>> I'M DANIEL JOHNSTON,
ACTING CHIEF OF THE
GYNECOLOGIC HEALTH AND DISEASE
BRANCH AT THE NICHD, ALSO CHIEF
OF THE CONTRACEPTION RESEARCH
BRANCH.
I'D LIKE TO WELCOME YOU TODAY TO
THE SYMPOSIUM HOT TOPICS AND
EMERGING TRENDS IN GYNECOLOGIC
PAIN RESEARCH, THE NICHD STAFF
IS EXCITED TO HEAR PRESENTATIONS
AND LISTEN TO DISCUSSIONS.
BRIEFLY THE BRANCH WAS FOUNDED
IN 2012, IT WAS LED BY DR. LISA
HALVERSON FROM 2014 UNTIL
OCTOBER OF LAST YEAR.
A DEFINED FOCUS ON GYNECOLOGIC
PAIN IS RELATIVELY NEW FOR THE
GYNECOLOGIC HEALTH AND DISEASE
BRANCH, AN AREA THE BRANCH FEELS
STRONGLY ABOUT AND IS EXCITED
ABOUT.
SUPPORT FROM NICHD MANAGEMENT IS
CLEAR BOTH DEMONSTRATED BY THE
HIRING OF A PROGRAM OFFICER,
SPECIFICALLY FOR THIS AREA, DR.
HELENA AHN WHO YOU'LL HEAR FROM
SHORTLY, ALSO IN ALLOWING US TO
HAVE THE WORKSHOP.
I WANT TO COVER WHAT ARE WE
TRYING TO GET OUT OF THIS
MEETING, WHAT IS THE NIH
INTERESTED IN.
FIRST, WE WANT TO UNDERSTAND
GENERAL INTEREST IN THIS AREA,
IT'S CLEAR INTEREST IS HIGH.
THERE ARE OVER 200 PERSONS
REGISTERED FOR THIS MEETING.
THAT'S EXCEPTIONAL.
WE WANT TO SHARE SOME SCIENCE
AND GYNECOLOGIC PAIN WE FIND
INTERESTING.
WE WANT TO STIMULATE DISCUSSION.
WE WANT TO HEAR THAT DISCUSSION.
AND I THINK ALL THAT IS PROBABLY
OBVIOUS.
I THINK THERE'S ANOTHER
OBJECTIVE, THAT IS THAT WE WANT
TO KNOW AND FEEL COMFORTABLE
COMMUNICATING WITH THE GHDB
PROGRAM STAFF.
PART OF THE OUR JOB IS TO
UNDERSTAND THE SCIENCE IN THE
AREA, UNDERSTAND WHERE THE FIELD
IS PRIMED TO GO, AND FACILITATE
THE OPENING UP OF NEW AREAS OF
GYNECOLOGIC PAIN AND CERTAIN
WITHIN GYNECOLOGIC PAIN.
PART OF THE JOY OF OUR POSITIONS
AT THE NICHD AND NIH IS
UNDERSTAND A VERY BROAD RANGE OF
SCIENCE.
WE SEE A LOT.
WE HEAR A LOT FROM THE
APPLICATIONS AND MEETINGS WE
ATTEND.
BUT WE ALSO WANT TO HEAR FROM
PEOPLE IN THE FIELD OUTSIDE OF
SCIENTIFIC MEETINGS.
WE WANT YOU TO FEEL COMFORTABLE
COMMUNICATING WITH US NOT JUST
TODAY, THROUGH YOUR
APPLICATIONS, BUT AT MEETINGS,
REACHING OUT TO COMMUNICATE.
IT'S IMPORTANT FOR THE FIELD AND
TO HELP US UNDERSTAND WHERE THE
FIELD IS, WHERE THE FIELD IS
PRIMED TO GO, AND HOW WE SHOULD
BE THINKING ABOUT ASSISTING THE
FIELD.
WITH THAT, I'D LIKE TO GIVE
CONTROL TO DR. HELENA AHN,
GYNECOLOGIC HEALTH AND DISEASE
PROGRAM OFFICER, WITH
RESPONSIBILITY FOR THE
GYNECOLOGIC PAIN PORTFOLIO.
HELENA?
>> THANK YOU, DR. JOHNSTON.
I WILL SHARE MY SCREEN.
CAN YOU SEE MY SCREEN?
>> YES.
>> SORRY.
THANK YOU FOR JOINING THE
GYNECOLOGY PAIN RESEARCH VIRTUAL
MEETING TODAY.
I'M HELENA AHN, PROGRAM OFFICER
IN THE GYNECOLOGY DISEASE
BRANCH.
DID I TURN ON MY CAMERA?
MAYBE NOT.
I'LL GO AHEAD.
SO FIRST I WOULD LIKE TO LET YOU
KNOW THE TECHNICAL CONSIDERATION
FOR THIS MEETING.
THIS MEETING IS BEING RECORDED.
A RECORDING WITH SPEAKERS
APPROVAL AND MEETING SUMMARY
WILL BE POSTED ON THE WEBSITE
AFTER THIS MEETING, ON THE GHDB
WEBSITE.
CLOSED CAPTIONING WILL BE
AUTOMATICALLY GENERATED, TITLES
VIEWED AT THE BOTTOM OF THE
SCREEN.
FOR ATTENDEES CAMERAS WILL BE
TURNED OFF.
LINES WILL REMAIN MUTED.
THERE WILL BE FIVE MINUTES AFTER
A 20-MINUTE TALK AND DISCUSSION
TOWARDS THE END OF THE MEETING.
IF YOU HAVE A COMMENT OR
QUESTION PLEASE USE THE CHAT
PANEL AT THE BOTTOM OF YOUR
SCREEN OR RAISE YOUR HAND.
I AM CURRENTLY OVERSEEING THE
GYNECOLOGY PAIN PROGRAM IN THE
GYNECOLOGY HEALTH AND DISEASE
BRANCH.
THE GYNECOLOGY PAIN PROGRAM
SUPPORTS CLINICAL TRANSLATIONAL
BASIC RESEARCH ON GYNECOLOGY
PAIN CONDITIONS.
THE GHDB RECENTLY RELEASED THE
INTEGRITY RESEARCH IN GYNECOLOGY
FOA, THE SCOPE INCLUDES
GYNECOLOGY PAIN SYNDROMES,
APPLICATION TODAY IS APRIL 18,
2022, IF YOU HAVE ANY QUESTIONS
REGARDING THIS FOA FEEL FREE TO
CONTACT CANDACE TINGEN.
THE INITIATIVE TO STEM PUBLIC
HEALTH CRISIS, IF YOU GO TO THE
NIH GRANTS AND FUNDING WEBSITE
HERE, IF YOU CAN SEE THE DETAILS
OF THESE TWO FOAs AND NOTICES.
TODAY WE INVITED SEVEN SPEAKERS
TO TALK ABOUT GYNECOLOGY PAIN
RESEARCH COVERING FIVE AREAS
RELATED TO GYNECOLOGY PAIN
INCLUDING HOT TOPICS AND
EMERGING TRENDS IN
CHRONIC/GYNECOLOGIC PAIN
RESEARCH, CHRONIC PELVIC PAIN,
DYSMENORRHEA, VESTIBULODYNIA AND
GYNECOLOGIC PAIN MANAGEMENT AND
TREATMENT.
I WILL MODERATE SESSION 1.
FIRST, THE SPEAKER IS FROM
UNIVERSITY OF MICHIGAN SCHOOL OF
MEDICINE.
NICKS DR. SUSAN SA-SANIE,
DEPARTMENT OF OBSTETRICS AND
GYNECOLOGY, TALKING ABOUT PELVIC
PAIN, UNIVERSITY OF MICHIGAN.
AND THEN DR. FRANK TU IS GOING
TO TALK ABOUT MENSTRUAL BRAIN
AND CHRONIC PELVIC PAIN
UNIVERSITY OF CHICAGO.
LASTLY DR. NACKLEY, DEPARTMENT
OF PHYSIOLOGY, DUKE UNIVERSITY.
SESSION 2, A MEDICAL OFFICER IN
THE JCB WILL MODERATE THE
SESSION 2.
THERE WILL BE A DISCUSSION
SESSION.
DR. TINGEN AND I WILL MODERATE.
I WOULD LIKE TO THANK THE
MEETING ORGANIZERS IN THE GCB
PROGRAM.
IF YOU HAVE QUESTIONS REGARDING
THE GYNECOLOGY HEALTH AND
DISEASE BRANCH FEEL FREE TO
CONTACT US AT ANY TIME.
I WILL STOP SHARING.
SO OUR FIRST SPEAKER IS DR.
DANIEL CHLOE.
COULD YOU SHARE YOUR SLIDES?
>> ARE YOU SEEING THEM OKAY?
>> YES.
>> ARE YOU READY FOR ME TO
START?
>> SURE.
YES, GO AHEAD.
>> GREAT.
THANKS FOR INVITING ME.
I'LL GIVE A WHIRL WIND TALK
ABOUT A NEW TERM FOR A REALLY
OLD TYPE OF PAIN, THAT IS
NOCIPLASTIC PAIN.
I'M CLINICALLY TRAINED AS A
RHEUMATOLOGIST,AT GEORGETOWN.
WE THOUGHT EVERYONE WITH THE
KNEE ON THE RIGHT WOULD HAVE
PAIN BUT THIS IS NOW ABOUT A
30-YEAR HISTORY OF RESEARCH IN
OSTEOARTHRITIS, POPULATION BASED
STUDIES IT APPEARED IN THE
'90s A RELATIONSHIP BETWEEN
WHAT PEOPLE'S X-RAY LOOKED LIKE
AND WHETHER THEY WERE
EXPERIENCING PAIN, AND HOW
SEVERE THE PAIN WAS GOING TO BE.
AND WHAT WAS MOST SURPRISING ARE
ALL THE INDIVIDUALS THAT HAD
REALLY BAD-LOOKING X-RAYS LIKE
THE ONE I SHOWED ON THE RIGHT
AND 30 TO 40% OF PEOPLE IN THE
U.S. POPULATION ACTUALLY, THAT
HAVE THAT X-RAY, DON'T HAVE ANY
PAIN, NEARLY ALL OF THEM ARE
MEN, AND I'LL EXPLAIN WHY THAT
IS, BUT IN OSTEOARTHRITIS THERE
WAS A FAIRLY RAPID MOVEMENT AWAY
FROM THINKING THAT WHAT YOU SAW
IN THE PERIPHERALLY ENTIRELY
EXPLAINED THE DISEASE, WHEN
PEOPLE SAW THEY INDIVIDUALS THAT
HAD PAIN THAT COULDN'T BE REALLY
EXPLAINED ON THE BASIS OF
PERIPHERAL FINDINGS THE FIRST
TENDENCY IS TO BLAME
PSYCHOLOGICAL FACTORS BUT IN
POINT OF FACT THEY DON'T EXPLAIN
THE VARIANCE BETWEEN WHAT YOU
SEE ON AN X-RAY OR MRI. OF THE
KNEE AND WHAT SOMEONE IS
EXPERIENCING WITH REGARD TO
PAIN.
THE OTHER PART I LIKE SHOWING,
THERAPIES WE USED TO THINK
WORKED WELL IN KNEE
OSTEOARTHRITIS, FOR EXAMPLE,
NON-STEROIDAL ANTI-INFLAMMATORY
DRUGS, I'VE ALWAYS BEEN
ANTI-OPIOID, EVEN SURGERY FAILS
TO RELIEVE PAIN IN 30% OF
INDIVIDUALS WITH KNEE OR HIP
REPLACED.
I'LL SHOW YOU DATA WHERE WE'VE
USED, IF YOU WILL, SURGICAL
RELIEF OF PAIN AS A MODEL TO TRY
TO HELP EXPLAIN OR UNDERSTAND
NOCIPLASTIC PAIN.
THE OTHER CONDITION I'M GOING TO
ALLUDE TO TODAY IS FIBROMYALGIA,
OUR GROUP IS INVOLVED IN
RESEARCH IN FIBROMYALGIA, BUT
THE ORIGINAL CRITERIA FOR
FIBROMYALGIA REQUIRED THAT THE
INDIVIDUALS HAD A CERTAIN NUMBER
OF TENDER POINTS AS WELL AS
HAVING WIDESPREAD PAIN,
ORIGINALLY SKEWED THE DIAGNOSIS
TO BEING ALMOST ENTIRELY WOMEN,
BUT MORE RECENTLY AS THE NEW
FIBROMYALGIA CRITERIA THAT I'LL
TALK ABOUT WERE DEVELOPED, NOW
FIBROMYALGIA IS ONLY ABOUT 1 1/2
TO 2 TIMES MORE COMMON IN WOMEN
THAN MEN.
WHAT I'M GOING TO TALK ABOUT
REALLY IS OVER THE LAST THREE
DECADES OR SO FIBROMYALGIA HAS
GONE FROM BEING THIS CONDITION
THAT NO ONE WAS SURE IT WAS REAL
ENTITY TO BEING THE POSTER CHILD
FOR THIS THIRD NEW MECHANISM OF
PAIN THAT IS MORE THAN JUST PAIN
BUT AGAIN THOSE OF US THAT ARE
PAIN RESEARCHERS HAVE COINED
THIS TERM NOCIPLASTIC PAIN.
I'M GOING TO TRY TO CONVINCE YOU
WE UNDERSTAND THE
PATHOPHYSIOLOGY OF THIS PROCESS
FAIRLY WELL.
ONE OF THE ANALOGIES I'VE BEEN
USING FOR A LONG TIME, FIRST TO
HELP UNDERSTAND, HAVE PATIENTS
UNDERSTAND PAIN, AND THEN MORE
RECENTLY DOCTORS AND SCIENTISTS,
THE AMOUNT OF PAIN SOMEONE IS
EXPERIENCING IS AKIN TO THE
LOUDNESS OF AN ELECTRIC GUITAR.
EVERYONE KNOWS THERE'S TWO WAYS
TO MAKE IT LOUDER, STRUM THE
STRINGS HARDER OR TURN UP THE
AMPLIFIER.
