamazepine,

the older medication, we start at a low
dose, we dose It twice a day, and
increase it every two to three days
because its half-life is 12 hours. There is
no doubt, as we're increasing it, we need
to watch for toxicity by monitoring blood
levels.
Certainly worthwhile trying
anticonvulsants. They're one approach to that shooting pain that comes from the disc, sciatica,
maybe even the metastases.
Opioids
We've talked about strategies to impact what might be happening in the periphery. What
about centrally?

But you and I have been using opioids
for years, and they can have a very
significant effect.
Let's think about John again. Three

months later, now he's got two-week
history of forearm stabbing, elbow pain,
and severe aching. He's got increased
burning in his hand. We've already
optimized the gabapentin, but his pain is
8 out of 10. And we've discovered that
he's got an increased apical mass causing
a plexopathy. He's got a mixed picture of
nociceptive and neuropathic pain.
We know that opioids are very effective

for nociceptive pain, but they can also
be very effective with neuropathic pain.
In fact, several experts would say they
might be first line for moderate to
severe neuropathic pain. I will admit,
personally, I might try some of the other
strategies first, but then I'll add these
and titrate to effect the same way I
would do with nociceptive pain.
What I'm aware of is if they're not really very effective, it's probably neuropathic pain, and I
need to think about an alternative to my classic morphine, or oxycodone or hydromorphone.

There are several positive trials. We can
see morphine has been helpful in
postherpetic neuralgia; oxycodone in
both diabetic as well as postherpetic
neuralgia. Methadone, and we'll talk
about that in a moment, is very useful in
mixed neuropathic pain, etcetera. Even
combinations, morphine, gabapentin
versus morphine alone, versus
gabapentin alone ̶ very effective. And maybe there's value even from some tramadol.
But what about that methadone? This is

an old medication that we now
understand much better than ever
before. It's a mixed Mu receptor agonist,
so it works like morphine. But it's also an
NMDA receptor antagonist. And what
did we say was happening as we get a
lot of neurotransmitters, the
magnesium flows out of the NMDA
receptor channel, and it becomes active
̶ very common with neuropathic pain.
So we can use this single product to actually titrate to effect, again, or side effects, but the
kinetics of this medication are very different. It has a very long half-life, five to seven days. It
does not follow first-order kinetics, and I'm going to recommend that you start using it in
partnership with either a palliative medicine or a pain management specialist who has had
experience.
Because of the side effects, yes, while there are approaches to opioid rotation, and some
people enjoy that, I personally prefer using methadone as a coanalgesics. If I've been using
morphine already, I'll actually add the methadone to that in very low dose. 2.5 - 5 mg every 12
or every 8 hours, and then slowly increase it. But remember, with a half-life of 5 to 7 days, I
need to do it increase every 25 - 35 days. There's no doubt that the cost is very preferential.
It's very inexpensive in most settings, and oral is less expensive than the parenteral.

In addition to the opioids, we might also
consider the corticosteroids. We know
that every solid tumor has an
inflammatory response associated with
it. It's got edema... What's been shown is
even when we're thinking it's nerve
damage, part of that pain production
may be this inflammatory response. I’ve
used it in bone, neuropathic pain,
lymphedema, and a variety of other
conditions.
Again, start with a moderate dose of 8 mg once a day. That has to do with a very low risk of
early side effects, and titrate to effect. And never forget, we can continue this for 2 or 3
months. In patients with a long survival, we're going to need to consider rotating to something
else.
Lidocaine & Other Therapies…

We've been talking about a variety of relatively conventional therapies that we might use to
manage neuropathic pain, but sometimes, we don't get the results we're hoping for.
So let's talk about the value of lidocaine

and some other medications.

Back to John. It's a week later. He has
burning, stabbing pain, still not well-
controlled, 7 out of 10. And allodynia ̶ he
can't stand the bedsheets, and he doesn't
like his clothing, particularly in his
periphery. We've already got him on
gabapentin, morphine, and some
methadone as a coanalgesic, as well as
dexamethasone.
What to do next? My suggestion is, as it's now complex, call one of your pain or palliative
medicine specialists who have some ideas about particularly newer medications where the
results are variable and we don't necessarily use them that frequently.
Let's start with the sodium channel

blockers of which lidocaine is our best
example. There are actually a few
randomized controlled trials in
neuropathic pain suggesting that if we
use a loading dose and it has an effect,
that we might actually use an infusion.
Some patients get pretty good
responses, and ultimately, could be
converted to an oral sodium channel blocker such as mexiletine.
The important thing with this particular

medication is that you and I need to
manage the pain and monitor for side
effects. As the concentration goes up in
the plasma, so does the risk of side
effects. We need to actually do
therapeutic blood level monitoring 8 - 10
hours after the start of the infusion. Some
patients will get a good response with this
particular approach.

