Hello. Good evening. We have quite a few people
still waiting to enter. We have a tremendous
turnout tonight, but we'd like to get started. I'm Gina Vild. I'm the Associate Dean for
Communications and External Relations at Harvard
Medical School. And I am so thrilled. This is my 10th year introducing
the Longwood Seminars. And I am just delighted to
see so many familiar faces and some new faces in our
Longwood Seminar family. So tonight's topic, The
Science of Pain Management is of tremendous
interest to many of you. We choose our topics by having
our Longwood Seminar audience vote. And this was definitely
a topic for which there was great interest expressed. We're going to talk
about the science of pain and how to manage pain
both temporary and chronic. And we're also
going to discuss how managing pain has
become, unfortunately, a national health crisis. We recognize that this
issue touches many lives throughout the country. And so, as a result,
we're going to provide you with even more information
then what you'll garner tonight on opioids and addiction. On a slide that will
be on the screen soon, there are three
additional resources. First, you'll find a
wealth of information offered by Harvard's
Harvard Health Publishing. Its content for
consumers and clinicians. And I invite you to take
a look at this site, because you'll find information
on addiction and pain, but also information
on diet, and health, and a whole range of topics. Second, last year
we brought together some of the country's
leading experts to discuss how education
can combat addiction. They included Governor
Charlie Baker, who led the governor's
opioid addiction working group, and Harvard's own
Dr. Bertha Madras, who you'll hear from tonight. The program was viewed
by tens of thousands of people around the world. And we invite you
to view it as well. And that website,
also, is on the screen at hms.harvard.edu/opiods. A third resource was a talk
given at Harvard Medical School last year by, again, one of
tonight's speakers Dr. Clifford Wolf. It had an outstanding
attendance. It was standing room only. And we invite you to
take a look at it. It's the link
hms.harvard.edu/talksat12. I want you to know that in
addition to those who are here in the auditorium, we're
welcoming thousands of you from throughout the world. So thank you for joining us
through the live stream Two weeks ago, for the
last Longwood Seminar, we have 30,000 people joining
us virtually from 82 countries . So to those who
are here in person and those who are here through
livestreaming, welcome. We hope you'll join us for the
next two Longwood Seminars, Bridging East and West-- New Frontiers in
Medicine on April 12, and Weighing the Facts of
Obesity will be held on May 9. Now, just a few brief
announcements and we'll get on with our program. Our speakers are delighted to
take your questions tonight, so please write
your questions down on the card you were
given, and our staff will be walking up and down the aisle
and they will collect those. If you are watching
through the live stream, you can write your
question in the feed-- the Facebook Live
comment box, and we will try to feed those questions
to our speakers as well. On the screen, you'll
see information related to obtaining
certificates of completion and professional
development points for teachers. OK. And we also invite you to visit
the Longwood Seminar's page on the HMS website, where
you can find past seminars and watch those
from previous years. Many of them are
evergreen topics. Now, we ask you to please
silence electronic devices, but do not turn them off because
we want you to join our Twitter conversation. Join with others in the room
and around the globe by using #hmsminimed. And now for this
evening's program. All of us at some point
experience pain, right? It may be the
result of an injury, the aftermath of
surgery, or just pushing our bodies during exercise. But we all experience
pain differently. Why is that? And if you have pain, what's
the best way to treat it? And there are millions who
suffer from chronic pain. How can they manage it without
the threat of addiction to prescription painkillers? Tonight you're going
to find answers to many of these
and other questions from tonight's speakers. And the three
speakers-- we're just thrilled to have them
here, because they're the leading voices in the
country on this topic. Our moderator,
Dr. Clifford Wolf, is a Harvard Medical
School Professor of Neurology and Neurobiology,
Director of the FM Kirby Neurobiology Center,
and Associate Director of the Intellectual and
Development Disabilities Research Center at Boston's
Children's Hospital. Dr. Bertha Madras is a Harvard
Medical School Professor of Psychobiology
at McLean Hospital. She also has a Massachusetts
General Hospital appointment. And in 2017, she was appointed
as one of six members-- it was a very small group-- to lead the
President's Commission on Combating Drug Addiction
and the Opioid Crisis. She's been an exceptional
resource for us at Harvard Medical School. And first, we'll hear
from Dr. James Rathmell. He is the Harvard Medical
School Leroy D. Vandam Professor of
Anesthesia, and Head of the Department of
Anesthesiology, Perioperative, and Pain Medicine at Brigham
Young Women's Hospital. Please give a warm welcome
to our guest speakers. [APPLAUSE] Well, thank you very much. It's a great
pleasure to be here. Gina did the great introduction
when I have not met before. And she made the quintessential
mistake-- the one that I have over
and over throughout my career of mistaking me for
somebody 20 years younger. So thank you. It's a great
pleasure to be here. [INAUDIBLE] No mic. There we go. Thank you. All right, microphone. So I'm going to talk
tonight about the title-- The Science of Pain Management. And I've put my title a
little bit differently-- The Science of Pain
and its Management. Because the two haven't
connected very well yet. We know a whole lot
about the science thanks to some of
the people you're going to hear from tonight. And I'm going to tell you a
little bit about the management and some of the things we've
been through that probably don't work as well as we had
first thought they would. I am a chronic pain
specialist by training. I've been in this 25 years. I also practice anesthesiology
in the operating room as part of my role as the
chair of the department there. So I'm very much
involved every day in the management of pain
after surgery and injury, as well as those who go on
to have persistent pain that lasts for long periods of time. So like any good teacher,
I want to tell you what I'm going to teach you. And then at the end,
I'm going to tell you what I just taught you. So we're going to
start with, what are the things I
want to get across? They're really
pretty simple, I want you to be able to
define what pain is and explain why we have pain. What's its purpose
physiologically? I want you to be
able to describe the differences between acute
pain, chronic pain, and then this special subset of chronic
pain we call neuropathic pain. Because it's important
to recognize, and the treatments
can be very different. I want to talk about how
opioid analgesics work to relieve pain. Because they do work and they
do have a very prominent role in our armamentarium. But then, I'm going
to go on and talk about why opioid analgesics
are important in the care of acute post-operative
pain, but they remain very controversial and
are getting more controversial in the treatment
of chronic pain, and where that
problem comes from. So let's start out
with, what is pain? So this is the definition. And it's put forward by the
International Association for the Study of Pain. It's the biggest
international group of clinicians and
researchers that have been working
at this for decades. And this is the definition
they put forward in 1986, pain is, "an unpleasant sensory
and emotional experience," because there are
both components to it, and both are very, very
important, that are, "associated with actual
or potential tissue damage or describe in
terms of such damage," So when you read
this definition, it's really important
to understand that, we as clinicians, don't
know what you're experiencing. We don't know either
the physical experience, or the emotional experience,
or how they're tied together. All we know is what
you're describing to us. And so we take it at face value. We come in, we take
it at face value, and we move forward from there. It is not measurable. We do not have a
magic algometer, all though there's lots of
work going on in that area. So if you're one of those
people who is very innovative, develop an objective
measure of pain and you will do very, very well. So here's the wiring-- the physiologic wirings-- from
one of my textbooks early on. So pain, what is it
and why do we have? Now, think about this. You put your hand on a
stove, you immediately pull away-- there's
a reflex arc that says, get that out of there. And then, you start to
feel this burning sensation where you've suffered injury. If you touch that-
area-- now, remember before you put your
hand on the stove, if you touch the area it
feels like normal light touch. Right? It doesn't bother you at all. Now, you pull it
off of the stove-- the tissue has been injured. And almost immediately,