WELL, THERE ARE SENSORY NERVES
REALLY QUITE ANALOGOUS TO THE
DIFFERENT STRINGS ON A GUITAR
THAT BRING DIFFERENT INFORMATION
ABOUT WHAT'S GOING ON IN
DIFFERENT AREAS OF THE BODY UP
TO THE BRAIN BUT ALL THIS
INFORMATION HAS TO GO THROUGH
THE SPINAL CORD AND BRAIN AND
REALLY THE SPINAL CORD AND BRAIN
ARE THE EQUIVALENT OF THE
AMPLIFIER ON AN ELECTRIC GUITAR
BECAUSE YOU CAN INCREASE THE
LIKELIHOOD SOMEONE WILL
EXPERIENCE PAIN SIMPLY BY, IF
YOU WILL, CHANGING THE SPINAL
AND CORTICAL ACTIVITY THAT'S
PROCESSING PAIN.
SO WE KNOW ONE OF THE REASONS
PEOPLE CAN HAVE PAIN EVEN THOUGH
THEY HAVE A NORMAL KNEE X-RAY
THERE'S AN INCREASE IN
DESCENDING FACILATORY, ALLOWING
MORE SIGNALS TO BE FELT AT PAIN
BUT THIS ALSO HELPS US
UNDERSTAND OR EXPLAIN WHY SOME
INDIVIDUALS HAVE BAD LOOKING
KNEE X-RAYS OR BAD LOOKING
SURGICAL FIELDS AND NOT HAVE ANY
PAIN, THEY JUST HAPPEN TO BE
FORTUNATE ENOUGH THEY HAVE LOWER
AMPLIFIER SETTING AND NOT PAIN
SENSITIVE.
WOMEN HAVE 1 1/2 TO 2 TIMES ANY
TYPE OF CHRONIC PAIN THAN MEN,
O.A. IS A GREAT MODEL, THERE'S
ALMOST NO DIFFERENCE BETWEEN
WHAT WOMEN AND MEN LOOK LIKE AND
KNEE ON KNEE X-RAY BUT ARE 1
1/2 TO 2 TIMES MORE LIKE LIE TO
FEEL, THEY HAVE A HIGHER
AMPLIFIER, NOISES, ODORS, IN
FACT THIS HYPERSENSITIVITY NOT
JUST TO PAIN BUT TO OTHER TYPES
OF SENSORY EXPERIENCES IS PART
OF THE DEFINITION FOR DISTURBED
MECHANISM OF PAIN, NOCIPLASTIC
PAIN.
WE LOOK FOR HOW WIDESPREAD THE
PAIN IS.
THE MORE WIDESPREAD, MORE LIKELY
COMING FROM AMPLIFIER RATHER
THAN GUITAR, LOOK FOR FATIGUE,
SLEEP PROBLEMS AND MEMORY
PROBLEMS, AND AGAIN LOOK FOR
OTHER TYPES OF SENSORY
SENSITIVITIES.
THIS REALLY SEEMS TO BE THE PAIN
MECHANISM THAT IS FRONT AND
CENTER IN CONDITIONS LIKE
FIBROMYALGIA, FUNCTIONAL G.I.
DISORDERS, A NUMBER OF DIFFERENT
CONDITIONS THAT THE NIH ACTUALLY
COINED THE TERM A COUPLE YEARS
AGO CHRONIC OVERLAPPING PAIN
CONDITIONS TO INDICATE THESE
CONDITIONS SUCH AS FIBROMYALGIA,
IRRITABLE BOWEL, TENSION
HEADACHE, ALL REALLY WERE MORE
LIKELY IF SOMEONE HAD ONE OF
THESE CONDITIONS THEY WERE MUCH
MORE LIKELY TO HAVE MANY OF
THESE CONDITIONS.
THEY RUN STRONGLY IN FAMILY.
AND IN FACT A LOT OF THESE
THINGS ARE MERELY LABELS FOR
PAIN THAT IS IN A CERTAIN AREA
OF THE BODY THAT CLINICIANS
CAN'T FIND AN ALTERNATE
EXPLANATION FOR.
AND SO MEASURING THE NUMBER OF
CHRONIC OVERLAPPING PAIN
CONDITIONS SOMEONE HAS BEEN
DIAGNOSED WITH OVER THE COURSE
OF THE LIFETIME IS A GOOD
PHENOTYPIC MARKER OF THE DEGREE
OF WHICH THEY HAVE THIS
NOCIPLASTIC PAIN PROCESS BUT WE
KNOW THE SAME NOCIPLASTIC PAIN
MECHANISMS OFTEN ARE
SUPERIMPOSED UPON NOCICEPTIVE
PAIN OR NEUROPATHIC PAIN.
30% OF PAIN WITH AUTOIMMUNE
DISORDERS LIKE ARTHRITIS OR
LUPUS HAVE THE SAME
FIBROMYALGIA-LIKE NOCIPLASTIC
PLAIN SUPERIMPOSED.
NEW CRITERIA FOR FIBROMYALGIA,
DON'T DO A TENDER POINT, HOW
WIDESPREAD ON THE LEFT SIDE AND
WHETHER SOMEONE HAS COMORBID
FATIGUE, MEMORY, SLEEP PROBLEMS.
THIS CAN BE QUANTITATIVELY
SCORED FROM ZERO TO 31, AND FRED
WOLF WAS A RHEUMATOLOGIST THAT
SHOWED WE SHOULDN'T REALLY THINK
OF FIBROMYALGIA AS YES OR NO.
WE SHOULD THINK OF DIFFERENT
PEOPLE HAVE VARIABLE DEGREES.
NOW AS WE MORE -- FIBROMYALGIA
BEING THE POSTER CHILD FOR
NOCIPLASTIC PAIN IT'S TRUE
NOCIPLASTIC PAIN IS NOT PRESENT
OR ABSENT, IT REALLY IS THAT WE
SHOULD THINK OF IT AS A VOLUME
CONTROL OR AMPLIFIER THAT IS
OFTEN SUPERIMPOSED UPON OTHER
ONGOING PAIN MECHANISMS OR CAN
OCCUR IN ISOLATION BUT REALLY,
AGAIN, IS AN AMPLIFIER OR CNS
DRIVEN PROBLEM.
YOU MIGHT IMAGINE IF SOMEONE HAS
PAIN IN A SINGLE LOCATION OF THE
BODY, THEY ARE QUITE DIFFERENT
THAN SOMEONE HAS PAIN ALL OVER.
THIS IS SOMEONE WITH MAD DOG
FIBROMYALGIA.
BUT WHAT WE KNOW NOW IS
EVERYTHING IN BETWEEN IS
IMPORTANT AND THAT THE PEOPLE
THAT CARRY LABELS LIKE
FIBROMYALGIA ARE THE TIP OF THE
ICEBERG.
MOST OF THE PEOPLE WITH THIS
SAME KIND OF PAIN CARRY LABELS
LIKE LOW BACK PAIN,
OSTEOARTHRITIS, ENDOMETRIOSIS,
SO WE KNOW THIS KIND OF PAIN IS
COMMON AND OFT EVERYBODY GOES
UNRECOGNIZED, UNTREATED, THE
PROBLEM IS THIS KIND OF PAIN
RESPONDS TO MARKEDLY DIFFERENT
TREATMENTS.
THIS IS A RECENT ARTICLE ON THE
OLD TERM FOR THIS CENTRAL
SENSITIZATION, POINTING OUT THAT
ACROSS ALL CHRONIC PAIN
CONDITIONS, IF SOMEONE HAS
CENTRAL SENSITIZATION, IT
MARKEDLY AFFECTS WHAT'S GOING TO
WORK AND NOT WORK WITH RESPECT
TO TREATMENT.
THESE ARE STUDIES WE DID IN OUR
GROUP, LED BY CHAD BROMET, KNEE
AND HIP REPLACEMENT SURGERY AS A
SURGICAL PROCEDURE WHERE WE
COULD MEASURE WHAT WAS GOING ON
IN THE PERIPHERY, COULD THEN PUT
IN A SHINY TITANIUM KNEE, AND
SEE THE DEGREE TO SOMEONE OF
WHICH SOMEONE DID OR DID NOT
IMPROVE.
MAIN HYPOTHESES FIBROMYALGIA
MEASURE WOULD BE STRONGLY
PREDICTIVE OF SOMEONE FAILING TO
RESPOND TO SURGERY.
AND WE DIDN'T JUST GIVE PEOPLE
THE FIBROMYALGIA MEASURE.
WE MEASURED ANXIETY, DEPRESSION,
CATASTROPHIZING.
THE ONLY THING UNIQUE IN THESE
STUDIES AS WELL AS THE ONES
SUSIE ASANI LED WHICH SHE WILL
TALK ABOUT AND I'LL ALLUDE TO,
WE GAVE THIS MEASURE ON THE DAY
OF SURGERY AND LOOKED AT THE
DEGREE TO WHICH IT INFLUENCED
LONG-TERM OUTCOMES AND FOUND FOR
EACH ONE POINT INCREASE IN
FIBROMYALGIA MEASURE PEOPLE
GETTING HEE OR ANYPLACE
REPLACEMENT SURGERY NEEDED MORE
OPIOIDS TO CONTROL THEIR PAIN,
MUCH LESS LIKELY TO GET
IMPROVEMENT.
THESE PHENOMENON WERE LINEAR,
NOTHING MAGICAL ABOUT THE CUT
POINT OF 13 THAT SAYS SOMEONE
HAS FIBROMYALGIA.
ONE POINT INCREASE LED TO LESS
LIKELY WOULD GETTER IF WE DID
SURGERY TO REPLACE KNEE OTHER
LIP.
THIS IS A DATA SLIDE FROM THOSE
KNEE AND HIP ARTHROPLASTIES, ON
THE Y-AXIS ARE THE NUMBER OF
PEOPLE THAT HAVE THE
FIBROMYALGIA SCORE, HERE IS THE
FIBROMYALGIA SCORE.
13 CUT POINT IS ON THE RIGHT
SIDE, PEOPLE ARE SAID TO HAVE
DIAGNOSIS OF FIBROMYALGIA BUT I
WANT TO POINT OUT THIS PATIENT
HERE HAS A HIGHER FIBROMYALGIA
SCORE THAN THIS PERSON HERE,
DOESN'T CROSS THE RED LINE,
DOESN'T HAVE FIBROMYALGIA BUT
LOOK HOW IMPORTANT THAT IS.
THIS PERSON, JUST BECAUSE THE
PAIN IS MORE WIDESPREAD, HE ALSO
HAS SOME FATIGUE, MEMORY
PROBLEMS, SLEEP DISTURBANCE,
FIVE TIMES LESS LIKELY TO HAVE A
50% IMPROVEMENT IN PAIN WITH
KNEE REPLACED, SUSIE REPLICATEED
ALMOST IDENTICAL WOMEN WITH
CHRONIC PELVIC PAIN GETTING
HISSERRECTOMY.
THESE ARE NOT SUBTLE FINDINGS.
IN REGULAR CLINICAL PRACTICE
PEOPLE HAVE MARKEDLY DIFFERENT
SCORES ON THIS MEASURE, IT
MARKEDLY INFLUENCES WHAT'S GOING
TO WORK AND WHAT'S NOT GOING TO
WORK BECAUSE WHAT WE'VE COME TO
REALIZE IS THAT ALL PAIN STATES
ARE MIXED PAIN STATES.
WE USED TO THINK ALL PEOPLE WITH
OSTEOARTHRITIS OR AUTOIMMUNE
DISORDERS HAD NOCICEPTIVE PAIN.
PEOPLE WITH DIABETIC PAINFUL
NEUROPATHY HAD NEUROPATHIC PAIN.
AND ALL PEOPLE ARE CONDITIONS
LIKE FIBROMYALGIA ONLY HAD
NOCIPLASTIC PAIN.
WE KNOW THESE OCCUR, THIS PAIN
MECHANISM OCCURS WITH THIS PAIN
MECHANISM AND PEOPLE DON'T
IDENTIFY THIS.
IF YOU SEE THE PAIN IS MORE
WIDESPREAD OR GIVE THE FORECAST
MEASURE AND THEY SCORE HIGHER,
IT DOESN'T TELL YOU WHAT ISN'T
GOING TO WORK BUT WHAT IS GOING
TO WORK.
THIS IS THE DRUG DULOXETINE,
APPROVED FOR USE IN
OSTEOARTHRITIS AND CHRONIC LOW
BACK PAIN.
WASN'T UNTIL WELL AFTER THE DRUG
WAS NO LONGER A BRAND NAME DRUG
THAT WE REALIZE THE GIVING
SOMEONE A BODY MAP WITH LOW BACK
PAIN WILL PREDICT WHO IS GOING
TO RESPOND TO THIS DRUG.
THE MORE SITES OF PAIN ON A BODY
MAP WITH LOW BACK PAIN, THE MORE
LIKELY DULOXETINE IS GOING TO
WORK.
SIMILARLY, SAME THING SHOWN IN
OSTEOARTHRITIS, THE MORE SITES
OF PAIN, THE MORE LIKELY
DULOXETINE WAS GOING TO WORK TO
TREAT OSTEOARTHRITIS.
WE KNOW ABOUT THE
PATHOPHYSIOLOGY, WE CAN DO
FUNCTIONAL BRAIN IMAGING THAT
SHOWS THEY ARE MORE SENSITIVE TO
NOT JUST PAIN BUT ANY TYPE OF
SENSORY STIMULI, THE DEGREE TO
WHICH BRAIN REGIONS ARE TOO
CONNECTED OR NOT CONNECTED
ENOUGH TO EACH OTHER.
AND THIS IS A FAIRLY
REPRODUCIBLE NEURAL SIGNATURE OF
NOCIPLASTIC PLAIN.