But in my experience, ketamine may be
a more effective agent.
It's newer. We now know that it

actually blocks the NMDA receptor.
Randomized controlled trials using
ketamine in combination with opioids,
either as single bolus or opioids have
had generally positive results, and it's
both water and lipid-soluble, so we can
use it in many different formats.
We found it to be very effective given

orally because the parent product is
metabolized in the liver into a more
potent analgesic, and particularly for
mucositis, low dose given every 8 hours
has been very effective for many
patients. We've also used it
subcutaneously in wound care, when
the topical lidocaine isn't enough.

And we've seen that infusions in some
patients with extreme pain ̶ the worst in
my experience has been sacral plexus
invasion ̶ actually could be fairly well
controlled with that infusion. The
important thing is to look for side effects
and maybe be preemptive. Use an anti-
sialagogue for excessive secretions and
maybe a bit of benzodiazepine to reduce
those dysphoric feelings.
We've talked about a variety of medications that can manage both nociceptive and
neuropathic pain. The important thing to recognize is there may be others that can be
effective as well.
Pharmacologically, we might use topical

capsaicin, topical lidocaine, the patches,
or even ketamine. New evidence is
coming forth about the effectiveness of
cannabinoids, particularly when they
impact the CBD receptors, baclofen and
alpha-adrenergic agents such as
clonidine.
But I never want you to forget the value

of non-pharmacological and
interventional anesthesia. Remember
that first response is muscle contraction.
Is the patient actually experiencing
chronic muscle contraction and pain,
causing the contractions to be even
worse? Touch, massage, acupuncture,
yoga. They have to reposition the patient
to relax those muscles and may actually
reduce the pain considerably. Aromatherapy, counseling, transcutaneous electrical nerve
stimulation, biofeedback have all been shown to be effective.

Think about how we can put this package together. And particularly in the patient where
we've tried all sorts of medications and they haven't worked that well, never forget total pain.
Is the nociceptive or the neuropathic pain, as we're thinking about it, actually the result of
psychological, social, and spiritual suffering?
There is no doubt, by understanding the

cause, we can then effectively choose
analgesics and coanalgesics and manage
most of our patients' pain experience.
And if we use the pharmacokinetics, we
can control it safely and .
rapidly
But it's complex. It's a frontier still, and

we will learn more in the coming years.
Success with your patients. I hope you
get their pain under control quickly and
safely.

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Pathophysiology & Management of Bone,

Abdominal & Neuropathic Pain

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 1 of 43

The International Association for the

Margo McCaffrey makes it much easier

In this module, our goal is going to be to

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 2 of 43

There are two types of pain. Nociceptive

Let's start off with nociceptive pain ̶

When you and I started out to develop

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 3 of 43

We developed projections from those

A thalamus receives thousands of

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 4 of 43

Nociceptive pain is about a stimulus that

At the end of those little axons are

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 5 of 43

C fibers are slower. Again, they follow

Neurotransmitters carry that signal

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 6 of 43

The signal then moves across to the

…the perception of pain. If the signal's

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 7 of 43

Based on how we're feeling, we also

So, nociceptive pain is really about a

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 8 of 43

Those prostaglandins will actually

So, as we think about nociceptive pain,

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 9 of 43

But no matter whether it's somatic or

He has cancer of the prostate with

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 10 of 43

So, what's the pathophysiology a bone

Most people would say, oh no problem.

In fact, the nociceptors are throughout

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 11 of 43

There are pressure chemical and

So, when metastases are growing in the

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 12 of 43

But along with that never forget that

Of course, edema also is associated with

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 13 of 43

Now tumors also secrete cytokines a

So in the face of that invasion and

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 14 of 43

Well, did you think of acetaminophen or

At the same time, we now know that

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 15 of 43

Now, we also know that in extreme

Now we know opioids can also be very

So never forget that expanding

It is much easier to do a surgical

And surgery may not even be possible in

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 17 of 43

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 18 of 43

But let's look at the story of John, a 54-

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 19 of 43

What we're going to need to do ̶

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 20 of 43

If your answer was pancreatic cancer,

Another patient, Mary. A 35-year-old

Pathophysiology & Management of Bone, Abdominal & Neuropathic Page 21 of 43

So traditionally, when we have