The Role of Weight Loss and Calorie Restriction in Pain Management

The Role of Weight Loss and Calorie Restriction in Pain Management

January 7, 2020 1 By Ewald Bahringer


[ Applause ]>>All right, well thank
you very much for having me. It really is a pleasure
and an honor. I work with all of these people, and I get to see them all
the time, and I’m still — every time I see everyone speak
together I’m really amazed at the continuity of the program and how much stuff is
really going on here. So very pleased to
be a part of it. Also, first time ever I’ve been
accused of being best dressed or possibly [laughter]
remotely in the running for best dressed,
anything of the sort. So I’m going to be
talking about weight loss and calorie restriction
today in pain management. And just a little bit of a
heads up, we’re really — this is a somewhat new
field in some ways. I probably will raise
more questions than I will give you
answers, but I still think that this is a very
exciting new area. I have no conflicts of interest
or commercial relationships that I need to disclose to you. So in exploring a relationship
between obesity and pain, it’s important to know that there is a pretty
well-established relationship in the sense that we know
that people who are overweight or obese are more likely
to experience pain. So generally speaking our
really high-quality surveys of the public will find
that maybe about one out of five people report having
chronic pain or persistent pain. The chances of you falling
into that group go up about 30% if you are overweight, meaning that you have a BMI
between 25 and 30. If you have a BMI of 30 or
above, then the chances go up to about 60%, and an odds
ratio of about 1.6, which is really I think a
significant increased risk. And when obesity is already
present in an individual who has a pain condition, we see something very
interesting happen, which is that most of the
symptoms tend to get worse, even if we can trace the origin
of the pain condition to a time when the person was not
overweight or obese. So in a nice study of 215
fibromyalgia patients, it was shown that those
patients who were overweight or obese had much
higher levels of fatigue, much greater sleep disruption, but they were also
more sensitive to pain on manual palpation
of tender points, which suggests something
a little bit different than just pain, say, in
the knees, or the ankles, or the hips, or the places that
we classically expect to see it, but actually more of this
central sensitization phenomenon may be part of obesity. In the classic view of
how obesity promotes pain, we really borrow pretty
heavily, actually, from sort of physical
engineering to describe why we
think it’s happening. And you’ll actually hear this
term “mechanical load” a lot to describe why patients
who are overweight or obese are reporting
a lot more pain in areas like the lower back, the hips,
the knees, and the ankles. These are, of course,
the load-bearing joints of the human body, and they’re
the ones that are most taxed by extra weight,
extra adipose tissue. But there’s something I think
that is missing from this, which is that if
you actually think about your clinical experience
— and I am not a clinician. I say that very openly. I help no one. I rely on all of you [laughter]
to do that kind of work. But if you think about your
patients, what I always hear is that this really doesn’t
describe the phenomenon of overweight and obese
people and the kinds of pain that they experience. And actually, high-quality
data has started to come out to show us that that
is definitely not true, that it’s confined to those
weight-bearing joints. In fact, people who are
overweight and obese are at much greater risk of having
migraine; tension-type headache. They’re more likely to
have abdominal pain with and without symptoms
that are similar to irritable bowel syndrome. They’re more likely to have
temporomandibular joint disorder, which primarily
presents as pain in the jaw, in the musculature of the face. I would contend that those kinds of pains are not very easily
explained by something like mechanical load,
and that we need to kind of expand our thinking about why
these connections might exist. So let me give you one
possible alternative view of why this happens. Adipose tissue is
not neutral as far as our immune systems
are concerned. Adipose tissue tends
to pull immune cells, cause them to migrate into the
tissue, especially monocytes, which are the great
chameleons of the immune system. Monocytes are there when a person is experiencing a
very severe inflammatory event, and they’re there
during wound healing. They can take on both roles in
the immune system of the body. So what happens is that in
adipose-derived inflammation, we tend to have those monocytes
migrate into the fat tissue, and then they start
to take on more of a proinflammatory phenotype. That is the monocytes
that we can actually pull out of adipose tissue are going