you have a sensitisation. Now you touch it, light
touch, it hurts, right? It's painful. And Dr. Wolf early in
his career worked out the anatomic correlates at
the level of the spinal cord. We actually increased the
gain of a normally light touch and it's called
spinal cord wind-up. That is the sensitisation
that occurs. And why does it occur? Now, think about that. You've just injured yourself. And the physiology
and the rewiring immediately says,
protect that area. Protect it, its injured,
tissue healing has to ensue. And if you keep using-- it if
you keep reinjuring that same area-- it won't heal. And we know that,
because in those who are born without
the sensation of pain, or in those who lose
it like in damage to the peripheral
nervous system that occurs in diabetic
neuropathy, they'll injure the same
area over and over and over, and they'll end
up with open wounds that don't heal and amputations. And that's the
important part of this. The other part is, so it
comes into the spinal cord level, goes across the
midline up to the brain-- the important part about
the way analgesics work is we can dampen that input. So you see that
modulation-- that descending limb that comes down
to that first order neuron. So I guess I should
orient you here. Out on the periphery, where
the flame is, that's your hand. Then it comes to
the spinal cord, which is the central part. There's a very specific area
in the spinal cord where that first order neuron comes
in and relays the signal up to your brain where
you perceive pain. The modulation comes from the
central nervous system downward to the spinal cord, and says,
we can reduce that input so that it's not as severe-- we can dampen it down
so that you can still function in the face of
pretty severe injury. So that's the function
of pain-- protective. Now, what about the
different types of pain? So we have acute pain. And acute pain
signals tissue injury. Just like I told you, it
says, keep it protected until all of the tissue heals. But at some point, in states
where you have recurrent tissue injury, or in those where
you've had permanent alterations of the nervous
system, you can pain that persists three
months, six months, there are different
definitions, but by and large, beyond three to six months,
we call it chronic pain. And chronic pain can come from
a recurrent condition that injures tissue over and over,
it can have a waxing and waning pattern, or it can be chronic,
persistent, and severe that never lets up. There are many
different types of pain, but what underlies it is, what
is the cause of the tissue injury? Now, there is a
special subset of pain that happens when you
injure the nervous system. And it's frighteningly
common after injury. When you injure
the nervous system, sometimes all the
tissue injury heals. If you look at the person,
if you look at the area that was injured, it looks normal. All of the tissue is healed,
but there's persistent pain in that same distribution. We call that neuropathic,
or abnormal pain associated with nerve function. And there are many
different types. People, if you think
about tic delarue, sudden shooting
pains into the face that can occur with
the stimulation of the trigeminal nerves-- just
suddenly lancinating pains. Hypersensitivity, even
in the area that's looks like it's healed-- we call those neuropathic pain. And it's important to identify,
because the treatments are very different
for nerve injury pain than for normal pain
after illness or injury-- that acute pain. All right. So now, how is pain treated? Now, we diverge from the
science a little bit here. So we call pain relieving
drugs analgesics. It's an agent that produces a
diminished sensation to pain. Without loss of consciousness
is the actual dictionary definition. And it comes from the Greek
algos for pain, and an, "without,"-- analgesia or analgesics. So we're going to talk about a
number of different analgesics. Now, first of all, when
we approach a person who has any type of pain. Remember, this is
a 20-minute talk, we're not going to get to
all different types of pain. But maybe we can entertain
specific questions at the end. Pain treatment always begins
with identifying the underlying cause. Absolutely critical to
identify the underlying cause. And then, you can
tailor the treatment to the cause of
the pain by knowing the expected
duration of the pain and what the
magnitude of that pain is based on what the
patient is telling you-- the person that is suffering
from the pain is telling you. We use analgesic drugs in a
variety of different forms, but it's a really small part
of managing patients with pain. I had a person in the
Harvard system come up to me at the beginning of this-- Carol Martin came up-- and told
me a little bit about her story and what she's suffering from. And she has focused completely-- early in the course of
her story, or her journey, she was focused on
pharmacological agents, and then transitioned to
complementary and alternative medicine means. There's a wide
range of them that can be very, very
effective for getting away from pharmacologic treatments. So I think it's
important to understand that drugs are a very small
part of managing pain overall. All right. But I'm going to focus for
a minute on analgesic agents and their uses. Now, here's the range of
what we have out there. And it begins with
acetaminophen. It's a very good analgesic. We don't know exact
mechanisms-- we have some ideas
of where it works in the central nervous system. It's different than the other
drugs like ibuprofen, which we lump into a class
called non-steroidal, anti-inflammatory drugs. It turns out they're very
effective pain relievers for mild to moderate
pain, and they really form the cornerstone
of management of pain after sports related injuries--
strains, and sprains, and the like. There's a group of
typical analgesics that work in different
ways on different receptors but have pretty good
analgesic effects. And tramadol is one of those
you might have heard about. Then there are neuropathic
agents that work better for neuropathic pain-- those nerve injury pains--
than they do for acute pain. And gabapentin is the
best known of those. Then we have an
alternative group of drugs that we use in various
ways, either topically or by injection-- the
local anesthetics. They actually work in a
completely different way. They block sodium
channels, and you get no conduction of nerve
traffic for a good long period of time, and we all know that. Lidocaine is the
prototypical one now, but the one people
know best is by brand name Novocaine or
procaine, that's used by dentists early on. It's not used much anymore
because of sensitivity reactions. And lidocaine is
the more common one. It doesn't work for
long periods of time. And it completely gets
rid of all sensations, so it's very
difficult to protect an area that's been anesthetized
with a local anesthetic. And that limits
their long-term use. And then, finally,
we're going to talk about opioid
analgesics, which is where a lot of this
controversy has come up. And the quintessential one,
or the two prototypical one, is morphine that
people know best. All right. Now, let's talk about
opiates and opioids. Opiates are drugs that are
derived from the dried latex of the oriental poppy. Now, this is actually a
northern poppy from my backyard up in Vermont when I lived
there several years ago. The oriental poppy
that's papaver somniferum has a very large seed pod. It's that in the middle. When, at the end of the growing
season, the pedals fall off, you can score that seed
pod and a latex drips out. And it has a number of
different compounds in them, morphine being one of them. But a number of different
alkaloids that can be extracted-- tincture of opium
is the raw black tar that dries in the sun. And this has been around
a long, long time. It's use dates back
thousands of years. The difference between
opiate and an opioid-- opiates come from
the poppy plant, and opioids are
either synthetically or semi-synthetically derived. And fentanyl is the
one in the news. It's a synthetic opioid that's
made in the laboratory that binds to the same receptors. But morphine and fentanyl work
in very much the same way. Their potency is
incredibly different, so you need a lot less fentanyl
to do the same thing as a much larger dose of morphine. So how does it work? Here's the mechanism
of action of this drug. And I've showed you that
first incoming neuron at the level of the spinal cord. And then, there's
a blow up here. We know the neurotransmitters
and the ion channels where these medications bind. And what they do is bind at
the level of the spinal cord and in the brain, and they
decrease the magnitude of the incoming traffic. And they're a beautiful system. We have endogenous
opioids that are released in the face
of danger, that bind to the same receptors. And they allow us to function. But it's not like
a local anesthetic, you can still feel where
the area been injured. It's just, the magnitude
of the pain is decreased. So one of the important things
to remember with the opioids is you never completely
get rid of pain until you reach unconsciousness
at very high levels. All right. So what of the side effects