YOU CAN START TO SEE THESE SAME
FINDINGS THAT WE AND OTHERS HAVE
BEEN PUBLISHING IN NOCIPLASTIC
PAIN FOR 15 YEARS NOW, YOU CAN
SEE THIS IN KIDS THAT ARE PAIN
FREE, TWO YEARS LATER DEVELOP
NEW MULTI-SITE PAIN IN THE ABCD
STUDY THAT WE CAN SEE ON BRAIN
IMAGING WHILE THE KIDS ARE STILL
SYMPTOM FREE AND ASYMPTOMATIC
THAT THEY ARE ON THEIR WAY TO
DEVELOP THIS KIND OF PAIN WHICH
IS REALLY EXCITING WITH RESPECT
TO OUR ABILITY TO PREVENT PEOPLE
FROM DEVELOPING THIS, ESPECIALLY
IF WE TARGET SOME OF THE STUDIES
IN ADOLESCENTS THAT ARE
DEVELOPING NEW PAIN.
EVEN THE SIZE AND SHAPE OF THE
BRAIN CHANGES IN NOCIPLASTIC
PAIN PROBABLY BECAUSE OF
NEUROPLASTICITY.
I'LL MOVE TO PELVIC PAIN, I'VE
STUDIED IT, WE'RE INVOLVED IN
THE NIH MAP NETWORK THAT STUDIED
PEOPLE WITH INTERSTITIAL
CYSTITIS AND CHRONIC PELVIC
PAIN, THE MAJOR FINDING BY A
LONG SHOT IS THE DEGREE OF
CENTRAL SENSITIZATION MARKEDLY
IMPACTS NOT JUST WHAT
QUANTITATIVE SENSORY TESTING OR
BRAIN IMAGING LOOK LIKE IN
STUDIES DONE IN THE MAP NETWORK.
BASICALLY PEOPLE WITH CHRONIC
PELVIC PAIN, I'M SORRY, GO BACK,
THAT HAD PAIN CONFINED TO THE
PELVIS, THAT'S ONE PHENOTYPE.
CHRONIC PELVIC PAIN WITH PAIN
STILL IN THE PELVIC REGION.
MORE WIDESPREAD PAIN IN THE MAP
NETWORK, ABOUT 15% OF THE
INTERSTITIAL CYSTITIS PATIENTS
HAD THIS PHENOTYPE, 20% THIS, 40
TO 50% THIS.
THOSE WITH WIDESPREAD PAIN
LOOKED IDENTICAL TO FIBROMYALGIA
PATIENTS, PEOPLE ARE LOCALIZE
THE PAIN NOCIPLASTIC PAIN HAD
NORMAL fMRIs, THEY DIDN'T
HAVE INCREASE IN AMPLIFIER.
WE STARTED TO COLLECT DATA WHAT
TREATMENTS PEOPLE WERE RECEIVING
FOR INTERSTITIAL CYSTITIS,
URINARY CHRONIC PAIN SYNDROMES
AND SOME EXCITING DATA SUGGESTS
THAT PERIPHERALLY DIRECTED
TREATMENTS LIKE PHYSICAL THERAPY
WORK REALLY, REALLY WELL IN
PEOPLE WITH THAT PAIN PHENOTYPE
LOCALIZED WHERE THEY ARE PAIN IS
LOCALIZED TO THE PELVIS BUT
PHYSICAL THERAPY BARELY WORKS AT
ALL IN THE PEOPLE WITH
WIDESPREAD PAIN.
CONVERSELY, DRUGS WORKING
CENTRALLY, SEROTONIN, NOR
NOREPINEPHRINE REUPTAKE
INHIBITORS WORK WITH PEOPLE WITH
MORE WIDESPREAD PAIN, RARELY
WORK WITH THE INTERMEDIATE
PHENOTYPE.
WE THINK PHENOTYPING STUDIES
LOOKING AT HOW WIDESPREAD, OR
ADDING FUNCTIONAL BRAIN IMAGING,
ANOTHER STUDY PUBLISHED A COUPLE
DAYS AGO, JUST PEOPLE GETTING
PHYSICAL THERAPY, WHERE THEY
WERE ON THE FIBROMYALGIA
CONTINUUM MARKEDLY AFFECTED
WHETHER P.T. OR NOT.
THIS IS BACPAC, COMPONENT OF
"HEAL" TRYING TO APPLY PRECISION
MEDICINE APPROACH TO PAIN.
THIS IS A STUDY THAT'S GOING TO
START IN THE NEXT COUPLE OF
MONTHS, FROM "HEAL," AND IN THIS
STUDY WE'RE USING SEQUENTIAL
RANDOMIZATION AND SMART AND
ADAPTIVE DESIGNS IN A DIFFERENT
WAY, USING THEM WHERE WE
ACTUALLY PHENOTYPE PEOPLE AT
BASELINE AND GIVE THEM SEVERAL
TREATMENTS WE KNOW WORK IN A
GROUP OF PEOPLE WITH CHRONIC LOW
BACK PAIN BUT DON'T KNOW WHAT
SUBSET OF PEOPLE WITH CHRONIC
LOW BACK PAIN THEY WORK IN.
WHAT WE'RE MOST INTERESTED IN IN
THESE STUDIES IS MATCHING THE
PHENOTYPE AT BASELINE WITH
WHAT'S GOING TO WORK.
AFTER WE DO INTENSIVE
PHENOTYPING RANDOMIZE PEOPLE,
THERE'S FOUR TREATMENTS THEY CAN
RECEIVE, ENHANCED SELF-CARE,
ACCEPTANCE COMMITMENT THERAPY,
BASICALLY PHYSICAL THERAPY, AND
DULOXETINE, STRONG A PRIORI
HYPOTHESES AND THINK WE CAN TAKE
A DRUG LIKE DULOXETINE OR
PHYSICAL THERAPY FROM RIGHT NOW
WHEN YOU USE IT IN AN UNSELECTED
POPULATION, THESE WORK IN ABOUT
A THIRD OF INDIVIDUALS, BUT WHEN
WE GET SMARTER ABOUT WHICH
TREATMENTS WE USE, WHICH PEOPLE,
WE THINK WE CAN RAISE THE
RESPONSE RATES OF SOME OF OUR
CURRENT TREATMENTS FROM 30% TO
ON A 50 OR 60% BY USING SIMPLE
PHENOTYPING THAT WOULD BE
BROADLY AVAILABLE IN CLINICAL
PRACTICE, STARTING WITH SIMPLE
THINGS LIKE A BODY MAP.
I'LL STOP THERE AND TAKE ANY
QUESTIONS THAT PEOPLE HAVE.
THANK YOU.
>> THANK YOU, DR. CLAUW, FOR
YOUR GREAT PRESENTATION.
CAN YOU SEE THE CHAT BOX?
>> I CAN.
DO YOU WANT ME TO --
>> SO, IF YOU HAVE ANY
QUESTIONS, OR COMMENTS, PLEASE
PUT YOUR QUESTIONS IN THE CHAT
PANEL.
CHAT BOX.
SO OUR FIRST QUESTION IS FROM
MARK GOODMAN.
IS THERE INCREASED INCIDENCE OF
FIBROMYALGIA DUE IN PART TO
INCREASED SUSTAINED STATIN USE?
>> A SMALL SUBSET OF PEOPLE ON
STATINS DEVELOP MYALGIAS, BUT
THEY DON'T DEVELOP THE OTHER
PART OF THE SORT OF FIBROMYALGIA
PICTURE WITH THE SLEEP AND
MEMORY AND ALL THOSE OTHER KINDS
OF PROBLEMS.
AND THAT REALLY WOULDN'T BE
CALLED FIBROMYALGIA.
THAT WOULD BE A SIDE EFFECT OF
STATINS.
YOU TAKE PEOPLE OFF AND EXPECT
THAT WOULD RESOLVE.
IT DOESN'T SEEM LIKE WHAT WE'RE
SEEING WITH RESPECT TO
FIBROMYALGIA -- THERE'S REPORTS
OF WHAT WE KNOW TO BE
FIBROMYALGIA IN THE SCIENTIFIC
LILT A -- LITERATURE GOING BACK
HUNDREDS MUCH YEARS,
RECONCEPTUALIZING WHAT WAS
CAUSED AT THE END OF THE LAST
CURRENTLY, NOT THE CURRENT
CENTURY, BUT THINKING EVOLVED
EVOLVED ABOUT THE SYNDROMES.
THIS IS A FAIRLY UBIQUITOUS
PHENOMENA, IT'S MORE COMMON IN
ENDOMETRIOSIS PATIENTS, BUT IF
YOU LOOK AT SUBTHRESHOLD
FIBROMYALGIA, A GROUP OF WOMEN
DIAGNOSED WITH ENDOMETRIOSIS
THAT MEASURE, THEY WILL BE
HEAVILY SKEWED TOWARDS HAVING
HIGHER DEGREES.
IF THE PAIN IS COMING MORE SO
FROM THE BRAIN AND CENTRAL
NERVOUS SYSTEM THEN SURGERY
ISN'T NEARLY AS LIKELY TO WORK
IN THOSE PATIENTS.
WE THINK THAT FIBROMYALGIA
MEASURE AT PRESENT IS THE BEST
SURROGATE MEASURE OF THE DEGREE
OF NOCIPLASTIC PAIN YOU CAN USE
IN A STUDY.
A BODY MAP ALONE DOES A GOOD
JOB.
JUST WE THINK THE OTHER
COMPONENTS OF THE FIBROMYALGIA
MEASURE GETTING AT THE COMORBID
FATIGUE, SLEEP, MEMORY PROBLEMS,
AND SENSORY SENSITIVITY, ALSO
HELPS IDENTIFY THAT PHENOTYPE AS
WELL.
>> SO WE HAVE ANOTHER QUESTION
FROM KATHLEEN.
WHAT JOURNAL WAS THAT PUBLISHED?
WHO WOULD BENEFIT FROM HAVING
PHYSICAL THERAPY?
>> OH, I WISH I KNEW.
IT WAS PUBLISHED IN A PHYSICAL
MEDICINE AND REHAB JOURNAL.
OOPS, I'M SORRY.
BUT I'LL TRY TO FIND THAT OUT
AND PUT IT IN THE CHAT.
>> AND THERE'S ANOTHER QUESTION.
>> LET ME RESPOND, I WANT TO
MAKE SURE I WASN'T UNCLEAR.
PSYCHOLOGICAL FACTORS ARE
INCREDIBLY IMPORTANT TO ASSESS
AND TREAT PEOPLE WITH CHRONIC
PAIN.
IT'S JUST THAT I THINK THEY HAVE
BEEN OVEREMPHASIZED WITH RESPECT
TO TRANSITION FROM ACUTE TO
CHRONIC PAIN.
THINGS LIKE CATASTROPHE IZING
ARE MORE A STATE THAN TRAIT,ING
WHAT CATASTROPHIZING OFTEN IS,
THESE ARE PEOPLE THAT HAVE HAD
PAIN FOR A WHILE, AND WHEN THEY
SEEK HEALTH CARE THEY HAVEN'T
BEEN RELIEVED OF PAIN.
THAT'S WHY THEY THINK THAT WAY.
I THINK THAT THERE'S A LOT OF
CHALLENGE OF SORT OF -- WHAT'S
THE DIRECTIONALITY OF THE
RELATIONSHIP BETWEEN MOOD
DISORDERS AND PAIN.
MOST PEOPLE USED TO THINK THAT
THE PSYCHOLOGICAL PROBLEMS
ALMOST ALWAYS CAME FIRST.
I THINK THE DATA ARE NOW
SUGGESTING THAT IT'S VERY
BIDIRECTIONAL AND WITH RESPECT
TO NUANCE PSYCHOLOGICAL FACTORS
MAY BE LESS IMPORTANT WITH THE
TRANSITION TO CHRONIC PAIN.
>> THANK YOU.
NEXT QUESTION, IS FIBROMYALGIA
MORE COMMON IN ENDOMETRIOSIS
PATIENTS?
>> YEAH, I ANSWERED THAT.
YEP.
IT IS.
IT'S A BIDIRECTIONAL, BECAUSE
ENDOMETRIOSIS IS ONE OF THE
TERMS OF THE NIH PROGRAM STAFF
THAT COINED THE TERM, CHRONIC
OVERLAPPING PAIN CONDITIONS,
THIS CAME FROM THE NIH PAIN
CONSORTIUM, THAT TERM.
AND THEY PUT ENDOMETRIOSIS IN
THAT BECAUSE OF THE DATA THAT
DID SHOW THIS BIDIRECTIONAL
RELATIONSHIP BETWEEN
ENDOMETRIOSIS AND SOME CHRONIC
OTHER OVERLAPPING PAIN
CONDITIONS.
>> ANOTHER QUESTION.
DO WE KNOW WHAT MAKES SOME
PATIENTS MORE SENSITIZED
CENTRALLY?
>> SOME IS GENETIC AND FAMILIAL,
STUDIES SUGGESTED THAT ABOUT
HALF OF THE RISK OF DEVELOPING
THIS IS GENETIC AND FAMILIAL.
WE KNOW EARLY LIFE TRAUMA AND
STRESS CAN CONTRIBUTE TO THIS.
SO CANNOT SLEEPING WELL AND NOT
EXERCISING ENOUGH, THINGS LIKE
THAT.
THIS IS WHY WE USE SLEEP AND
ACTIVITY AND EXERCISE SO
AGGRESSIVELY IN TREATING
NOCIPLASTIC PAIN.
SOME RECENT STUDIES WE'VE DONE
ALSO LOOKING AT THE ABCD DATASET
THAT I SHOWED YOU CHELSEA'S
ARTICLE SUGGESTS BEFORE KIDS
DEVELOP NUANCE AT A MULTI-SITE
PAIN SLEEP DISORDER IS ALMOST
ALWAYS PRE-DATING THAT, AS DO
SOME FATIGUE AND SOME MEMORY
PROBLEMS.
AND SO I THINK WE'RE ALSO
GETTING -- GOING BACK TO EARLY
STUDIES, APPRECIATING HOW
IMPORTANT SLEEP IS ESPECIALLY,
AGAIN, IN THAT TRANSITION FROM
ACUTE TO CHRONIC PAIN AND IN
REALLY TRYING TO GET CHRONIC
PAIN PATIENTS SLEEPING WELL
BECAUSE IT SEEMS TO BE
INCREDIBLY IMPORTANT, AS DOES A
CERTAIN AMOUNT OF ACTIVITY OR
EXERCISE.