to look a lot like the monocytes that we would find
in infected wounds. They’re very proinflammatory;
they’re spitting out cytokines. And what can happen even is that
those monocytes and other cells that are in the adipose
tissue begin to secrete proinflammatory
cytokines at a sufficient concentration
to actually start to change the rest of the
immune system, and even maybe to start to signal the brain. These are just some basic
points about the qualities of the immune cells
in adipose tissue. But how is it that these immune
factors would sensitize the central nervous system,
if this is true? So this is the question I
probably get asked the most because I usually talk
about inflammation and the immune system and
how it relates to the brain. People often say this to me, “How is it that the
immune system and the cytokines are
affecting the brain?” Most of us learned, right, that
there’s something called the “blood-brain barrier”
that serves as a barrier and protectant against
peripheral inflammation. And that is absolutely true,
the blood-brain barrier is there to keep out those nasty
cytokines and signals of sickness from the
periphery of the body. But our brain and our
immune system engage in constant bidirectional
communication. We would not survive
or function very well if our brain didn’t
know what was happening in the peripheral immune system. They’re constantly talking. So one of the things
that can happen is that if cytokines reach a
sufficient concentration in blood, they can
actually diffuse across the blood-brain
barrier directly into the brain and spinal cord. And that means that you all
of the sudden have [inaudible] and tumor necrosis factor
[inaudible] beta talking to the immune cells
in your brain. Now, this normally only happens when somebody is
really quite sick. This is something that’s mostly
associated with septic shock or something like that. But there’s another route
that we know a lot less about, but we’ve learned more about
in maybe the last ten years. The immune cells
themselves, not the cytokines, those monocytes themselves,
can actually cross over through our vasculature in
the brain and enter our brain and set up residence there. If you label them
in animal models and then stress the animal,
you can subsequently see them in various parts of the
brain that are associated with anxiety, and
depression, and pain. So that means that those immune
cells that are not supposed to be getting up here
are in fact doing that. They’re getting up there
and they’re staying there, and they’re changing the
characteristics of the brain in a way that could promote
a lot of these symptoms that we think are really nasty. And in case there’s any doubt
about this, this is something that I’m really happy
about and proud of — actually my friend Neil Basu
[assumed spelling] played a major role in this analysis. But when Neil came here, we
looked at some RA patients, we did an analysis of the levels
of inflammation in the periphery in a group of RA patients, and
we looked at how that seemed to be associated with the brain. And what we see are profound
changes in the function and structure of the brain in an
individual who has high levels of peripheral inflammation. And this is obviously just a
proof of the basic concept, because this is not in obesity. But I think it’s very important
to say that evidence is mounting that as those levels of peripheral information
are increasing, so the brain is responding
in a commensurate way. So in order to address
this question of obesity inflammation, weight
loss calorie restriction, again, like I said before, I have to
really, really take my hat off to the clinicians who are
involved in these projects. And Amy Rothberg is somebody
who’s in family medicine here. She has been doing
a fantastic job of running a weight
management program here at the University of Michigan. At this point, several thousand
patients have actually passed through the program. And what it is primarily
designed to do is give people
an opportunity to lose weight very rapidly, and then actually get additional
support for another 21 months to take a person out to two
years where they have a period of intense weight loss, and
then they get that maintenance and that additional
support with a nutritionist and seeing the clinician
regularly for a long period after that to actually help
them maintain the weight loss, which we know is
critical to success here. The weight loss itself
is induced through a very low-energy diet. That’s another way of just
saying you don’t eat very much. You have a very low
level of calorie intake, typically something like six to
eight hundred calories a day. That is enough to keep your
internal organs healthy and not much else. That is enough to
keep you going, and after that it is
essentially a loss. Of course, any energy
you expend above six to eight hundred
calories per day, which most of us do just being, is going to end up
being weight loss. And that occurs for
about 12 weeks. After that, they enter the