of the opioid analgesics, of this specific class? So very common side effects-- almost universally they can
produce nausea, vomiting. When you take them for
long periods of time they decrease the motility
of the gastrointestinal tract and you get constipation. Itching is very common
with it-- pruritus-- sedation at higher doses, and
what we fear most in overdose is respiratory depression. You stop breathing. And I have a little
diagram of mouth-to-mouth. It turns out, we as
anesthesiologists, often use large doses
of these and respiration stops in the operating room. But we have mechanical
ventilation at hand, we can breathe for you
during the period of surgery. Opioids are very
good in high doses. They're very easy on the
cardiovascular system, and they form the cornerstone
of very stable anesthetics for things like cardiac surgery. But we have to be there as an
anesthesiologists to breathe for you. So if you take a very
large dose and overdose, and there's not
someone there at hand, or you're not there to help
breathe for your colleague, then brain death ensues
within five to seven minutes. OK. Now, it turns out that
sedation comes first. And most people get
a level of sedation, but their heart's
still pumping-- they're not responsive. And that's why naloxone
has been so helpful. Naloxone is this pen
or a nasal spray. If your heart's still
beating and it can circulate, that actually
blocks the receptor where the opioid binds
and completely reverses all of the depression. It's really kind
of miraculous when you get he patients wake up, or
a person wakes up immediately. So what's the big controversy
about opioid analgesics? They're really good pain
medications, particularly in the post-operative period. They work. They work universally. As an anesthesiologist,
I could not get through the
day helping people with their post-operative
pain without these. This is written by Thomas
De Quincy at the turn of the 19th century. He was the son of
publishers in London, and he wrote a three-volume
set called The Confessions of an English Opium eater. And in the final volume of this
set, there's a chapter on-- it was mostly about all
the wonderful things he experienced in the
drug induced state-- all of these wonderful
insights into life. But the last chapter is about
how opium gives and takes away. It tears at the fabric. It's very, very reinforcing. You come, back oftentimes, for
the euphoric effects not just the pain relieving effects. We know that it
has this potential, and it falls under addiction. So here are the three
things we talk about. If you take an opioid
analgesic-- morphine-- over and over and over,
you'll need higher doses to get the same
degree of pain relief. That's a normal phenomenon. It's called tolerance, and
we know how that occurs. If you stop it all
of a sudden, you'll go through withdrawal--
jitters, and shaking, and high heart rate. That's called
physical dependence. Addiction is very different. And it's hard to
summarize, but it's really when you lie, cheat,
and steal simply to get access to
that drug because of its reinforcing effects. And it's a disease of the brain. We know a lot about
why it occurs. It's not a bad person
that does this, it's a very physical,
reinforcing effect. What we worry about most
though, as physicians, is when we write this and the
person takes that prescription and sells it on the street-- diversion. And that occurs, and
we worry about that. Those are the downsides
of the opioids. All right. Now, to finish up, is acute
pain different than chronic? Chronic pain, I told you
three to six months or more. It's extraordinary. This is the Institute of
Medicine's report in 2011, and 116 million Americans
suffer with pain that persists beyond three to six months. And it can often
be debilitating. Opioid analgesics are extremely
effective for treating acute post-operative pain. I've told you, I could not get
through the day without them. So it's important that we don't
eliminate their availability. We would not be able to treat
pain associated with illness, injury, at the end of life,
very advanced illnesses, on obstetrics during
labor and delivery. They're very important in that. But until recent years,
we did not use opioids for treating chronic pain. It was very limited,
because we've known about these terrible,
adverse effects, including the addictive effects
of the medications. We thought addiction
was very, very uncommon. It turns out it's more common
then we at first believed. And some people are more
predisposed on exposure to that than others. The science behind
this has become more clear in the
last several years. And this is the
2015 NIH workshop that centered on
prescription drug abuse. The bottom line is, there
really is no science that's suggests that long-term
use of chronic opioids, particularly in high doses,
is effective for treating any chronic pain condition. That's the stark reality of it. And as you go up in dose,
a number of side effects appear with greater and
greater frequency, including the risk of things like
myocardial infarction and death from overdose as you
get to higher doses, even if you're taking
them for chronic pain. And that's very frightening
and sobering to us. We're going to learn
more about what that's done at the national level. So just to finish up,
I want to summarize by hoping you can answer each of
these questions-- what is pain and why do we have pain? What are the differences between
acute, chronic, and neuropathic pain? How do opioid analgesics
work to relieve pain? And then, why are
opioid analgesics important as part of our
everyday armamentarium for short-tern acute pain, but
more controversial in treating chronic pain. And I'll leave it at that. Now, next up is Dr. Madras. Did I do it right? [APPLAUSE] Wonderful. Thank you very much
for coming, and thank you Gina and Harvard
Medical School for inviting me to
this important event. The ancient Greeks-- we invoke
the Greeks again for a term called pharmakon. Pharmakon cone means a
medicine and it means a poison. And I don't think there's
some more apt description for opioids than
the word pharmakon, because pharmakon can have
remarkable effects in relieving acute pain and it can also
produce addiction and pleasure. And both of these can co-exist
in individuals whether or not they're feeling pain or not. Pain is the number one
self-reported medical reason for using drugs with
abuse potential. And pain and pleasure
centers in the brain are closely allied and linked. Let's quickly go through-- as professors always
do, they tell you what they're going
to talk about-- the opioid crisis,
the root causes of it, the commission
recommendations, and lessons learned for the future. The United States leads the
world in prescription opioids. These are the 30 highest,
most prescribing countries in the world. And the United States
is number one by far. And on average, it prescribes
five times more opioids than any other
nation on average. Why is this the case? And let's try to understand it. It also has the
dubious distinction of leading the world in
opioid overdose deaths. And in the past year, where
we have good statistics from the CDC, we've had 64,000
deaths due to all drugs-- prescription opioids about
10,000, heroin, about 15, and fentanyl is leading the
way right now with regard to the fastest rising number
of opioid overdose deaths. What are the root causes
that gave us this problem? It is so important to remember
that the United States has had opioid addiction due to
medical reasons in the past. In the 19th century we had a
very severe opioid addiction epidemic in this country,
because morphine, which was so prominent
at the time as one of the most
effective medications that physicians had was given
liberally to many people, primarily to women, and
then during the Civil and after the Civil
War to men who suffered tremendous injuries. But what happened
since that time-- since around 1910-- is that
we, for that period of time and up till very
recently, physicians were quite reluctant
to use and prescribe opioids for chronic pain. We have a case of
generational forgetting. We have a problem
of quality science. We had very little
training with regard to pain management and
opioid prescribing. And we had a gigantic
disconnect between addiction serve services
and medical services, so that rehabilitation
centers were no longer connected with medicine. And as a result of
this giant disconnect, led medical schools,
medical education, to largely ignore the issue
of addiction, especially with regard to opioids. Generational forgetting
was a big problem. For decades prescription
opioids were avoided for chronic pain because
of the fear of addiction, because of the fear of overdose,
and because of the fear that there was no good evidence
for their use in chronic pain. I have excavated the New
England Journal of Medicine in Countway Library which is
right down the street here, and there were examples
of publications in the 1920s of people trying
to figure out how to surmount and overcome an overdose. And in some cases they use
vinegar to make people vomit. And in other cases
they used a tube that they stuck into
the intestinal tract to try to extract the drug. So physicians were
aware for 200 years that these compounds could
give rise to problems. And then, something,