>> NEXT QUESTION, IF 15% OF I.C.
IS LOCALIZED DO WE KNOW HOW MUCH
OF MYOFASCIAL PELVIC PAIN IS
LOCALIZED VERSUS CENTRALLY
SENSITIZED?
>> NO, THAT'S A GREAT QUESTION,
BECAUSE AGAIN THE MAPP STUDY
STRONGLY SUGGESTED PEOPLE THAT
RESPOND TO P.T. WERE PEOPLE WITH
THE MORE LOCALIZED PAIN, BUT I
KNOW A LOT OF CLINICIANS SEE A
LOT OF THAT SORT OF THOSE
MYOFASCIAL TENDER POINTS AND
TRIGGER POINTS IN THE PELVIC
REGION, AND THINK THAT'S A GOOD
MARKER OF SORT OF CENTRAL
SENSITIZATION OR NOCIPLASTIC
PAIN.
THOSE AREN'T MUTUALLY EXCLUSIVE
BUT WE HAVE TO BETTER STUDY SORT
OF THE INTERSECTION OF
MYOFASCIAL PAIN AND THEN ALL THE
WAY TO CENTRAL SENSITIZATION
NOCIPLASTIC PAIN AND WHAT DO THE
PEOPLE AT DIFFERENT POINTS IN
THAT CONTINUUM RESPOND TO
ESPECIALLY WITH RESPECT TO
P.T.-BASED MODALITIES.
I'M A HUGE FAN OF THE P.T.-BASED
MODALITIES BUT THEY CLEARLY ARE
OF DIFFERENTIAL BENEFIT IN
PEOPLE THAT ARE AT DIFFERENT
POINTS IN THIS CONTINUUM.
>> CAN YOU MAKE AVAILABLE THE
BODY MAP OR FM SCORE FOR THE
AUDIENCE?
>> YEAH, I'M HAPPY TO SEND
ANYTHING YOU WANT.
JUST SEND ME AN E-MAIL,
DCLAUW@MICHIGAN.EDU, HAPPY TO
DISTRIBUTE THAT.
>> ONE MINUTE LEFT.
NEXT QUESTION, ANY
RECOMMENDATION TO USE THE
C.S.I., CENTRAL SENSITIZATION
INVENTORY TO DETERMINE WHICH
PATIENTS WOULD BENEFIT FROM THE
PELVIC PHYSICAL THERAPY OR
ENDOMETRIOSIS SURGERY?
>> C.S.I. IS PURPORTED TO
MEASURE, WE DON'T THINK IT WORKS
AS WELL AS THE FIBROMYALGIA
MEASURE.
WE HAVE ONGOING STUDIES
INCLUDING CENTRAL SENSITIZATION
INDEX AS WELL AS FIBROMYALGIA
MEASURE, NOT PUBLISHED YET, BUT,
AGAIN, WE'RE QUITE COMFORTABLE
THAT REALLY THESE STUDIES WHERE
WE REPLICATED ALMOST EXACTLY
THAT FIBROMYALGIA MEASURE
PREDICTED SO STRONGLY OPIOID
NONRESPONSIVENESS AND SURGERY
NONRESPONSIVENESS, THE C.S.I.
NEVER HAD STUDIES THAT SHOWED
CLINICAL OUTCOMES WERE THAT
HEAVILY PREDICTED BY THAT PRO.
WE THINK THE FIBROMYALGIA
MEASURE IS BETTER AND ARE
COLLECTING MORE DATA TO SHOW
THAT.
WE THINK THERE'S NEWER BETTER
MEASURED CONSTRUCTED, WE'RE
GOING TO TRY TO DEVELOP A MORE
DATA-DRIVEN MEASURE THAT STARTS
WITH SOME OF THE ELEMENTS OF THE
FIBROMYALGIA MEASURE BUT THEN
WEIGHTS THEM DIFFERENTLY, ADDS
SENSORY SENSITIVITY, BECAUSE WE
THINK, YOU KNOW, A NEW GOOD
MEASURE OF NOCIPLASTIC PAIN WILL
NOT -- WE WON'T STILL BE USING
THAT FIBROMYALGIA MAYBE 3 TO 5
YEARS FROM NOW, WE'LL HAVE A
BETTER MEASURE THAT CAPTURES
THOSE DOMAINS.
>> THANK YOU.
WE WOULD LIKE TO MOVE ON DUE TO
TIME REMAINING.
OUR NEXT SPEAKER, DR. SUSAN
ASANI.
WOULD YOU SHARE YOUR SLIDES.
>> CAN YOU SEE MY SLIDES?
>> YES.
>> GREAT.
I WOULD LIKE TO THANK YOU AS
WELL AS THE NICHD FOR ORGANIZING
THIS REALLY IMPORTANT SEMINAR AS
WELL AS OPPORTUNITY TO SHARE
WORK IN UNDERSTANDING THE
NEUROBIOLOGICAL MECHANISMS OF
PELVIC PAIN.
I COULD JUST STOP HERE AND JUST
SAY THAT EVERYTHING THAT DR.
CLAUW SAID WE REPLICATED A LOT,
SPECIFICALLY IN PELVIC PAIN AND
ENDOMETRIOSIS, BUT WE'LL GO
THROUGH THE CONTENT.
THESE ARE MY DISCLOSURES.
OAMPED
ENDOMETRIOSIS IS ONE OF THE MOST
ENIGMATIC FIELDS.
WE STILL KNOW VERY LITTLE ABOUT
THE RELATIONSHIP BETWEEN THE
ACTUAL ENDOMETRIOSIS LESIONS AND
PELVIC PAIN SYMPTOMS.
SO IF I ASKED WHICH OF THESE
PATIENTS HAS PELVIC PAIN AND HOW
SEVERE WOULD IT BE, LOGIC WOULD
DICTATE INTENSITY AND FREQUENCY
SHOULD INCREASE WITH WORSENING
PATHOLOGY AS YOU GO FROM TOP
SLIDE TO BOTTOM SLIDE.
AS WAS MENTIONED, SIMILAR TOO
EVERY OTHER CONDITION, THE
DEGREE OF PELVIC PATHOLOGY DOES
NOT DEGREE WITH SEVERITY OF
PATIENT SYMPTOMS.
IT'S QUITE COMMON FOR THE
PATIENT WITH NORMAL ANATOMY TO
EXPERIENCE SEVERE PAIN AND ONE
WITH STAGE 4 ENDOMETRIOSIS TO
ALSO HAVE LITTLE OR NO PAIN AT
ALL.
THIS QUESTION OF WHICH PATIENTS
WITH ENDOMETRIOSIS EXPERIENCE
PAIN AND WHY, ABOUT 25% OF WOMEN
WITH ENDOMETRIOSIS EXPERIENCE
PERSISTENT PAIN DESPITE ALL
AGGRESSIVE TREATMENT AS
INTERESTED AND FRUSTRATED ME
SINCE I WAS A RESIDENT IN
OB/GYN.
BEFORE I TALK ABOUT THIS, I
WANTED TO SAY THAT I PURSUED A
CAREER AS A CLINICIAN SCIENTIST
AND HAVE BEEN VERY FORTUNATE TO
DO SO AT THE UNIVERSITY OF
MICHIGAN BECAUSE I'VE HAD THE
PRIVILEGE TO BE MENTORED BY DR.
CLAUW.
BUT THIS IS ALSO INCLUDING THE
OPPORTUNITY TO WORK WITH HIS
TEAM AT THE CHRONIC PAIN AND
FATIGUE RESEARCH CENTER, BEFORE
I DIVE INTO GIVING YOU AN
OVERVIEW OF OUR COLLABORATIVE
EFFORTS I WANT TO RECOGNIZE AND
THANK THESE EXCEPTIONAL
SCIENTISTS WHO MADE THIS WORK
POSSIBLE.
DR. CLAUW, - HARRIS, SCHREPF,
HARTE, HASET AND BRUMMET, ROBERT
TAYLOR AND STACY MISSMER.
MY OBJECTIVES TODAY ARE FIRST TO
PRESENT EVIDENCE THAT
NOCIPLASTIC PAIN IN PRESENT TO
REVIEW CLINICAL IMMRI
IMPLICATION, AND FINALLY TO
PROPOSE STRATEGIES TO INTEGRATE
MEASURES OF NOCIPLASTIC PAIN IN
CLINICAL RESEARCH STUDIES WITH
OVERALL HEALTH GOAL OF ENHANCING
PATIENT CARE.
AS YOU KNOW, ENDOMETRIOSIS IS
DEFINED AS PRESENCE OF
ENDOMETRIAL TISSUE OUTSIDE THE
UTERUS, MOST WIDELY HELD VIEW OF
ENDOMETRIOSIS IS A NOCIPLASTIC
PAIN CONDITION THAT OCCURS TO
DIRECT ACTIVATION BY THE
LESIONS, AND SIGNALS INTERPRETS
THE SIGNAL OF PAIN.
CERTAINLY THERE'S A SUBSTANTIAL
AMOUNT OF EVIDENCE THAT
ENDOMETRIOSIS CAN CAUSE PAIN DUE
TO THE NOCIPLASTIC MECHANISM,
ENERVATED BY SENSORY FIBERS AND
ENDOMETRIOSIS LESIONS RELEASE
CYTOKINES AS WELL AS OTHER PRO
NOCICEPTIVE MOLECULES THAT CAN
ACTIVATE RECEPTORS.
AS WAS DESCRIBED, THERE'S NO
CHRONIC PAIN CONDITION ENTIRELY
EXPLAINED BY PERIPHERAL
PATHOLOGY, BECAUSE CENTRAL
NERVOUS SYSTEM HAS ABILITY TO
AMPLIFY AND DAMPEN SIGNALS.
MODERN UNDERSTANDING PAIN IS
OUTPUT OF THE BRAIN, BALANCE
BETWEEN THE PERIPHERAL INPUT AND
CENTRAL NERVOUS SYSTEM OR VOLUME
CONTROL.
NOCIPLASTIC PAIN CAN LEAD TO
PAIN INDEPENDENT OF THE SIGNAL.
WHAT DO WE KNOW ABOUT
ENDOMETRIOSIS, CHRONIC PAIN AND
THE BRAIN?
USING A DESIGN TO UNDERSTAND THE
RELATIONSHIP.
WE RECRUITED PATIENTS WITH AND
WITHOUT ENDOMETRIOSIS AND LITTLE
TO NO PAIN, NO SIGNIFICANT
DYSMENORRHEA, COMPARED TO EACH
OTHER AND HEALTHY CONTROLS.
THREE KEY STUDIES ARE SHOWN,
USING THIS DESIGN WOMEN WITH
CHRONIC PELVIC PAIN INCLUDING
THOSE WITH AND WITHOUT
ENDOMETRIOSIS DEMONSTRATE
INCREASED SENSITIVITY.
CHANGES IN BRAIN STRUCTURE,
WOMEN WITH CHRONIC PELVIC PAIN
DEMONSTRATE DECREASED GRAY
MATTER VOLUME, IN THE THALAMUS,
CINGULATE GYRUS, AND CHANGES IN
BRAIN FUNCTION WITH INCREASED
LEVELS OF EXCITATORY
NEUROTRANSMITTERS IN THE INSULA
AND INCREASED CONNECTIVITY
BETWEEN PAIN REGULATORY REGIONS
SUCH AS ANTERIOR INSULA AND
PREFRONTAL CORTEX, FOUND IN
WOMEN WITH PAIN COMPARED TO PAIN
WITH CONTROLS AND WAS
INDEPENDENT OF THE PRESENCE OR
SEVERITY OF ENDOMETRIOSIS.
I WANT TO POINT OUT BECAUSE
WE'RE SPECIFICALLY WANTING TO
DEMONSTRATE THESE WERE SPECIFIC
TO PATIENTS WITH ENDOMETRIOSIS
AND NOT JUST THOSE WITH
OVERLAPPING PAIN CONDITIONS,
THESE BRAIN NEUROIMAGING STUDIES
WE ONLY RECRUITED PATIENTS THAT
HAD ENDOMETRIOSIS AND SCREENED
OUT PATIENTS THAT HAD
ENDOMETRIOSIS WITH OVERLAPPING
PAIN CONDITIONS.
SO THESE ARE TRULY PATIENTS
WITHOUT ANY OTHER IDENTIFIABLE
SOURCE OF PAIN.
THESE FINDINGS SUGGESTED THESE
MEASURES OF NOCIPLASTIC PAIN ARE
RELATED TO EXPERIENCE OF HAVING
CHRONIC PAIN, IN THESE PATIENTS,
NOT JUST LIMITED TO THOSE WITH
ENDOMETRIOSIS OR OTHERWISE WE
SHOULD HAVE SEEN THESE CHANGES
IN WOMEN THAT HAVE PAIN-FREE
ENDOMETRIOSIS.
SO WHAT ABOUT THE PATIENTS WITH
PAIN-FREE ENDOMETRIOSIS?
CAN THE BRAIN EXPLAIN WHY SOME
OF THESE WOMEN EXPERIENCE LITTLE
TO NO PAIN AT ALL?
SO AS I MENTIONED BEFORE, THREE
STUDIES I REVIEWED, THESE WOMEN
WITH PAIN-FREE ENDOMETRIOSIS
LOOK VERY SIMILAR TO HEALTHY
CONTROLS.
THEY DID NOT DEMONSTRATE
HYPERALGESIA AND DID NOT HAVE
CHANGES IN BRAIN FUNCTION EXCEPT
FOR ONE THING.
THESE PAIN FREE WITH
ENDOMETRIOSIS OVER 50% HAD STAGE
4 DISEASE.
THESE WOMEN DID HOWEVER SHOW ONE
CRITICAL DIFFERENCE COMPARED TO
PAIN-FREE CONTROLS, INCREASED
GRAY MATTER VOLUME IN
PERIAQUEDUCTAL GRAY, AN AREA OF
THE BRAINSTEM CRITICAL FOR
DESCENDING PAIN MODULATION, BY
WAY THE BRAIN WITH ATTENUATE OR
DOWNREGULATE NOCIPLASTIC SIGNALS
SUGGESTING ONE REASON WOMEN
PAIN-FREE ENDOMETRIOSIS, LITTLE
TO NO PAIN, A CHANGE THAT
DAMPENS THE NOCICEPTIVE INPUT.