maintenance phase of the program where they’ll get to regularly
meet with a nutritionist and try to maintain the loss
that they have achieved. In studies of the larger
numbers of people who have gone through the program, the
results are really, really nice. What you see are all sorts of
different reductions in BMI, blood pressure, cardiovascular
health risk factors, fasting, glucose, risk of diabetes,
et cetera, et cetera. Not only that, but it appears
to be very cost-effective. I say this just in case
anybody is, you know, sort of wondering how
would this actually fits into a clinical setting,
and could you ever argue that this is actually
cost-effective for your patients. I think the answer is yes; and there’s some nice
data to support that. But what we were really
interested in is, “Well, so what happens when
these patients do go through this period
of rapid weight loss? Do they experience some
improvement in pain?” So this is very much
an observational study. And our only entry
criteria was essentially that you were taking part of
the weight management program, and that you indicated that you
had pain in one or more areas of the body using the 19 sites on the fibromyalgia
survey criteria, which you’ve all heard
a lot about today. The [inaudible] survey criteria
gives us a chance to look at how widespread
pain is in the body, and it also gives
us a sense of some of those other comorbid symptoms
that are really troublesome for patients like fatigue,
disruption of sleep, cognitive difficulties, and some
of those other symptoms as well. So what we did is we took 123
patients who had it with pain in at least one site and put
them through the program, and we just gave them the
fibromyalgia survey criteria before and after. It was really actually
that simple. Additionally, 31 of
those patients agreed to have a blood draw before
and after, so we were able to do an analysis of
proinflammatory cytokines just in serum, as well as some
anti-inflammatory cytokines like interleukin 10. So this actually shows
you the raw data of BMI as people go through
the program. And this is truncated to really
focus on the intervention phase, those first 12 weeks where
people are losing weight. And what you can see, I think, is just this really nice
downward slope in BMI indicating that people are in fact losing
a good amount of weight. And if you kind of look
at the individual lines, what you can see is that if
people stay in the program, the vast majority of them
lose quite a bit of weight. And then during the
maintenance phase, they tend to regain a little
bit, but largely maintain. So what happened? If we look at the body map — and this is a somewhat
complicated figure, but hopefully you can see
some of the dots showing up a little bit clearly here. What we’re doing is we’re
looking at patients who lost at least ten percent
of their body weight, versus those who did not. And what the circles indicate
is how many of them at baseline, the bigger the circle, said
they had pain in that body part when they started the study. And then the color tells you
whether or not it got better or got worse after they went
through the weight loss. What we see is that all
throughout the lower limbs, and in the lower back, and
especially in the abdomen, the chest, and also somewhat
even in the jaw and face, people reported pain
improvement, such that they were about 20% less likely to say
that they had pain in any of those regions after
they lost ten percent of their body weight. There was no such effect in
those people who did not lose at least ten percent
of their body weight. Additionally — hopefully
this is going to show up a little better. That’s sort of hard to see. Those are raw changes in
their depression scores. On the left where it says,
“Worsen,” those are the patients who actually showed a
little bit of worsening of their depressive
symptoms, and then you can see on the other side those
who actually improved on their depressive symptoms. It’s a really strong
preponderance of patients who are involved in the program who showed a really
substantial increase — or I should say “benefit”
from a depression standpoint after taking part
in the intervention. Additionally, the
vast, vast majority of patients either showed
an improvement in fatigue, or showed no change, with
very few showing worsening of fatigue, suggesting, again, that you’re also seeing some
benefit on those other symptoms. And this was all
true when we looked at the symptom severity score,
which I’m sure Dan talked about this morning and
others, showing the sort of constellation of
symptoms getting better. Very interestingly,
we saw no difference in proinflammatory cytokines after the intervention
was complete. What had changed is that the
anti-inflammatory cytokine, interleukin 10, had gone up
dramatically in the patients after they lost weight. So what you see there
are sort of paired — each of the bars
represents an individual. The blue shows you what their