something happened. There was a
five-sentence article published in the same New
England Journal of Medicine saying that narcotics
are not addictive when given to pain patients. Five sentences, and it
catalyzed a movement to blame a provider for
inadequate pain management, a patient movement that began
to advocate for opioids, a huge investment by
pharmaceutical companies to train physicians,
to train patients, to train pain societies that
opioids of certain formulations were safe and effective for pain
management and not addictive. 20,000 specific
events were sponsored by specific
pharmaceutical companies to train people that this was
a safe form of medication, ignoring 200 years of history
in the biomedical journals. And detailers went
to doctors offices to try to convince
physicians to use opioids The veterans
Administration responded by adopting a principle of
pain as the fifth vital sign. And they mandated
pain evaluation and aggressive
treatment for pain. Two years later,
the Joint Commission started to consider pain
as a fifth vital sign. The other for our blood
pressure, heart rate, temperature, and the rate
at which you breathe. And there were other pressures
to satisfy patients pain. And some of the reimbursements
for individual physicians and hospitals were
based on whether or not pain was treated aggressively. So there was tremendous
pressure on physicians. And then, every doctor's
office and hospital room had a pain assessment
tool placed on the walls. The focus turned to pain
management and prescribing of opioids. The health care
community, their feet were on the fire because of
an adequate medical education. Because there were no real
guidelines for using opioids for chronic pain, because
of the fifth vital sign, the patient movement, CMS-- the Centers for Medicare
and Medicaid Services-- were actually
discouraging the use of non-opioids for treatment. There were other
financial incentives, and the FDA was languid
during this initial period. And then, as prescription
opioids began to tighten, there was, in some populations,
a transition to heroin, with no contingency to
provide substance use disorder treatment-- no contingency to
provide medications. During this period of time
opioid prescribing increased by over 300 percent-- threefold. And we became a awash
in opioids, so much so that, currently, upward of 12
million people misuse them. More than 2 million people
have a prescription opioid use disorder-- that means
they are addicted to prescription opioids. More than 600,000 people
have a heroin use disorder. And everyone who knows these
numbers knows that these are under estimates-- these are
the National Survey on Drug Use and Health, which
goes to households, but does not
scrutinize individuals that are not currently living. What are the pathways
to opioid use disorder from prescription opioids? Very few studies have
actually addressed this. But one recently did
by looking at people who are in treatment for this
disorder and questioning them-- how did they get to this point? A small percentage said-- a few said-- we didn't
have adequate pain control so we kept escalating the dose. Another cohort said, I liked
opioids on my initial encounter with them, they
really felt good. And others said, I
just wanted to use them for psychoactive purposes-- I had no pain. And others said, I need relief
from emotional distress. And others said, I had a
heroin addiction before, and I was prescribed
it, the physician did not ask if I'd had
a prior, and as soon as I got the opioids,
I knew I liked them. But the scene is shifting. In 2005, 90% of the people
in treatment for heroin had their first exposure
with prescription opioids. 10 years later,
that number is down to 67%, which means more people
are starting with heroin rather than prescription opioids. And now fentanyl, in 2013,
has come on the scene. And if you look at this
copper penny, right beside it is the amount of fentanyl
that can kill a person. And if you look at the three
vials, one of them is heroin, the middle one is carfentanil,
and the right one is fentanyl. And that's the amount that
is required to kill people. And you can see the amount
that can kill of fentanyl and fentanyl analogs is far
less than heroin itself. And we had a perfect
storm in our nation. The president
organized a commission to find solutions
to this crisis. And these were the
commissioners-- Governor Christie, who
chaired, governor Charlie Baker from Massachusetts,
Governor Roy Cooper from North Carolina, former
Congressman Patrick Kennedy, and this is a very short,
ancient lady on Charlie Baker's left-hand side. The commission's tasks
were quite simple. What federal
funding is currently available to treat this--
to approach this problem? What is the availability of
addiction treatment overdose reversal currently? How can we prevent-- what is available currently in
terms of prevention, in terms of educating the public,
educating physicians, educating them on prescribing practices,
and monitoring prescriptions of patients using prescription
drug monitoring programs? What is the effectiveness
of educational messages for prevention? Are they good? Are they obsolete? What can we do in terms of
promoting prevention, and what are federal prevention
and treatment programs, and make recommendations
to the president. So the commission
response looked at every phase of the
cycle of addiction, from supply, which is
part of prevention, to risk factors, initiation,
escalation, addiction, withdrawal, relapse, treatment,
abstinence, recovery, lifelong abstinence, overdose,
and rescue, and the impact of this on children, on
families, and friends. The recommendations
could be summarized, and I will tell you
that when I started to draw the first
outline for the report, I had 253 headlines. And Governor
Christie said, kid-- he flattered me by
calling me kid-- he said, kid, we'll never get
anyone's ear with 253 topics, we have to simplify. So we simplified and simplified. The recommendations were in
prevention, in treatment, in rescue, in recovery, in
research, who would do it, and accountability. And that was a very important
part of the introduction. There were 56 recommendations-- federal funding, how to
streamline it, how to track it, how to make sure that
states and local communities are accountable for tax dollars
that go to this problem. How to prevent in terms
of individuals, youth, and the national
media, how to prevent in terms of supply
reduction, which is in the purview of the
Department of Justice. How to prevent in terms
of patient education, physician, alternatives
to opioids, prescription drug monitoring
program, and pain management. Big data analytics, which
we had a large chapter on after I spent a great deal
of time interviewing companies that have data
acquisition in real time, compared to the
federal government that sometimes lags
two years with regard to statistics on overdoses and
treatment needs and so forth. What are the barriers
to treatment, poor quality of treatment,
insurance coverage barriers, inadequate number of treatments
slots, inadequate staffing and training,
medications assisted treatment that is inadequate
in terms of distribution, and also, people in the
criminal justice system. How can we help them as well? What are the barriers to rescue? Naloxone availability
is one barrier, but the most important
part of naloxone rescue is also to ensure that
people who are rescued have the option of
developing a treatment program for themselves,
and, as well, access to medications
to help tide them over the inevitable withdrawal. Recovery support
services for families, for children, half-way homes,
support services in colleges, providing housing
and employment. And research-- research into
medications which we'll hear about in two minutes,
research into to improved pain medications-- improved medications assisted
treatment, improved overdose drugs, because naloxone, as
much as it is a miracle drug, in some cases is not adequate
for fentanyl analogs, which can surmount the antagonism. President Trump accepted
all 56 recommendations. I have it in writing. [LAUGHTER] And, in terms of
prevention, we said the old model of fried
eggs on your brain has to be replaced by modern
methods of communicating through social media,
modern methods of screening young people through
electronic devices and others. We decided that
all the root causes that related to the medical
community we have to eliminate. And there were many
recommendations-- 26-- to reverse
engineer what had been done in terms of
pressuring the medical community and unleashing their
degrees of freedom in order to prescribe according
to their best conscience. We had a number
of recommendations in terms of compliance
with parity laws, and reimbursement of the true
costs of treatment, quality outcome measures-- I can go on and on. We currently have medications
to assist treatment. There are three
FDA approved ones-- methadone, buprenorphine,
and naltrexone. But these are terribly, terribly
under-utilized in our system, less than 35% of the 14,000
treatment centers in the nation offer them. 60% of rural communities
lack a physician that has a waiver to
administer buprenorphine, and even those physicians
that have been trained in medications assisted