SHIFTING GEARS TO RECENT WORK TO
FURTHER EXPLORE THE
NEUROBIOLOGICAL MECHANISMS, WE
KNOW IT'S WELL ESTABLISHED
ENDOMETRIOSIS IS AN ESTROGEN
DRIVEN DISEASE.
I PROVIDED DATA THAT NOCIPLASTIC
PAIN IS ALSO AN IMPORTANT
MECHANISM.
THIS RAISES AN IMPORTANT
QUESTION, WHETHER THERE'S A LINK
BETWEEN SYSTEMIC INFLAMMATION
AND NOCIPLASTIC PAIN.
IN OTHER WORDS, SYSTEMIC
INFLAMMATION AND MECHANISM BY
WHICH ENDOMETRIOSIS TO LEAD TO
NOCIPLASTIC PAIN.
THIS IS A COURTESY OF A
COLLEAGUE AND COLLABORATOR AND
ILLUSTRATES ONE OF THE PATHWAYS
BY WHICH SYSTEMIC INFLAMMATION
LEADS TO NOCIPLASTIC PAIN
INVOLVING MICROGLIA, STAINED
GREEN, CELLS IN THE CENTRAL
NERVOUS SYSTEM KNOWN TO MODULATE
COMMUNICATION BETWEEN NERVE
FIBERS STAINED RED.
MICROGLIA AND AND ASTROCYTES
ACTIVATE TOLL-LIKE RECEPTORS, ON
THE CELLS IN THE DORSAL HORN OF
THE SPINAL CORD SHOWN TO RELEASE
PRO-INFLAMMATORY CYTOKINES.
THIS IS THOUGHT TO BE ONE OF THE
CONTRIBUTING MECHANISMS FOR
NOCIPLASTIC PAIN CHARACTERIZED
BY WIDESPREAD AND AND FATIGUE,
NON-RESTORATIVE SLEEP, MEMORY
DIFFICULTIES.
MEMBERS OF THE MAPP NETWORK
INVESTIGATED THIS RELATIONSHIP
SPECIFICALLY IN FEMALE PATIENTS
WITH PAINFUL BLADDER SYNDROME.
THIS EXAMINES THE RELATIONSHIP
BETWEEN CYTOKINE RESPONSE TO LPS
STIMULATION WITH DEGREE OF
WIDESPREAD PAIN.
FOR EVERY ONE STANDARD DEVIATION
INCREASE THERE WAS 60% INCREASE
OF LIKELIHOOD REPORTING
WIDESPREAD PAIN.
AS SHOWN IN THIS BODY MAP WHERE
THE DARK COLOR REPRESENTS A HIGH
PROPORTION OF PATIENTS WITH PAIN
IN THE AREA, YOU CAN SEE
PATIENTS WITH THE LOW STIMULATED
INFLAMMATORY RESPONSE ARE
GENERAL REPLACEMENT THOSE WITH
FOCAL PAIN IN THE PELVIS.
HOWEVER THIS IS IN CONTRAST TO
PATIENTS WITH A VERY STIMULATED
INFLAMMATORY RESPONSE
CHARACTERIZED BY HAVING
WIDESPREAD PAIN, CARDINAL
FEATURE OF NOCIPLASTIC PAIN.
DR. SHREPF LED THE FOLLOWING
ANALYSIS AIMED TO DETERMINE
WHETHER THERE'S A SIMILAR
RELATIONSHIP IN WOMEN WITH
CHRONIC PELVIC PAIN.
MIHYST IS A STUDY LED BY ME AND
DR. CLAUW TO INVESTIGATE
CORRELATES OF POST HYSTERECTOMY
PAIN, RECEIVING SELF-REPORT
MEASURES OF PAIN AND SYMPTOMS,
PATIENTS UNDERGO STANDARDIZED
PELVIC EXAM, BLOOD SAMPLES
ASSESS SYSTEMIC INFLAMMATION, AS
WELL AS SUBSET OF FUNCTIONAL MRI
AND QUANTITATIVE SENSORY
TESTING.
AT THE TIME OF HYSTERECTOMY WE
RETRIEVED FLUID AND PERFORMED
ENDOMETRIAL BIOPSIES, SENT TO
DR. TAYLOR FOR MEASURES OF
NEUROANGIOGENESIS.
PARTICIPANTS COMPLETE SURVEYS TO
ASSESS PELVIC PAIN ASSOCIATED
SYMPTOMS FOR ONE YEAR AFTER
HYSTERECTOMY.
THIS STUDY IS ONGOING, USING
PRELIMINARY DATA WE'VE 17, WE
ASKED 17 WOMEN, 11 HAD SURGICAL
CONFIRMED, BLOOD WAS DRAWN AND
STIMULATED WITH LPS SIMILAR TO
THE MAPP STUDY FOR 24 HOURS
PRIOR.
WE EXAMINED THE CORRELATION
BETWEEN LPS STIMULATED CYTOKINES
AND CHEMOKINES AND SELF-REPORT
INDICES OF PELVIC PAIN.
RESULTS ARE SHOWN HERE.
YOU CAN SEE IN CORRELATION
PLOTS, WE LOOKED AT SEVERAL
DIFFERENT CYTOKINES, BUT THE ONE
THAT STOOD OUT WAS ASSOCIATED
WITH ALL SUBTYPES OF PELVIC PAIN
INCLUDING INTENSITY OF PAIN,
BLADDER PAIN, BOWEL PAIN.
SO TO VALIDATE FINDINGS IN A
SECOND COHORT CONDUCTED THE SAME
ANALYSIS IN 15 PRE-MENOPAUSAL
WOMEN, CONFIRMED ALMOST EXACTLY
THE SAME RELATIONSHIP IN
PATIENTS IN THIS NETWORK WITH
BLADDER PAIN.
WE EXAMINED THE RELATIONSHIP
BETWEEN PROVOKED SYSTEMIC
INFLAMMATION AND FUNCTIONAL
BRAIN IMAGING.
THEY SPECIFICALLY CONDUCTED A
SEED REGION TO WHOLE BRAIN
ANALYSIS, MODULATED BY SYSTEMIC
INFLAMMATION.
THEY USED A SEED REPRESENTING
THE PELVIC TRUNK AND GENITAL
PORTION SHOWN HERE OF THE
PRIMARY SOMATOSENSORY CORTEX,
THE AREA WAS PREVIOUSLY SHOWN TO
BE STRUCTURAL DEFICIENT IN WOMEN
WITH UROLOGIC PELVIC PAIN.
WHAT WE FOUND WAS, AGAIN, THE
SAME CYTOKINE I SHOWED
MIP1-ALPHA, THE PELVIC S1 AREA
BECAME MORE CONNECTED TO THE
MEDIAL PREFRONTAL CORTEX AS THE
MIP1-ALPHA LEVELS INCREASED
SHOWING THE RELATIONSHIP IN THE
CENTRAL NERVOUS SYSTEM WITH
INVOLVEMENT OF PRECISELY THE
EXPECT THE BRAIN REGION THAT S1
REGION THAT YOU WOULD EXPECT IN
PELVIC PAIN PATIENTS.
WE FEEL THIS IS UNLIKELY A
SPURIOUS FINDING BECAUSE THE
SAME REGION, MEDIAL PREFRONTAL
CORTEX WAS IMPLICATED IN SIMILAR
ANALYSIS OF SYSTEMIC
INFLAMMATION AND BRAIN
CONNECTIVITY IN PATIENTS WITH
RHEUMATOID ARTHRITIS PUBLISHED
IN NATURE COMMUNICATION IN 2018.
WHY DOES THIS MATTER?
I SPEND QUITE A BIT OF TIME
SEEING PATIENTS, WE NEED TO
REMEMBER THE GOAL OF RESEARCH,
STUDYING MECHANISMS OF DISEASE,
TO IMPROVE HEALTH AND QUALITY OF
LIFE OF PEOPLE WHO SUFFER FROM
THAT DISEASE.
THIS KNOWLEDGE SHOULD DRIVE
CLINICAL DECISION MAKING
INCLUDING WHICH TREATMENTS ARE
MOST LIKELY TO BE SUCCESSFUL,
AND WHICH TREATMENTS MIGHT EVEN
BE HARMFUL.
AND CLINICIANS MUST CARE
PARTICULARLY THOSE OF US WHO ARE
SURGEONS BECAUSE OTHERWISE WE
MIGHT DO MORE HARM THAN GOOD.
TO EXAMINE CLINICAL RELEVANCE,
WE PERFORMED A COUPLE STUDIES,
SOME WERE MENTIONED.
THIS WAS ONE OF THE FIRST
STUDIES, PROSPECTIVE,
ADMINISTERED FIBROMYALGIA SURVEY
SCORE PRIOR TO HYSTERECTOMY,
LOOKED AT OPIOID USE AND DAILY
PAIN SCORES FOR TWO WEEKS AFTER
SURGERY.
PATIENTS STRATIFIED BY
PREOPERATIVE TERTILE OF THE
FIBROMYALGIA SCORE, YOU SEE IN
PATIENTS WITH THE HIGHEST
TERTILE OF FIBROMYALGIA SCORE
HAD GREATER OPIOID CONSUMPTION
FOR LONGER PERIODS AND HIGHER
POST POP PAIN SCORES WITH
SIGNIFICANT RECOVERY.
THIS PAPER DR. CLAW MENTIONED,
WE USED IN A DIFFERENT COHORT OF
PATIENTS UNDERGOING
HYSTERECTOMY, LOOKING AT
INCIDENCE OF PERSISTENT PAIN SIX
MONTHS AFTER SURGERY.
IN OUR PARTICULAR COHORT THE
INCIDENCE OF SUCCESS AFTER
SURGERY WAS QUITE HIGH, ONLY
11%, REPORTED LESS THAN 50%
IMPROVEMENT IN PAIN, AT SIX
MONTHS THAT RELATIONSHIP BETWEEN
SURGICAL -- PRE-SURGICAL
FIBROMYALGIA SCORE WAS STRONGLY
PREDICTIVE OF PAIN.
YOU MIGHT WONDER WHAT ABOUT
CLINICAL FACTORS THAT WE WOULD
TYPICALLY THINK TO PREDICT
PERSISTENT PAIN WERE NOT SHOWN
TO PREDICT PERSISTENT PAIN,
ADENOMYOSIS, PRESENCE OF LARGE
UTERINE FIBROIDS, SURGICAL
FIBROID, DID NOT --
FIBROIDS, ADENOMYOSIS DID NOT
PREDICT RISK OF PERSISTENT PAIN.
ALL RIGHT.
HOW SHOULD WE INTEGRATE MEASURES
OF NOCIPLASTIC PAIN TO RESEARCH
STUDIES TO ENHANCE PATIENT CARE?
FIRST AND FOREMOST RESEARCH MUST
ACKNOWLEDGE THAT CHRONIC PELVIC
PAIN IS A SYMPTOM AND THERE ARE
MANY OVERLAPPING PATHWAYS THAT
CAN LEAD TO CHRONIC PELVIC PAIN.
THIS MEANS THE MECHANISM OF PAIN
CAN VARY FROM PERSON TO PERSON,
INFLAMMATION AND NEURO
ANGIOGENESISES ASSOCIATED WITH
ENDOMETRIOSIS FOR EXAMPLE CAN BE
A SOURCE OF DIRECT NOCICEPTIVE.
PAIN CAN BE DUE TO COMBINATION
OF OTHER CONDITIONS IN THE
GASTROINTESTINAL, UROLOGIC AND
MUSCULOSKELETAL PAIN GENERATORS.
THESE MIGHT CO-OCCUR,
INDEPENDENT OF ENDOMETRIOSIS
LESIONS.
THIS MEANS JUST BECAUSE THE
PELVIC PATHOLOGY IS PRESENT SUCH
AS ENDOMETRIOSIS OR ADENOMYOSIS
OR FIBROIDS IT'S NOT NECESSARILY
THE CAUSE OF PAIN IN THAT
PATIENT.
FINALLY IT'S NOTABLE THAT ALL OF
THESE FACTORS ARE INFLUENCED BY
GENETIC VARIABILITY, EARLY LIFE
TRAUMA, ENVIRONMENTAL STRESSORS,
PSYCHOLOGICAL FACTORS.
THE IMPLICATIONS ARE MULTIPLE
BUT THE MOST IMPORTANT IS ALSO
SOMETHING THAT DR. CLAW SPOKE
ABOUT, THAT MOST CHRONIC PAIN
CONDITIONS REPRESENT A HIGHLY
HETEROGENEOUS POPULATION THAT
LIE ALONG A CONTINUUM BETWEEN
THOSE PURELY PERIPHERAL VERSUS
THOSE PURELY NOCIPLASTIC.
ON THE LEFT SIDE THERE'S A GROUP
OF WOMEN PELVIC PAIN IS PURELY
NOCICEPTIVE, ON THE OTHER SIDE
LESIONS ARE NO LONGER RELEVANT
AND PAIN IS ENTIRELY
NOCIPLASTIC.
THERE'S PROBABLY A LARGE GROUP
OF WOMEN IN THE MIDDLE WHOSE
PAIN IS A MIX OF NOSICECPITE AND
NOCIPLASTIC PAIN.
AND REMOVAL OF ENDOMETRIOSIS
MIGHT REDUCE IT.
IMPLICATIONS CANNOT BE
UNDERSTATED.
IT'S LIKELY THE PATIENTS ON THE
FAR LEFT WILL HAVE A VERY
DIFFERENT OUTCOME THAN THOSE ON
THE FAR RIGHT.
IF THE RESEARCH STUDY DOES NOT
RECOGNIZE OR MEASURE THIS,
PATIENTS ARE ANALYZED AS SINGLE
GROUP, WE CAN'T UNDERSTAND OR
PREDICT WHICH PATIENTS ARE MOST
LIKELY TO BENEFIT.