IL-10 levels were at baseline. The orange shows you
after the intervention. You can see them
just sort of spiking up patient after patient. Interleukin 10 is going
up in these patients, which we would expect would
broadly control inflammation, and might have a
positive impact on some of those central pathways
that I was talking about. That was true when we normalized
interleukin 10 to levels of C reactive protein
just to see. So it really looks like there’s
a positive inflammatory tone change in those patients
after they lose weight. In some secondary analyses, we
saw some interesting things. Men tended to actually show a
greater improvement in fatigue than women did, but women still
got a nice healthy benefit in terms of improvement
in depression and pain. It really looked as if
patients who did not reach that ten percent threshold
did not get as much benefit from the intervention
over the 12-week period. And interestingly, that
improvement was not dependent on how much more they said
that they were exercising; which we thought was one of
the sort of obvious confounds or potential explanations
for why this was happening; sleep being another one, but we did not have a good
objective measure of sleep in this particular study, something that we’re
following up on. So now let me give you a
little bit more data that — this has not yet been published
so this is a bit of sneak peek. What we’re looking at here
now is the follow-up study where we said, “Okay, we see that there’s clearly
some benefit for pain. When does it happen? How long does it take before
people start experiencing an improvement in pain? And when do we see these
inflammatory changes?” And so what we’ve done is we’ve
invited people to take part in the study, but now those
who have much more severe pain to begin with; and what
we do is we put them on that very low-energy
diet for three weeks, and then we put them on
a normal diet for a week, and then we put them back
on the very low-energy diet. What we’re doing is sort of
an on-again/off-again ABC — or ABAB design to
try to see whether or not inflammation
is going down and up, and the symptoms are
going down and up as we’re varying
their calorie intake. On the left there, those are
FM survey criteria scores from a small group of people
that we’re sort of thinking of as a pilot study here. And we’ve divided them up by
those who had really high levels of FMness, medium levels of
FMness, and low levels of FMness when they started the
study, to see what happens over the first 12 weeks, with a
special emphasis on week three. And what you see here that I
think is really remarkable is that the patients are
showing a dramatic improvement really quickly. This is prior to
major weight loss. Most of these people have
lost less than five percent of their body weight, and a lot of that body weight
loss is water. And what we’re seeing here is
about a halving of FM symptoms. I remember when I first
showed this to Dan, he said, “We don’t have any drugs
that work that well.” That was really remarkable
to me. And it’s true, we
don’t have drugs that in three weeks can cut
fibromyalgia symptoms in half. What’s interesting,
too, is that it appears that this improvement just
sort of stops at three weeks, and then is maintained
throughout the rest of the period. As long as they keep engaging
in the diet, and they seem to continue to experience
that benefit. Those that actually meet
fibromyalgia criteria — those are those on the right, you can see that they’re showing
absolutely dramatic improvement in even just a small number of
patients who have FM symptoms. So this tells us something
that’s really interesting. It looks like weight loss
per se is not necessarily the whole story. In fact, it may be that the
calorie restriction itself is capable of inducing
these rapid changes in pain processing in the body. And it could be through
inflammatory pathways, it could be through
central nervous system, neurotransmitter
pathways, we’re not sure. But this is the next
step so that we can begin to understand this
phenomenon better. And finally, a little bit more
complicated model suggests that we probably have increased
inflammation as a result of adiposity that is
affecting both the brain and the peripheral joints. It’s not either/or; we have
inflammation affecting both sides of the pathway. In conclusion, it looks
like these common symptoms, the ones that you
probably see in clinic, are dramatically
improved by weight loss and calorie restriction. It’s possible that an
anti-inflammatory activity, rather than proinflammatory
activity, is where most of the action is occurring, why we’re seeing this
angalsic benefit. And finally, it looks like
these changes occur very early, such that a very low-energy
diet by itself may be one that doesn’t even have to
necessarily lead to weight loss, could be beneficial
for some patients. And thanks again to Amy
and all of her staff who actually run the study. [Inaudible]. Thanks. Happy to
take any questions. [ Applause ]