do not engage at all-- they are not interested
in this community. Patient education is critical. The patient has the right to
know and the right to refuse, that any one of these compounds,
which can target the Mu opioid receptor can kill. And research the alternatives
to opioids for pain management, improved opioid use disorder
medication, improved rescue drugs, improved devices, and
fast track approval by the FDA. We have to eliminate
stigma, which prevents some
people from sharing their woes, their griefs, with
addiction with their families, with their physicians. What are the lessons learned? The lessons that we learned
were that vast sums of money were spent to promote opioids-- millions upon
millions of dollars to transform medical
care amongst physicians and in the minds of patients
that these were safe, effective, and non-addictive. They were promoted for
many medical conditions, like migraine headache,
which they don't work for, and there are a number
of medical conditions where long-term opioids
simply are not indicated. They were promoted to
safe and non-addictive. They were promoted without
scientific evidence for the use in chronic conditions. Advocates received
attention, but the opponents did not receive equal time
on the stage of opinion. Addiction and diversion
were not anticipated amongst many
well-meaning physicians who imprudently prescribed. Illicit drugs
flooded the nation. Medical education
lagged far behind. And government regulations of
those very tightly controlled class of drugs failed
to protect the public. And so I close
with two thoughts-- we hear of Michael Jackson, and
Prince, and Anna Nicole Smith, and kinds of people in the
entertainment industry who die. And the newspapers
lament their passing. But alas, for those
who never sing but die with all the music in them,
weep for the voiceless who have known the cross
without the crown of glory. Oliver Wendell Holmes
is one of the landmark-- his dad is the one who wrote
this, his son was at HMS. I think this problem can be
solved with wisdom, resolve, leadership, and adequate
financial support. And right now, budget
looks very promising. Thank you very much. [APPLAUSE] Good evening. My name is Clifford Woolf,
and I have the privilege of completing this discussion. The two speakers have really
identified the problem. Dr. Rathmell indicated
to us than the challenge that he faces as a
physician dealing with patients who have
acute post-operative pain and chronic pain. He said that he cannot function
as a physician in the absence of opioids. And Dr. Madras has
clearly indicated to us the perfect storm that we face
by the utilization of opioids. So the question
then is, what to do. And that's something that
I'm going to try and address. So what are the problems
with the existing analgesics? One of the major
problems is, most of them don't work very effectively. And it's quite
extraordinary, the FDA sees as its prime
purpose is to protect us by ensuring that the drugs
that we take are safe. And that is, obviously,
very important. But they place
much less emphasis on how effective they
are in treating us. And indeed, almost every
drug that has approval from the FDA for the
treatment of pain leaves many patients who do
not respond to that Treatment and that is a real problem. And so, there's a
low responder rate. And this is to the extent that,
for chronic neuropathy pain, for example, something
like 60% of patients who get the available drugs
are not helped by those drugs. Can you imagine that? So you have pain, you
go to a physician, and they give you the FDA
approved drug, and 60% of you will not respond. And what is even
worse than that, is that there are no means
to identify who will respond and who won't respond. And there's no research that
has attempted to make that link. There are enormous side effects. We've learned about the abuse
liability, the tolerance, the constipation, the
other features that are part of the opioid crisis. But other drugs have terrible
side effects as well. They make people feel dizzy. They reduce the function
of their brains in a way that they would
rather have the pain than take these analgesics. And so, this is something-- we
have to deal with all of those. We have to improve efficacy. We have to improve
the responder rate. We have to reduce the
side effect burden. And, most importantly
of all, we have to find a way of overcoming
this abuse liability that is part of opioids. It is inevitable that those
drugs, such as morphine, fentanyl, and others,
as described, which act on the Mu opioid
receptor, inevitably have an abuse liability. So how are we going
to make progress? To make novel and
superior analgesics? Well, the first step is
to identify and validate new targets. And targets are
proteins that exist in the body that
contribute to the function of the nervous
system, for example. And there are some targets
that, if we identify them and we could either
activate them or inhibit to them, we may be able to block
those neural processors that lead to our conscious
awareness of pain. How to do that? Well, one way is to
use human genetics. Not all of us feel
pain in the same way. Some of us feel a lot of
pain to a minor injury, and others are
quite stoic and do don't complain when
they have major injury. Using twin studies, we
now know that at least 50% of that variance is due to
our heritability-- our genes. If we can dissect out
which of the genes are protecting us
from pain, this was going to be one way that
we can identify new targets, because we can
say, here are genes that enable this person to have
less pain than that person. Can we pharmacologically
mimic the effects of the pain protective genes and eliminate
the effects of those genes that amplify and increase the pain? Part of this is-- and this
is one of the big technology breakthroughs of
the last decade-- that we can move away from just
testing one thing at a time. We now know the entire genome. We know every
single gene, and we can scan every gene to see what
happens if we either decrease or increase the activity of
each gene on pain, for example. And this is now possible. And I'll say a little
bit about that. But it's going to
require a transformation of the way we do our science. And it's big science,
and it's going to require a collaborative
effort from many individuals scientists and
many institutions. So we've got to
identify targets. And then, the next step is
we've got to identify drugs that can act on these targets. How to do that? And this is an
example of a screen that was run in my laboratory. Which is quite
extraordinary, because this is an academic laboratory
just across the road in Boston Children's Hospital,
and we are now running industries
scale screens and are beginning to get hits that
are looking very promising. And these have to feed
on to our identification of the potential targets
that can interrupt that flow of information that
leads to the sensation of pain. And we're beginning to do this
both by going for the targets and also conducting what
we call phenotypic screens. And I'll explain what
that is in a moment, because this is going to be
a complete transformation in the way that we approach
a pharmacological discovery. Until now, the industry has
identified targets usually on the basis of what is known
about the biology of pain, and then they run
screens with millions of compounds against the target
to find a single compound that selectively acts only on that
target and on nothing else. And then, they introduce it
into preclinical models and then into patients. And most of them fail. We need a different way. And I'll explain how we can
begin, at last, to do something that will, I predict,
transform the entire way that the pharmaceutical industry
can approach this problem. One of the problems that
the industry confronts when it tries to
develop new therapies is how to test novel
analgesics pre-clinically. Dr. Rathmell indicated
to us that pain is a subjective experience. We can report it, as he
said, and we take it on trust that when someone
says they have pain, they do have pain, even though
we have no objective measure. And that's true as
well what do you want to test your
analgesic before you put it into patients. How can you test it? How can you see that
this new compound that you've made against a novel
target is effective or not? How can you evaluate that? And in fact, almost every
existing model that is used now turns out to be very
poor predictors, because we get a whole
series of compounds that look very promising
preclinically, but you go into the patient
and they fail to work. Something is wrong
and we have to fix it. Well, here's an attempt
that we've done. This is an instrument
that was built by a graduate student in
my lab, David Robeson, that he calls the palm reader. And it enables us to
look at the behavior of a freely moving animal. This happens to be a mouse
just minding its business. And as you can see,
there's color on its paws. We can detect the
contact of the mouse as it moves on the surface. And this information can
be captured, analyzed, and we can use machine learning
algorithms to interpret exactly what the animal is doing
and how its behavior changes in different
circumstances, We can detect features of
this animal's behavior that reflect anxiety, fear,