IF YOU RECOGNIZE THIS AND
EXCLUDE PATIENTS ON THE FAR
RIGHT, THOSE WITH WIDESPREAD
PAIN, GENERALIZABILITY AND REAL
WORLD EFFICACY ARE SEVERELY
LIMITED.
THE NUMBER OF PATIENTS IN THIS
CATEGORY SHOULD NOT BE
UNDERESTIMATED.
41% OF THESE PATIENTS ARE
WIDESPREAD PAIN, HIGHER IN
PATIENTS WE SEE AS REFERRAL
CLINIC, HOWEVER IF OUR GOAL IS
TO IMPROVE PAIN FOR ALL
PATIENTS, INCLUDING REFRACTORY
TO FIRST LINE PATIENTS WE NEED
TO INCLUDE THESE PATIENTS AS
WELL.
I WANT TO THANK THE NIH FOR
CONDUCTING THIS AND GIVE A FEW
SUGGESTIONS, ACKNOWLEDGING THIS
IS MY BIAS BUT THIS IS MY BIAS
AS A CLINICIAN, VERY ACTIVE
CLINICAL PRACTICE AND SURGICAL
PRACTICE WITH PATIENTS WITH
PELVIC PAIN AND ENDOMETRIOSIS
AND HAVE THE OPPORTUNITY TO SEE
FIRST HAND THE COMPLEXITY OF
THIS PATIENT POPULATION AND
AMOUNT THEY SUFFER FROM ONE
TREATMENT TO ANOTHER.
FIRST I THINK WE NEED TO REALLY
EXPAND OUR FOCUS FROM
ENDOMETRIOSIS LESION TO
RECOGNIZING ENDOMETRIOSIS AND
PELVIC PAIN AS SYSTEMIC DISEASE,
NOT THAT THE ENDOMETRIOSIS
LESION IS NOT IMPORTANT BUT IF
WE DON'T TAKE IT INTO THE
CONTEXT OF THE WHOLE PERSON,
WHOLE BODY, I DON'T THINK WE'LL
MAKE FORWARD PROGRESS.
SECOND WE NEED TO ACKNOWLEDGE
THE EXPERIENCE OF PAIN CAN BE
CAUSED BY MULTIPLE BIOLOGICAL
MECHANISMS, WHICH ARE MODIFIED
BY BOTH SOCIAL, AS WELL IT'S A
ENVIRONMENTAL AS ENVIRONMENTAL
FACTORS.
LOOKING AT THE LESION,
BIOLOGICAL PATHWAYS, YOU REALLY
CAN ONLY DO THE ENTIRE RESEARCH
IN HUMANS THAT ARE IN THE
CONTEXT OF THEIR ENVIRONMENT.
AND FINALLY WE REALLY WILL ONLY
SUCCEED IF WE CHARACTERIZE
INTERACTION OF BIOLOGICAL
MECHANISMS BY WHICH PELVIC PAIN
BECOMES PERSISTENT.
IN ORDER TO DO THIS WE NEED TO
CONDUCT LARGE MULTI-CENTER
PROSPECTIVE STUDIES THAT REALLY
CAREFULLY PHENOTYPE ALL THE
PUTATIVE FACTORS THAT INFLUENCE
PAIN.
AS DR. CLAW MENTIONED, THIS
COULD BE MODELED AVALANCHED
NIDDK MAPP RESEARCH NETWORK,
PRODUCING AN IMPRESSIVE AMOUNT
OF DATA AS WELL AS PROFOUNDLY
CHANGING THE WAY WE THINK ABOUT
UROLOGYOGIC APPROACH AND SUPPORT
TEAMS WITH EXPERTISE IN
GYNECOLOGIC PAIN AS WELL AS PAIN
SCIENCE, IN ADDITION TO
REPRODUCTIVE BIOLOGISTS THAT
WORK HEAVILY IN THIS FIELD AND
NIECE ARE ALL DISTINCT GROUPS
THAT NEED TO BE BROUGHT
TOGETHER.
AND FINALLY STUDY SECTIONS WHO
REVIEW GRANTS NEED TO HAVE THE
INTERDISCIPLINARY EXPERTISE
RESEARCHERS ARE STUDYING AT.
THANK YOU.
>> I'M SORRY FOR THE
INTERRUPTION.
>> THAT'S OKAY.
WE'RE ALL HERE.
>> WE WOULD LIKE TO MOVE ON.
WE'LL ADVANCE THE QUESTIONS IN
THE CHAT DURING THE DISCUSSION
SESSION, IS IT OKAY?
>> YEAH, OF COURSE.
THANK YOU.
>> THANK YOU FOR YOUR
UNDERSTANDING.
OUR NEXT SPEAKER IS DR. FRANK
TU, TALKING ABOUT MENSTRUAL PAIN
AND CHRONIC PELVIC PAIN RISK.
DR. TU, CAN YOU SHARE YOUR
SLIDES?
>> CAN YOU HEAR ME OKAY?
>> YES.
>> AND SLIDES LOOK OKAY?
>> YES.
GREAT.
>> ALL RIGHT.
FANTASTIC.
I WANT TO ECHO COMMENTS, MY
APPRECIATION TO NICHD FOR
SETTING UP THIS WEBINAR TODAY.
MY TALK DYSMENORRHEA AND CHRONIC
PAIN IS ALREADY PRESAGED BY MY
TWO CLOSE COLLEAGUES,
COLLABORATORS, MENTORS SPEAKING
ABOUT SPECTRUM OF DISEASE, WE'VE
BEEN FOCUSED ON CHRONIC PELVIC
PAIN WITH THE HELP OF NICHD AND
NIDDK WE'VE SHIFTED ATTENTION TO
DYSMENORRHEA, RECOGNIZING
LOOKING EARLIER ON INTO THE
TRAJECTORY OF THE EMERGENCE OF
CHRONIC PAIN MIGHT LEARN
DIMENSIONS OF WHAT MATTERS,
DYSMENORRHEA.
I WANT TO LOOK AT TRANSITION IN
RELATION TO CONCEPTUAL MODELS.
I SUSPECT MANY PEOPLE ARE
ALREADY FAMILIAR WITH THE
PATHOPHYSIOLOGY OF DYSMENORRHEA,
RELATED UTERINE DISORDERS,
STILL WORTH LOOKING AT.
LASTLY TO TALK ABOUT PUTATIVE
INTERMEDIATE PHENOTYPE THAT
WE'VE BEEN LOOKING AT OVER THE
PAST SEVEN YEARS THAT WE HOPE IS
AN OPPORTUNITY TO TALK FURTHER
ABOUT BETTER WAYS TO IDENTIFY
EARLIER FORMS OF CHRONIC PELVIC
PAIN THAT MIGHT BE AMENABLE TO
TREATMENT AND PREVENTION.
SO, DYSMENORRHEA IS WELL KNOWN.
IT'S A COMMON PERHAPS PREVALENT,
UP TO 85% OF WOMEN OF
REPRODUCTIVE AGE, NOT ALL
SEVERE, 15% BUT A SUBSTANTIAL
AMOUNT HAVE MODERATE TO SEVERE
ONLY LIMITED TO A FEW DAYS,
THERE ARE WORSE VERSIONS.
WE TALK ABOUT A PRIMARY VERSUS
SECONDARY CLASSIFICATION.
SECONDARY CAN FALL INTO THE WE
CAN SEE IT OR FEEL IT, PRIMARY
IS RELATED TO ONES WITH NO
OBVIOUS CAUSE AND TYPICALLY
IDENTIFIED AS START OF
IMMEDIATELY AT THE TIME OF
MENARCHE, CLOSE THEREOF.
PATHOPHYSIOLOGY, IN THE '50s
IN "NATURE," IDENTIFIED PRESENCE
OF PROSTAGLANDINS, WORK '40s
IDENTIFIED HYPERCONTRACTILITY,
MANY PATIENTS HAVE SOME FORM OF
SENSORY DYSREGULATION AKIN TO
WHAT WAS REFERRED TO.
TREATMENTS ATTEMPT TO FOCUS ON
SUPPRESSING INFLAMMATION RELATED
TO RELEASE OF UTERINE LINING ON
A CYCLICAL BASIS, REMARKABLE
WORK SINCE THE LATE '70s TO
REDUCE PROBABLY 80% OF THE
BURDEN OF DISEASE WITH NSAIDs.
AND WITH REGARD TO SECONDARY
CAUSES, SURGEONS ARE CALLED UPON
TO EXCISE THESE UTERINE PAIN
GENERATORS, WHETHER
ENDOMETRIOSIS, MEIOSIS, WITH
SOME DEGREE OF SUCCESS.
SO WHAT COMPELLED US TO LOOK AT
PAINFUL PERIODS WAS THE FACT
MANY PATIENTS TOLD US THEY HAD
PAINFUL PERIODS FOREVER AND
CHRONIC PAIN THEY HAD BEEN
SEEING US FOR MORE RECENTLY BUT
EPIDEMIOLOGY IS SUMMARIZED
SHOWING A HEAVY OVERLAP, IF YOU
HAVE CHRONIC PELVIC PAIN 80% OF
THE TIME YOU REPORT COMPONENT OF
PAINFUL PERIODS.
AND STARTING WITH THAT WOULD BE
INSUFFICIENT, ALL PEOPLE MIGHT
NEED TO BE STUDIED TO IDENTIFY
THOSE WITH CHRONIC PELVIC PAIN,
30% WITH DYSMENORRHEA APPEAR TO
HAVE THIS RELATIONSHIP.
THE SEARCH WAS ON FOR BETTER
SPECIFICITY.
ZONDERVANT'S WORK PROMOTES
INQUIRY, DOING DEEPER WHERE TO
FOCUS ON MECHANISMS.
DR. AS-SANI POPPED ON THE
CONCEPTUAL MODEL.
I THINK IT'S CRITICAL TO
RECOGNIZE WE TEND TO FOCUS AS
CLINICIANS ON SYMPTOMATOLOGY AND
HEALTH CARE UTILIZATION, THE
SHIFT AWAY FROM THESE IN
PERIPHERAL FIELDS, GYNECOLOGY
AND NEUROLOGY, HIGHLIGHTED
IMPORTANCE OF THE CENTRAL
NERVOUS SYSTEM.
WE TENT TO FOCUS ON UTERINE AND
PELVIC ORGAN PHYSIOLOGY,
STRUCTURAL OR ANATOMIC ISSUES
BUT THEY ALL INTERFACE TO A
LARGE DEGREE AS DAN AND SUSIE
ALLUDED TO, TREMENDOUS
OPPORTUNITIES TO NOT JUST LOOK
INSIDE BOXES BUT DO STUDIES THAT
LOOK AT INTERACTIONS BETWEEN HOW
ONE CRITICAL COMPONENT INTERACTS
WITH OTHER CRITICAL COMPONENTS.
WE TEND TO FOCUS ONLY ON THE BOX
ENDOMETRIUM, WE CAN LEARN A LOT
FROM THE MODEL.
THIS FOLLOWS DISEASE FRAMEWORK.
I WILL TALK ABOUT SOME WORK THAT
NICHD IS FUNDING US TO DO THAT
DOES TURN OUR ATTENTION TO
EARLIER FACTORS THAT SUSI
ALLUDED TO.
WE WANT TO LOOK AT EARLY
INFLUENCES, ENVIRONMENTAL
FACTORS, AS THEY HAVE CERTAINLY
DONE IN A NUMBER OF PEDIATRIC
DISORDERS.
AND I THINK THAT'S A REALLY
IMPORTANT OPPORTUNITY FOR US TO
BUILD ON.
SO WHAT I THINK WE SHOULD TALK
ABOUT RELATING TO CONCEPTUAL
MODEL IS BROADER AREAS AND GET
INTO DETAILS OF WORK WE'VE DONE.
WE DON'T KNOW THAT MUCH ABOUT
GENETICS, GIVEN THAT THESE ARE
COMPLEX POLY GENOMIC DISORDERS,
THE FINDING OF ZMIZ1 IS ONLY ONE
ASPECT.
NOT A MAJOR STORY THERE.
WHEN YOU THINK ABOUT MENSTRUAL
PAIN, YOU ASSUME IT COMES FROM
THE UTERUS, THE BLADDER AND
UTERUS AND BLADDER AND COLON OR
UTERUS AND COLON OR UTERUS AND
SKELETAL MUSCLE TISSUES COULD BE
THE FUNDAMENTAL SOURCE OF
PATIENT SUFFERING.
IN SMALL WORK BY A FORMER GRAD
OPPORTUNITY OF OF ANDREA
NACKLEY, OUR POSTDOC, WE WERE
ABLE TO LOOK AT SOME, FOR
EXAMPLE, EVIDENCE MUCH ABDOMINAL
WALL ACTIVITY THAT MAY BE LINKED
TO SYMPTOMS IN PATIENTS WITH
PAINFUL PERIODS SUGGESTING AS IS
KNOWN IN ANIMAL WORK THAT THE
PRIMARY SOURCE OF NOCICEPTION
MIGHT NOT BE IN THE UTERUS BUT
COULD BE IN THE ABDOMINAL WALL
OR PELVIC FLOOR IN SOME
PATIENTS.
SOME OF OUR WORK WILL SHOW YOU
HOW WE'VE LOOKED AT WAYS TO
QUANTIFY A PERSON'S RELATIVE
SENSITIVITY.
SUSIE HAS DONE ELEGANT WORK AS
AS THE LARGER MICHIGAN GROUP,
I'M LOOKING AT CONNECTIVITY
BETWEEN DIFFERENT CORTICAL
SITES, STRUCTURAL AND
METABOLISM, IF YOU LOOK AT SOME
WORK THAT'S BEEN DONE BY KATIE
VINCENT, PRELIMINARY WORK OUT OF
LAURA PAYNE'S GROUP AND WORK OUT
OF TAIWAN, THERE IS EVIDENCE
THAT EVEN IN PRIMARY
DYSMENORRHEA THERE ARE
ALTERATIONS IN THE FUNDAMENTAL
NEURAL FRAMEWORK, CRITICAL TO
UNDERSTAND TO REDUCE
SENSITIVITY.
THERE'S A NUMBER OF SPEAKERS ON
THIS CALL WHO SPENT TIME LOOKING
AT THE ENDOMETRIAL ENVIRONMENT,
WE STILL HAVE YET TO MARRY WORK
IN ADENOMYOSIS OR ENDOMETRIOSIS
TO LOOK AT DYSMENORRHEA
SPECIFICALLY, LOOKING AT
INFLAMMATORY REGULATION,
CERTAINLY LOOKING AT VARIATION
HORMONES WITHIN AND ACROSS
INDIVIDUALS COULD BE A CRITICAL
AREA TO BETTER UNDERSTAND WHY
DYSMENORRHEA POSES PAIN.
I THOUGHT IT WOULD BE IMPORTANT
TO TALK BRIEFLY ABOUT CONCEPTS
DAN CLAW SHARED EARLY IN MY
CAREER.
THIS WORK FROM MY CLOSE
COLLEAGUE, WORK EARLY ON, HE
LOOKED AT OVERALL PRESSURE PAIN
SENSITIVITY OF THE PELVIC FLOOR
IN INDIVIDUALS WITH AND WITHOUT
CHRONIC PAIN, AND SOME WEIGHTED
WITH MORE PAINFUL PERIOD.
I POINTED OUT LOOKING AT
INDIVIDUAL ASSESSMENT OF SENSORY
SENSITIVITY ISN'T SUFFICIENT.
IF YOU LOOKED AT A SECOND
COMPONENT, WHETHER OR NOT THAT
PERSON AFTER HAVING CONTROLLED
PROVOCATION OF PELVIC FLOOR WITH
NOVEL PAIN PROVOCATION, IF YOU
HAD MORE PAIN SENSATION AFTER
APPLICATION OF THIS TESTING, IT
WOULD AFFECT LIKELIHOOD YOU
ACTUALLY HAD CHRONIC PELVIC PAIN
AT THE TIME OF CLASSIFICATION
BASED ON THRESHOLD, THRESHOLD
WAS RELEVANT, AS RELEVANT AS
WHAT HAPPENED WITH ANOTHER
COMPONENT.
IT'S IMPORTANT TO NOTE
FORTUNATELY MOST PEOPLE DIDN'T
HAVE THIS COMPONENT, NOT
SURPRISING, MOST PEOPLE DON'T
HAVE CHRONIC PAIN IN THE
POPULATION.
IT WAS A LESSON YOU COULDN'T
LOOK AT SENSORY SENSITIVITY IN
ISOLATION.
A SECOND OUTPUT, WE IDENTIFIED
THAT WE HAD PATIENTS TESTED FOR
BLADDER SENSITIVITY, IN THAT
STUDY, IT WAS AN ATTEMPT TO LOOK
AT SOME OTHER NOVEL WAYS TO
IDENTIFY BLADDER PAIN SYNDROME.
WE FOUND THAT IF YOU HAD HIGH
LEVELS OF PERIOD PAIN, UPPER
QUARTILE IN THIS B GRAPH HERE,
YOUR MAXIMUM BLADDER PAIN, WHEN
YOU HAD YOUR BLADDER FULL AFTER
DRINKING A LARGE AMOUNT OF
WATER, WAS AT A HIGH LEVEL, IN
THIS CASE 6 OUT OF 10 ON
AVERAGE, NOT NUMBERS WE WOULD
HAVE EXPECTED OUT OF THE GENERAL
POPULATION.
THIS WAS A VALIDATION STUDY,
TREATING THESE WOMEN OFF COLLEGE
CAMPUSES, REPORTED CHRONIC PAIN
FREE YET THIS NUMBER IS AS HIGH
AS YOU SEE IN PATIENTS WITH
CHRONIC BLADDER PAIN.
SUGGESTION PERHAPS WE NEED TO
TURN AWAY FROM PELVIC FLOOR,
LOOKING AT THE VISCERA, AND WERE
FORTUNATE TO GET NIDDK TO FUND A
STUDY LOOKING AT THIS GROUP OF
WOMEN WITH BOTH PAINFUL PERIOD
AS WELL AS HAD THIS SILENT
BLADDER SENSITIVITY.
SO THEY DON'T HAVE A COMPLAINT
OF BLADDER DISTRESS OR
DISCOMFORT THEY ARE AWARE OF.
I WANT TO GO OVER SOME RESULTS
QUICKLY OF THOSE STUDIES HERE.
CRAMP, WHAT THIS R01 WAS FUNDED
TO DO, LOOK AT SEVERAL THINGS,
ONE TO CONFIRM THERE WAS A GROUP
OF WOMEN SINCE WE HAD ONLY FOUND
THIS IN 15 OR SO WOMEN INITIALLY
THAT HAD THIS DYSMENORRHEA PLUS
BLADDER SENSITIVITY PHENOTYPE,
SO WE DID A LARGER SAMPLE SIZE.
THEN TO SAY, WELL, IF THEY HAVE
THIS LEVEL VISCERAL SENSITIVITY
ON A SIMPLE BLADDER TEST
INVOLVING JUST DRINKING 20
OUNCES, WAITING TO FILL, RATING
PAIN, DO THEY HAVE OTHER
NEUROPHYSIOLOGICAL FEATURES WITH
MEASURES OF ANXIETY AND
DEPRESSION, EVEN IF THEY ARE
YOUNG AND FEEL LIKE THEY ARE
HEALTHY PEOPLE.
FINALLY WE ATTEMPTED
INTERVENTIONAL ARM TO SAY AS A
PERSON'S DYSMENORRHEA CONTINUES
UNCHECKED, HOW MUCH OF THE
ACTUAL PAIN EXPERIENCE VERSUS
THE FACT THEY MAY HAVE ALTERED
SEX HORMONE LEVELS IMPACTS ON
FACTORS RELATED TO CHRONIC PAIN,
IMPAIRED MODULATION, OR
UNDERLYING SENSITIVITY.
WE WERE ABLE TO VALIDATE THIS
BLADDER TEST DOES WORK, WOMEN
HAVE THIS PHENOTYPE AND HAVE
BROAD PAIN SENSITIVITY AND
PSYCHOSOCIAL DYSREGULATION.
THIS WAS MORE DRAMATIC THAN JUST
WOMEN WITH MODERATE TO SEVERE
DYSMENORRHEA ALONE.
PECULIAR, WHEN YOU ASKED SIMPLE
QUESTIONS LIKE HOW MUCH PELVIC
PAIN IN THE LAST WEEK, WE
LEARNED SOME PRACTICAL
IMPLICATION ALSO IF YOU ASK
PEOPLE THIS QUESTION YOU LEARN
WERE SOME DRUG TRIALS ARE HARD
TO DO.
THAT IS THAT WOMEN WITH
DYSMENORRHEA ALONE WHEN RATING A
MON MENSTRUAL PAIN WEEK THE WEEK
BEFORE REPORT AVERAGE PAIN 25
OUT OF 100.
WOMEN WITH DYSMENORRHEA PLUS
BLADDER PAIN 35 OVER 100,
DESPITE THE FACT THEY DO NOT
CONSIDER THEMSELVES TO HAVE
CHRONIC PAIN, IMPLICATIONS
CREATING FLOOR EFFECTS FOR
FUTURE DRUG TRIALS IN PELVIC
PAIN.
SOME SPECIFIC DATA OFF CRAMPP,
SEVERAL PAPERS GOT PUBLISHED,
WAS TO SHOW IN THE GROUP OF
WOMEN WE CONSIDER AT RISK THIS
IS THE SISOMETRY, PROVOKED
BLADDER FEELING THIS HEALTHY
GROUP OF WOMEN WITH PAINFUL
PERIODS HAVE INDEED ALMOST AS
MUCH BLADDER PAIN AT MAXIMAL
CAPACITY.
YOU CAN SEE THIS EFFECT IS LESS
DRAMATIC AT FIRST SENSATION BUT
IMPORTANT TO CORROBORATE INITIAL
WORK.
PELVIC FLOOR WORK WE CONDUCTED
EARLIER SHOWS THAT THERE WAS NOT
ONLY REDUCED PELVIC FLOOR
SENSITIVITY, THIS IS MEASURED IN
THE AMOUNT OF NEWTONS TO PROVOKE
PAIN AT DIFFERENT SITES IN THE
VESTIBULE, WE FOUND IN BOTH
BLADDER PAIN AND DYSMENORRHEA
PLUS BLADDER PAIN GROUPS
COMPARED TO HEALTHY CONTROLS BUT
FOR PELVIC FLOOR SITES PRESENT
IN JUST DYSMENORRHEA PATIENT
ALONE SUGGESTING SOME DEGREE OF
VISCERAL SOMATIC CONVERGENCE IN
THE BROADER POPULATION OF WOMEN
WITH JUST DYSMENORRHEA.
THIS WORK IN TOTAL LED US TO
THINK ABOUT WHAT COULD WE DO
NEXT.
THESE ARE IMPORTANT IMPLICATIONS
IN FINDING POTENTIAL
INTERMEDIATE PHENOTYPE.
IF YOU LOOK AT THE WORK FROM
CAREENA ZONDERVAN, DOES THIS
HELP US GET CLOSER?
BIRTH CONTROL PILLS TO THESE
WOMEN TO ELIMINATE EXPOSURE TO
PAINFUL PERIOD FOR A PERIOD OF
TIME, SEE IF SOME MEASURES
REDUCED, WE FOUND OVER 40% OF
WOMEN OFFERED BIRTH CONTROL
PILLS DECLINED OFFER SAYING THEY
WERE SUSPICIOUS THAT THE PILL
WOULD GIVE SIDE EFFECTS OR HAD
MAIN SIDE EFFECTS, NOT WELL
DESCRIBED IN PREVIOUS
POPULATIONS THERE'S A GROUP OF
WOMEN THAT DON'T TOLERATE BIRTH
CONTROL WELL, SOLD OVER THE
COUNTER IN MANY COUNTRIES, MILD
DRUG EVEN THOUGH IT HAS VENOUS
THROMBOLISM RISKS.
THERE'S OTHER THINGS TO DO.
IF YOU LOOK AT DATA PRODUCED BY
DR. TU'S PROGRAM AT TAIWAN,
NATIONAL HEALTH DATABASE OUT OF
TAIWAN AND SUGGESTED INDEED RISK
OF FIBROMYALGIA DEVELOPING IN
PATIENTS WITH PAINFUL PERIODS
DOES SEEM TO BE ATTENUATED BY
PRIOR EXPOSURE TO BIRTH CONTROL
PILLS.
SIMPLER STUDY DESIGNS MAY BE
NECESSARY IF THIS GROUP IS
HIGHLY SENSITIVE CENTRALLY.
ANOTHER THING IS POSSIBILITY WE
COULD PERHAPS LOOK AT OTHER
DIMENSIONS.
THIS IS A SMALL STUDY, WHAT'S
INTERESTING, IT SHOWS WHEN A
PERSON'S BLADDER IS FILLING,
TYPICALLY AN INDIVIDUAL DOWN
HERE, NORMAL HEALTHY INDIVIDUAL,
PAIN FREE, DOESN'T HAVE PAINFUL
PERIODS, ONCE THEY HAVE GOTTEN
BLADDER TO FILL UP THE HEART
RATE DROPS, ALMOST LIKE THAT'S
OBVIOUS, YOU KNOW, RELIEF THAT
WE ALL GET.
YET WHEN LOOKING AT THE SAME
HEART RATE MEASUREMENT IN THESE
INDIVIDUALS WHO HAVE PERIOD
PAIN-FREE OR BLADDER PAIN
SYNDROME FAIL TO GET THIS
RECOVER.
MORE DYNAMIC TESTS MIGHT BE
NEEDED SUCH AS WEARABLES, GIVING
US FUTURE DIRECTION.
THIS IS A VIRTUAL CONFERENCE.
I WANT TO SHOUT OUT AS WAS DONE
FOR MENTORS AND COLLABORATORS,
THIS IS A SHOT AT TOKYO BAY,
DAN CLAW SAT DOWN WITH ME WITH
THIS AMAZING VIEW TO TALK ABOUT
WHERE WE OUGHT TO TAKE THIS
WORK.
THERE'S THIS CONCERN MAYBE
CONTAMINATION OF SOME RELEVANT
CONSTRUCTS IN CHRONIC PAIN
PATIENTS HAPPENS BECAUSE WE
STUDY LATER IN DISEASE PROCESS,
ENCOURAGING US TO CONSIDER
COMING TO NICHD TO LOOK AT
YOUNGER PATIENTS BEFORE CHRONIC
PAIN EMERGES AND SO WE ACTUALLY
IN THE COURSE OF THE DISCUSSION
WITH DAN ON THE SECOND FLOOR OF
THE HOTEL INTERCONTINENTAL
DECIDED TO STUDY THEM ACROSS THE
MENSTRUAL PAIN TRANSITION.
I WANT TO DO SOME BRIEF
INTRODUCTION OF WHAT WE FOUND
THERE.
EMPATHY IS RECRUITING 400 AT THE
AGE OF MENARCHE, SLOWED BY
COVID, BLADDER PAIN SENSITIVITY,
NEUROPHYSIOLOGICAL MEASURES, EDG
WORK WITH A POSTDOC GIVING US A
CHANCE TO LOOK AT CENTRAL
CORRELATES, EVEN MORE SO.
THIS SLIDE SHOWS THE FEASIBILITY
DATA TO SHOW YOU CAN GET A YOUNG
GIRL WHO NEVER THOUGHT ABOUT
SCIENCE OR HER BLADDER TO
DEMONSTRATE SHE CAN FIGURE OUT
MAXIMUM TOLERANCE, URGENCY AND
PAIN, DATA IS VALID, A SMALLER
BLADDER THAN ADULT WHICH
SUGGESTS THIS IS IN FACT SOME
VALID DATA AS WE HOPED FOR.