pain, and relief of pain in a way that has not
been possible before. And we're very excited to roll
out this new technology, which is almost ready for prime time I mentioned phenotypic screens. How can we move away
from just looking at one target at a time? And this is where stem cell
technology is going to make an enormous transformation. We can now take cells from
the patient-- a blood sample-- turn them into stem
cells, and then turn those stem cells
into those neurons that generate the signals that
lead us to feel pain. Over there on the
right is an example of a plate of sensory neurons. Those neurons that are activated
by intense or noxious stimuli. And they are identical
in every Respect They're made in a dish from
a patient stem cells, but their behavior and
properties, in every respect, resembles those of a patient who
has a noxious stimulus applied to them. So we can study pain in a dish. And we can now begin to
screen against pain in a dish. And this is the phenotypic
screen that I mentioned. It's a phenotype-- a pain
phenotype rather than a target. The colors over here reflect
the activity of the neurons. We can not only culture
these human neurons derived from patients that
are pain neurons, but we can look at how
their activity changes, and we can screen for compounds
that can reduce or increase their activity. And again, this represents
a completely different way to study pain and to begin to
screen for new therapeutics. Here-- I mentioned
human genetics-- there are some mutations
in ion channels that produce, in some
patients, spontaneous pain. These are patients
who, out of the blue, will suddenly have very
severe pain in their limbs-- pain that is so severe that they
walk around with buckets of ice and put their arms into them,
because they cannot stand the pain. The pain is spontaneous
and it gets worse with increased heating. We've taken-- we have
identified the mutation. We've taken stem cells. We've introduced this mutation. We've made these pain
neurons from the stem cells, and we're now
recording the activity. In the top row are
the control cells that don't have the mutation. And you can see
there's less color, because they are less active. Normally, these
pain neurons are not activated unless they are
exposed to a noxious stimulus. Then in the bottom
two panels, which is where the mutation
has been introduced, the pain neurons
are now beginning to fire spontaneously,
exactly as in the patients where their
pain arises spontaneously. But even more so,
you can see there's more activity at higher
temperatures, which is exactly what the
patients complain about. So we now have a phenotype
in the dish which copies the phenotype
of the patient, and we can now
understand exactly what is driving that
mechanistically and begin to screen for new
therapies that can alleviate this particular
phenotype or pattern. So we've dealt, then, at least
with some of the changes that can occur in the way we
approach the study of analgesics and pain preclinically. How to test novel
analgesics if we get one? We've identified a new target. We've identified new compounds. We've tested them preclinically. How do we now test
them in our patients? And again, we run
into the same problem. We would rely on
patients' report. We all know how varied that is. Your pain is not
the same as my pain. My pain today is not the
same as it will be tomorrow. My pain may be affected
by the fear that I have that I will lose my job. My pain may be
influenced by the fact that I think that the treatment
the doctor has given to me is going to work-- in other words, a
placebo response. All of these are
confounders that make it extremely difficult.
And Dr. Rathmell issued the challenge to the
audience, how can we measure pain objectively? Well, I'm not going to
claim the prize from him, because I'm not responsible. But we can use functional
imaging of the brain as a readout of the
changes in activity that occur in our brain
during the experience of pain. This is a recording from
a colleague of mine, Irene Abrams from
Oxford University, and she is one of the
leaders in measuring changed function in
the brain that reflects the presence of pain or not. And her recordings
are so accurate now, that instead of doing a
clinical study on 200 patients to see an analgesic signal,
she can see a signal on five patients or less. So again, a transformative
change in our approach to the development
of new analgesics. So what are the new
strategies for developing new modes of managing pain? I'll just give you two examples. First is a discovery that was
made by a colleague of mine at Harvard Medical
School with me. This is Dr. Bruce
Bean, who works in the neurobiology faculty
at the medical school. And we looked at the challenge
that, in fact, Dr. Rathmell mentioned. He mentioned that if
you go to the dentist and you get a shot of
lidocaine or Novocaine, you do relieve pain, but you
also block all sensation. You become numb. Not only do you
block all sensation, but you block all
motor function-- you become paralyzed. And anyone who has had an
epidural knows that, yes, you get the relief
from childbirth, but you cannot walk. And if you stood up, your
blood pressure would fall. So local anesthetics,
they do work, but they have a real problem. And the real problem is that
they are non-selective-- they act on every
excitable cell. They act on motor neurons
to cause paralysis. They act on those neurons that
generate tactile sensations. And indeed, they act on the
excitable cells in our heart and in our brains. So there's what we call very
limited therapeutic index-- the difference between
the amount of drug that you need to get
an analgesic effect and the amount that
causes unwanted effects is almost zero. How to overcome that? Well, we came up with
an idea by saying, well, what is unique to pain
neurons-- those neurons in the periphery that are
activated by noxious stimuli and whose activity
is the trigger for the sensation of pain? And it turns out
these neurons have a particular cause of ion
channels called large pore channels. And that's exactly
what they are. When they are activated,
their pore is large-- much larger than
most other channels. And it turns out,
they are large enough to allow drugs to enter
into those neurons. So we said, well,
how can we find a way to selectively use this
drug delivery device that's only present on pain neurons. And what we did was we took
the lidocaine-type drugs and we converted them in a
way that they were inactive unless they got
into pain neurons through these large
pore channels. And this is work that has
happened here in the Longwood area and which we are hoping
to get a company that will use this this technology this year. And hopefully, we'll
have our first studies in patients within a
relatively short period. So this may be one way that
we can help Dr. Rathmell. We can ween know him
of his need for opioids by developing an
alternative strategy. [LAUGHTER] What about chronic pain? Well, here is the
strategy-- again, this is this happens to
be examples from my lab, there are many other people
who are doing other, very exciting and important work. Well, the other strategy was
to go back to this notion that we had that if a patient-- if one patient-- happens to
have a mutation in a gene that is pain protective,
can this inform us about a potential way of
developing analgesics. And this is a study that we
published relatively recently where we identified
exactly that, a pain protective haplotype-- a pain
protective variant in the gene. And if you have it--
and about 2% of us have that, two copies of it
in both our chromosomes-- you are protected from
certain-- you still will feel pain when
you're pinched, but if you have surgery
you won't require opioids, and you'll do much better. Your pain reports are less. And we have identified the gene. We have identified the
pathway, and are now developing drugs that
can interact and mimic the effect of this pain
protective haplotype. So what I've given you today is
an example of the kinds of work that I've been doing. But we've got to
look to the future. And part of what I do is to
train the future-- people who will take over and develop
completely new therapies. So for the first
time in my career, I am pleased to say that I
have a living next slide, which is one of my entrepreneurs
who came has come from my lab, and who's going to tell
you about his strategy, and, indeed, two other
former members of my lab who are working on a new way
of developing new analgesics. [APPLAUSE] Thanks so much, Clifford. When Clifford told me that
I have to be living slide, I realized I have
to be very lively. So I'm going to do my very best. [LAUGHTER] So what am I'm going to do in a
very, very short period of time is give a bit of an overview
of the last couple of years of my journey with founding
this company Blue Therapeutics, and what we are up to. I would also like to highlight
how the ecosystem at Harvard and the greater
Boston area itself has been so instrumental in
getting this off the ground. And how entrepreneurship
is such a important part of this and piece of this puzzle
to realize the very next step. To talk about the
founding story, I think there are a
few different layers. The first layer
itself is something that our esteemed speakers
have all touched upon, which is the tremendous
opioid crisis that our country is facing. When we were conceiving of
this idea in about 2013-2014, the number of opioid overdose
deaths that were happening were something like
60 to 70 deaths a day. I'm really sorry to report
that in 2016 that has doubled to 145 deaths a day. It's a major, major problem
where we need to have impact. The second part of it is
that in the drug discovery and development process, you
can think of it as a pipeline. We first discover
a novel strategy, then we develop
[INAUDIBLE] towards that. But then to take it into
the clinic and the market, you have to first show
that there is a good safety tolerability profile. From there you convince
the FDA and then start human clinical trials. And then, there are three phases
to the clinical trials as well. In first phase you look
at safety and tolerability in human populations. Then you go on and do a
proof of concept efficacy study in phase 2, where you can
actually see if it's actually going to work in a small
population of people suffering from a particular condition. So what typically happens is
that, for a pharma company to be interested
in a strategy, they get involved when the
strategy has already been de-risked a little bit. So it typically tends
to be in the phase two, or afterwards in
the clinical trial. But how do we then get it
from the point of discovery, and get it all the way
to that phase two step? And that's where I think
entrepreneurship has a major, major role to play. And we-- myself,
Michio, and David, we are all in Clifford's
group at this time. And one of the ideas
we had was, let's live this dream of trying
to actually have impact on this profound problem. And then we focused
on technology that I developed during my
PhD with Phil Portoghese, who is also a co-founder and
the scientific mentor for this company. And I'll talk a little bit
about the technology itself. Very quickly summarizing
what we already have-- the other speakers have done
a phenomenal job with this already, but just to mention a
key point, all of the opioids that we've heard about
and that have been used, like morphine, heroin, fentanyl,
carfentanil, all of them target an individual and
a single opioid receptor called the Mu opioid receptor. So this opioid
receptor is involved in a phenomenal process
which does cause pain relief, but it also projects into
different brain regions which lead to the side effects, like
withdrawal, like addiction, and also the main reason
why people actually die during overdose, which
is depression of breathing. So what we set out to
do was some new research that had come out showing that
receptors actually need not exist as individual receptors,
but they may actually couple with another receptor
physically to form a dimer. And we got very
interested in this, and our idea was, can we
do a systematic screen to identify ligands
that would target different heterodimeric
receptors, and that way delineate which
dimer leads to, let's say, pain relief and which
maybe leads to some of these horrific side effects. So if we can separate
that out, maybe we can develop targeted
therapies that would only cause pain
relief but would not have those side effects. So that effort lead to our
lead molecule, Blue181, which essentially is a
non-narcotic and very effective painkiller, because
it's 50 times more potent than morphine. So that means we need to
use 50 times less of it to get the same
amount of pain relief. But it does not have any
of the common opioid side effects, like abuse
potential, constipation, most importantly respiratory
depression as well-- and also, almost no tolerance. So these are some
of the major facets of this that makes what
you're doing very interesting. So what you're doing
currently is moving this from out of that discovery
phase and getting it into safety tolerability
trials, so that very soon we can file the IND and
then start our phase 1 human clinical trial. So that's kind of where
we are as a company. And just to highlight,
again, how important this whole process is and
how this ecosystem has really helped is, first of all,
the Harvard Innovation Lab took us in and
incubated us with them. So that was again
very, very powerful. The second part of it was
also, the Dean's challenge between the medical school
and the business school, and how that really helped
and gave us the expertise that was needed to
kind of move us along. And finally, I'd like
to thank all the funding agencies, like NIH,
Department of Defense, and all of them who have
given us the funding to get this off the ground. With that, thank you very much. I also want to just say,
even though Clifford was not associated with
this work, he's been so instrumental in guiding
us and mentoring us on this journey. So thank you all for
listening, I appreciate it. [APPLAUSE] So we now have an
opportunity for our panel to answer some of
your questions. I'll start with a
question to Dr. Rathmell. As an anesthesiologist,
what do you think is your role in
combating the opioid crisis? So is my microphone--
yeah, microphone is on. So as a traditional
anesthesiologist giving anesthetics for
surgical procedures, I think that we have
a tremendous role to play in reducing
the need for opioids. Even during major surgery
we've really put together what combines a wide range of
different non-opioid analgesics often coupled with peripheral
nerve blocks that can reduce pain after surgery-- regional anesthesia. And it turns out that
we've developed protocols that can reduce or eliminate
the need for opioids even after a lot
of major surgeries. As a chronic pain
specialist, it's very different in
the clinic when someone has persistent pain
associated with a chronic pain condition like
chronic low back pain or pain toward the end of life. It's really having frank
discussions about what the role of opioids is, and
minimizing the number of people that are started on
new doses of opioids, and then minimizing the
maximum doses that they reach. So I think there's
two roles, depending on which hat I'm wearing. Dr. Madras, what
has been the biggest impact on the opioid crisis of
involvement of the government. I think there are three
ways the government has pioneered in the past year. One is to organize
a commission that would design a roadmap for
how to alleviate the crisis. Number two is to declare this
a public health emergency. And number three, based
on my insider information, is to summon all the
cabinet secretaries and involve them intimately,
daily in what they're going to do in terms of
action plans related to our 56 recommendations. And I've seen that in action
quite frequently recently. Dr. Rathmell, one
of our audience asks, what is the likelihood
that this individual, as a patient, could
develop tolerance addiction from post-operative
opioids, say, for hernia, [INAUDIBLE]
surgery or appendicectomy? And should they refuse opioids
and ask for NSAIDs instead. So the likelihood
that short-term use will lead to persistent use
down the road is extremely low. We've done-- this is the
heart of my current research. For instance, a woman
who comes to delivery and has a cesarean section, and
has never had an opioid before, gets a dose, or two, or three
for the first several hours after cesarean
section has probably about a 1% chance of still using
those opioids a year or more after surgery. It's quite low, but 1%-- 1 in 100-- that's not zero. Should you refuse opioids? Well, I think you should
have a frank discussion with your anesthesiologist or
the treating surgeon, and say, are there ways that I can
minimize my opioid use, or even eliminate it. Because in many of the
major surgeries you have, including cesarean
section, we've come up with just
superb strategies for avoiding them
altogether without having to suffer through. I don't think you should
suffer in silence-- there are alternates to
opioids in most circumstances. Related to that, and please,
both of you answer this, how long does it
take for a patient who is taking opioids
for legitimate treatment to become addicted? But the answer
is, we don't know. Can a single exposure lead
to such reinforcing effects that people go back
and experience it? Well, certainly we know from
both alcohol and opioids, and many other
drugs of addiction, that someone who's never
exposed but has a predisposition doesn't develop the
disease of addiction. So a single exposure. It's not out of the
realm of thought. But we also know that
millions of patients receive these drugs every
year and do just fine without going on to addiction. And they are extraordinarily
effective for treating pain. Well, there is some
evidence that people who are treated with opioids
for longer than seven days are much more likely to
continue using them for months and even longer than that. So there is, among
many state governors, a desire to limit
opioid prescribing to three days or seven
days for acute pain, and then wait to see what
happens after that, rather than giving a month's supply
with an open-ended refill possibility. I'm going to counter that-- real quickly-- because the
problem with the seven-day rule is that all painful conditions
are not created equal. Someone who has a major
spinal surgery for instance, with instrumentation, we
know the course of resolution of pain is weeks and weeks. And sending that person home
with a seven-day prescription is just a license-- you're going to fail. They're going to return
to the emergency room. They'll have a horrible,
horrible experience. And so, we have to
tailor what's needed to the magnitude and duration
of the expected recovery. This is conundrum. It's a conundrum. Of course, and I don't-- I'm not going to
counter, but one of the root causes of the
30 that I've excavated is the fact that with the
current financial accounting and hospitalizations, many
people have been released from hospital very
prematurely compared to what they used to
be released in time, and released with
hefty doses of opioids so that they don't
have to come back, rather than caring for them in
a hospital setting where they would receive adequate nursing
care, adequate pain relief, and then go home when they
no longer were in acute phase post-surgically, Yeah. This has happened. And that's probably a very
small but significant reason why we have fed this problem. So the next question,
again for both of you, is whether addiction
incidence differs across age, gender, and race. That's easy. [LAUGHTER] Yes. The younger you begin
using, the much likelier you are to become addicted. I don't think that
that principle can be disputed for every class of
drugs, which includes alcohol, tobacco, marijuana, cocaine,
opioids, m inhalants stimulants. That principle holds for all. And one of the most
important things, I think, in terms
of prevention, is choosing not to be exposed to
drugs with addictive potential at early ages. Here's a challenging one
does pain shorten lifespan? I mean, that's so
broad as to be-- pain-- Let me answer in a flipped way. I mention human
genetics as being one of our ways of interrogating
the role of different genes in the generation of pain. And I mentioned an
example of a mutation that caused spontaneous pain. But there are mutations
that completely eliminate our capacity to feel pain. And these are
patients who have what we call a congenital
insensitivity to pain. They don't feel any pain. And in consequence, if
they go to Starbucks they can tell the
difference between coffee that is pleasantly
warm and scalding hot. And when they eat, they can't
tell the difference, often, between food and their tongue-- and they chew their tongue. And their life expectancy is
reduced very substantially, because if you have a
fracture they don't report. If they have appendicitis,
there's no clue. And so, pain-- the
early warning mechanism that Dr. Rathmell highlighted--
is something crucial, and we have to preserve
it in our treatments. But the reverse question
is more difficult. I would say that
the consequences of severe, persistent
pain are devastating. They are absolutely devastating. So we've talked about the
limitations in the treatment. I go to clinic-- every time I'm in clinic I
face someone who is suffering, and suffering with very,
very real pain with a very, very real cause that we
cannot get to the root of. And that has
consequences on people. And yes, it probably
shortens life. And yes, the suicide rate
is dramatically higher in those who suffer from
chronic painful conditions. So it has profound consequences. I'm not here to say
don't use opioids, because I have that
conversation all the time. But what then? They work-- they work for
short periods of time. But what then? And we don't have
answers to what then. And that is the
motivation to find-- so related to then,
is the question whether there's a
danger of taking nsaids or Tylenol regularly
over long periods of time? Is it truly a safer alternative? Well, so that's a hard
question to answer, because it's very contextual. So I think for
the acetaminophen, it seems to be an extremely
safe drug all the way up to the extremes of life if
you stay under a certain dose threshold. But if you start getting
up above four grams a day, particularly if you drink
alcohol concomitantly, there's a pretty significant
risk of liver injury. So that's acetaminophen-- very,
very safe at the lower doses. The non-steroidal
anti-inflammatory drugs like ibuprofen are
also quite safe, except for very
specific populations where it inhibits
important mechanisms that lead to proper blood flow to
the kidneys, for instance. So if you're someone who has
terrible congestive heart failure and is on
lots of diuretics, and you take even normal
doses of non-steroidal anti-inflammatory drugs, you
risk very significant kidney injury. And same thing
goes for people who have a predisposition
to complicated ulcers and so forth. So there are at-risk
populations for the nsaids. But by and large, if
you're young and healthy and use over-the-counter
doses of non-steroidal
anti-inflammatory drugs, they're quite, quite safe. Dr. Madras, do you see
a place for marijuana in management of pain? Glad you got that-- And what are the risks
that that may involve. Well, certainly we
don't have good data on the use of marijuana. We have four randomized
controlled trials on the use of marijuana
in neuropathic pain. The trials lasted
just a few weeks. And every subject except for a
few were not marijuana naive. So they knew precisely
what to expect. With regard to
long-term use, we don't have the data on what the
effects of chronic daily, and more frequent than
daily use of marijuana is on quality of life,
cognitive function, addiction, and all the other outcomes. We do have evidence
that people who use marijuana for
chronic pain have higher rates of opioid misuse-- prescription opioid misuse--
and opioid addiction. And people who
use marijuana also have higher rates of opioid
addiction and opioid misuse. We also know that people
who are in treatment for opioid addiction
and use marijuana have much higher dropout
rates from their treatment. So the evidence at this point
weighs on the side of marijuana not being a good solution. The evidence also weighs on
the side of there being no FDA approval for the whole
plant, which is completely unregulated in terms of dose,
in terms of ratio of THC to CBD, in terms of quality, purity,
and specific indications, and long term comes. And in summary, I'm not a fan. [LAUGHTER] We have 100 other questions,
which, unfortunately, we are not going to be able-- one of them seems to be
as long as War and Peace. But there's one
question here, which I think we can all
have a little bash at, was, what was the reason
that you, you, all of us, chose this field of study. Well, that's very easy for me. When I was an undergraduate at
college, I was 16 years old, and I was in honors
biochemistry. And our professor gave
us a choice of 10 topics to choose to write a
lengthy research paper on. And I didn't like
any of the topics. And I went, and I said, I'd
like to pick my own instead of what is in this list. And I searched the literature
and found a disease called phenylketonuria. And phenylketonuria
is an inborn error of metabolism, which is caused
by having a genetic deficiency and enzyme. If the disease is not
detected right after birth, the child goes on to develop
a very serious brain disease depending on their genetics--
some not so serious, some very, very
significant brain injury. And if it's detected
and they're put on a phenylalanine-free
diet, they can go on to live a normal
life with a normal IQ. And I was mesmerized
by this paper. And I said, if we can
understand the brain and understand what errors there
are that make a brain go awry, we can change the course of a
life of an individual in such a dramatic way. I was-- that was it. That was my moment in life. And from then on, the
brain was my calling. Oh, I get a chance here. OK. [LAUGHTER] Pardon? I went into-- so I went
into anesthesiology because I very much like
seeing science in action. In the operating room,
the goals are clear. It's really producing a
pain-free state without recall, and taking care of patients
in that very acute setting. It's very appealing. I call it science in action. It's like when you do
experiments in the lab. It's that day you actually
do the experiment. You give the drug,
you see it work. But what I lost from
my medical training was the long-term
relationship with patients. And that's why I ventured
into chronic pain and eventually from
primarily anesthesiology to all chronic pain for a
large portion of my career. Including pain in those near the
end of life, which I very much enjoy because of the challenges
and the extremely intense interactions with patients
where you can really make a difference in their lives. So for me, my experience
as a medical student training in South Africa at a
time when South Africans were still remembering
the opioid problem, and did not prescribe opioids
fro post-operative pain management, as a
medical student I went into the
post-operative recovery, and all of the patients
were screaming and crying, and in terrible pain. And I said to the surgeon,
what's going on here? And he said, well,
what do you expect? They've have surgery. And that was the attitude. Wow. And I just said, this is wrong. And that was my
turning point, when I decided to devote my
life to understanding paing and helping develop
new medications. Thank you all. Thank, you all. [APPLAUSE] We look forward to a new future.