LIKEWISE WE DO BASIC TESTS LIKE
PRESSURE PAIN THRESHOLD TESTING,
SKIPPED PELVIC FLOOR TESTING
SINCE THAT'S QUITE CHALLENGING
IN ADULTS, KNEE AND SHOULDER
PRESSURE PAIN THRESHOLDS GET
SIMILAR RESULTS IN ADULTS, AND
CAN FIND EVIDENCE FOR DESCENDING
MODULATION.
THIS WAS PUBLISHED THIS YEAR IN
"PAIN," A NICE TESTIMONY TO OUR
COLLEAGUE GLEN WALKER,
TREMENDOUSED A LESS --
ADOLESCENT PAIN PSYCHOLOGIST.
I'M GRATEFUL TO NICHD FOR
FUNDING THIS.
LAST COMMENTS AND WE'LL TAKE
TIME FOR QUESTIONS.
NIH IPRCC INDICATED WE SHOULD
FOLK UNDER THE CIRCUMSTANCES ON
FINDING -- FOCUSED ON FINDING
BETTER MARKERS AND HOPE THIS IS
A PATHWAY TO LOOK FOR CHRONIC
PAIN VULNERABILITY.
WE RELY ON YOU TO CONTINUE TO
THINK ABOUT WAYS TO TEST
TREATMENTS AND SEE IF THEY
IMPACT ON THESE MARKERS OR HELP
US REFINE THEM.
I WANT TO SUGGEST THERE ARE A
COUPLE KEY AREAS WE NEED TO LOOK
AT BETTER ACROSS TIME,
DESCENDING MODULATION BEING ONE.
WE DIDN'T TALK ABOUT INFLUENCE
OF SOCIAL MODEL, AN IMPORTANT
AREA LOOKING AT YOUNGER GIRLS
AND THEIR PARENTS.
A NUMBER OF MOLECULAR SCIENTISTS
ON THE CALL TO HELP US WITH
DYNAMIC MODEL, IN RELATION TO
MORE GROSS METHODS.
MY LAST SLIDE, TO EXPRESS
GRATITUDE FOR COLLEAGUES FROM
NIDDK AND NICHD FUNDING, MY
ORIGINAL K23 WAS HERE, THE GYLL
LAB, POSTDOCS, DAN CLAUW AND LYN
WALKER OUT OF VANDERBILT, AND
TWO VERY DIFFERENT SCIENTISTS,
TOM CHELIMSKY WHO LOOKS AT
AUTONOMIC FUNCTION AND GERRI
GEBHART IN RETIREMENT AGREED TO
DRINK COFFEE WITH US AND
CRITIQUE.
FORMER ISB PRESIDENT, PIONEER IN
THE PAIN WORLD.
I'LL TAKE QUESTIONS IF WE HAVE
TIME.
>> THANK YOU.
IF YOU HAVE QUESTIONS PUT YOUR
QUESTION IN THE CHAT.
WE HAVE ONE MINUTE.
IF YOU DON'T HAVE SPECIFIC
QUESTIONS FOR DR. TU WE CAN MOVE
ON.
IF YOU NEED TIME TO THINK OF
QUESTIONS WE'LL ADDRESS THAT IN
THE DISCUSSION SESSION.
IT'S 2:25, I'D LIKE TO MOVE ON.
DR. NACKLEY, WOULD YOU TURN ON
YOUR CAMERA AND SHARE YOUR
SLIDES.
DR. NACKLEY IS GOING TO TALK
ABOUT VESTIBULODYNIA.
>> YOU CAN SEE MY SLIDES
CLEARLY?
>> YES.
>> GREAT.
SO, I'D LIKE TO BEGIN BY
THANKING DR. AHN AND ORGANIZERS
FOR PUTTING THIS WORKSHOP
TOGETHER TO DISCUSS CURRENT AND
FUTURE NEEDS.
IT'S BEEN AN UNDERREPRESENTED
AREA.
I'D LIKE TO GIVE THANKS FOR
INTRODUCING TERMINOLOGY AND
CONCEPTS WHICH I THINK ARE
COMMON THROUGHOUT OUR SESSION.
FOR THE NEXT 20 MINUTES I'D LIKE
TO TALK ABOUT MY GROUP'S WORK IN
THE AREA AND EMPHASIZE
IMPORTANCE OF WHAT'S BEEN
DISCUSSED ABOUT CONSIDERING PAIN
BEYOND THE LOCAL ORGAN OF
PRIMARY CHIEF COMPLAINT.
PAIN BEYOND THE VESTIBULE AND
EVEN THE PELVIS.
MY SLIDES ARE NOT ADVANCING.
I'LL PROVIDE AND OVERVIEW, SHARE
FINDINGS WHERE WE IDENTIFIED
CLINICAL FEATURES AND BIOMARKERS
THAT DISTINGUISH SUBTYPES.
I'LL INTRODUCE THE CLINICAL
TRIAL TO SEEKS TO DETERMINE
TREATMENT FOR DIFFERENT BBD
SUBTYPES WHILE MEASURING
BIOMARKERS TO UNDERSTAND
PATHOPHYSIOLOGY.
IT IS CHARACTERIZED BY PROVOKED
PAIN AT THE AREA OF THE VAGINA,
THREE MONTHS OR LONGER, THE MOST
COMMON FORM OF SEXUAL PAIN, 16%
OF REPRODUCTIVE AGE WOMEN IN
THE UNITED STATES, IT REMAINS
INEFFECTIVELY TREATED BECAUSE WE
DON'T UNDERSTAND CAUSE, CLINICAL
PRESENTATION IS HETEROGENEOUS IN
NATURE.
SOME WOMEN PRESENT WITH
LOCALIZED PAIN THAT'S RESTRICTED
TO THE VAGINAL VESTIBULE, OTHERS
HAVE VESTIBULAR PAIN AND
GENERALIZED PAIN AT OTHER
GENERAL PELVIC SITES.
STILL OTHERS HAVE VBD.
VBD CO-OCCURS OR OVERLAPS WITH
CHRONIC PAIN CONDITIONS THAT
AFFECT OTHER PELVIC OR ABDOMINAL
SITES.
FOR EXAMPLE, UPWARDS OF 35% OF
WOMEN WITH VBD HAVE (
INDISCERNIBLE).
75% HAVE TMD WHICH AFFECTS
OROFACIAL MUSCLES, 25% HAVE
FIBROMYALGIA, AND IS PREVALENT
WIDESPREAD MUSCULOSKELETAL PAIN
CONDITION.
NEUROPATHIC PAIN RESULT FROM
INJURY TO NERVES OR SPINAL CORD
OR INFLAMMATORY PAIN FROM
ACTIVATION OF IMMUNE CELLS IN
RESPONSE TO ANTIGEN EXPOSURE OR
TISSUE INJURY, VBD AND THESE
OTHER CHRONIC OVERLAPPING PAIN
CONDITIONS ARE CHRONIC PRIMARY
PAIN UNEXPLAINED BY PHYSICAL
FINDINGS, NOCIPLASTIC PAIN
CONDITIONS.
THE OVERLAP IS HIGHLIGHTED IN A
REPORT RELIEVING PAIN IN
AMERICA, SUGGESTING COMMON
ETIOLOGY.
I'D LIKE TO SHARE PRIOR WORK
FOCUSED ON IDENTIFYING SOME
DISTINGUISHING CLINICAL
BIOMARKERS, FEATURES UNIQUE TO
WOMEN WITH LOCALIZED VBD VERSUS
THOSE THAT HAVE OVERLAPPING PAIN
CONDITIONS.
WOMEN WITH VBD HEALTHY CONTROLS
RECRUITED BY LOCAL
ADVERTISEMENTS IN PAIN CLINICS,
FOLLOWING SCREEN STATUS VERIFIED
BY SELF-REPORTED PAIN.
COPC CASE STATUS USING STANDARD
CONDITION SPECIFIC DIAGNOSTIC
CRITERIA, IN THIS STUDY, AND
EXPERIMENTAL PAIN TESTING WAS
PERFORMED AT LOCAL AND REMOTE
SITES, QUESTIONNAIRES
ADMINISTRATE TO EVALUATE,
FINALLY SAMPLES WERE COLLECTED,
IN THIS CASE BLOOD SAMPLES, TO
EVALUATE CIRCULATING LEVELS OF
CYTOKINES AND microRNAs.
SO WHAT WE FOUND IS THAT PAIN
INTENSITY AND THRESHOLD MEASURED
AT SITES 5 AND 7 ON ONE, 6 ON
THE OTHER, THESE SITES, WHEN
PRESSURE WAS APPLIED
PARTICIPANTS HAD INCREASED PAIN
INTENSITY, REDUCE THE PRESSURE
PAIN THRESHOLD IN BOTH THE VBD
LOCALIZED GROUP AND VBD WITH
COPC GROUP.
AS YOU CAN SEE THOSE WITH
OVERLAPPING PAIN CONDITIONS ARE
SIGNIFICANTLY GREATER PAIN.
WHEN WE MEASURED PAIN AT REMOTE
BODY SITES SUCH AS TRAPEZIUS
MUSCLE WOMEN WITH VBD PLUS COPC
HAD REDUCEED THRESHOLD, VBD
ALONE DID NOT.
WOMEN WITH OVERLAPPING PAINS
EXHIBITED GREATEST DEGREE TO
THERMAL PAIN, INDICATIVE OF
CENTRAL SENSITIZATION.
SO WHEN WE LOOKED AT THE RESULTS
FROM THE QUESTIONNAIRE DATA, WE
ALSO FOUND THAT WOMEN WITH VBD
AND OVERLAPPING PAIN REPORT
GREATER ACHING, MORE LIKELY TO
HAVE HISTORY OF SPONTANEOUS
GENITAL PAIN, HALLMARK OF
CENTRAL SENSITIZATION.
WOMEN REPORT FOR GENERAL HEALTH
AND PHYSICAL HEALTH RATINGS MORE
SOMATIC AWARENESS, GREATER
IMPACT OF PAIN ON DAILY
ACTIVITY.
IN CONTRAST TO OTHER STUDIES
OBSERVING POSITIVE CORRELATION
BETWEEN PAIN SEVERITY AND VBD
ONSET, WOMEN IN THE GROUP WERE
LESS LIKELY TO HAVE EARLY ONSET
WITH FIRST INTERCOURSE OR TAMPON
INSERTION, THAT COULDN'T EXPLAIN
THE DIFFERENCE IN THE PAIN IN
THE TWO GROUPS.
IN SOME IT'S CLEAR FROM THESE
FINDINGS, POOR OVERALL HEALTH.
NEXT WE MEASURED LEVELS OF
CYTOKINE PROTEINS AND SMALL
REGULATORY RNAs IN BLOOD
SAMPLES COLLECTED FROM THE
COHORT IN HOPES OF IDENTIFYING
BIOMARKERS.
CYTOKINES ARE SIGNALING PROTEINS
CREATED BY IMMUNE CELLS, AND
NOCICEPTORS, SKIN CELLS.
THEY CAN PROMOTE WOUND HEALING
AND REPAIR.
SUSTAINED INCREASES PROMOTE
CENTRALIZATION AND CENTRAL
SENSITIZATION, EITHER THROUGH
ACTIVATION OF TRANSDUCER
CHANNELS AND INDUCING EXPRESSION
OF OTHER PRO-INFLAMMATORY AND
PRO NOCICEPTIVE MOLECULES.
HERE WE IDENTIFIED SIGNIFICANT
CASE CONTROL DIFFERENCES IN TWO
CYTOKINES.
IL-8 IS A PRO-INFLAMMATORY
CYTOKINE, CAN SENSITIZE
NOCICEPTORS, IL-1 BINDS TO
REGULATE ACTIVITY AND CAN
REGULATE OR SUPPRESS EXPRESSION
OF IL-8.
SO YOU CAN SEE WOMEN WITH
LOCALIZED VBD HAVE INCREASED
IL-8 ALONGSIDE INCREASED IL1RA.
WOMEN WITH VBD PLUS COPC HAVE
INCREASE IN IL-8, WE OBSERVED
SAME SIGNATURE IN A CASE CONTROL
STUDY, INDIVIDUALS WITH
LOCALIZED TMD ARE INCREASE IN
IL1RA, THOSE WITH TMD WIDESPREAD
PAIN HAVE INCREASED LEVELS OF
IL-8 WITH NO COMPETENCE TORE
INCREASE IN IL1RA.
THE SAME MARKERS MAY BE ABLE TO
DISTINGUISH OVER THE PRESENCE OF
OVERLAPPING PAIN, IN THIS CASE
WE FOUND IL-8 AND IL1RA TO BE
THE SUBTYPES SELECTIVE
BIOMARKERS.
WE VALUED EXPRESSION OF 750
microRNAs, SMALL MOLECULES
THAT PLAY A VITAL ROLE IN
REGULATING EXPRESSION OF GENES
IMPORTANT FOR ALL NORMAL
PHYSIOLOGIC PROCESSES INCLUDING
PAIN AND INFLAMMATION.
THEY ARE LOOKING AT
INTRACELLULAR NUCLEATED CELLS.
THEY REGULATE THE EXPRESSION OF
GENES BY BINDING TO THE THREE
PRIME UTR OR UNTRANSLATED REGION
OF TRANSCRIPTS TO PREVENT
TRANSLATION OR TARGET THEM FOR
DEGRADATION.
WE IDENTIFIED 17 microRNAs,
SO DOWNREGULATED microRNAs
ARE SHOWN IN RED, UPREGULATED
SHOWN IN BLUE.
SYSTEMIC DYSREGULATED, FOUR IN
BOTH GROUPS, SIX SPECIFIC TO
VBD, SEVEN SPECIFIC TO VBD PLUS
COPC.
IN ORDER TO PUT THIS
DYSREGULATION IN CONTEXT, WE
USED PATHWAY ANALYSIS SOFTWARE,
MIRAPLAST, PREDICTED TO BE
DYSREGULATED BASED ON RNA
RESULTS.
THE FOUR microRNAs ARE IN
THE TGF-BETA PATHWAY, AN
IMPORTANT REGULATOR OF
INFLAMMATION THAT CAN INHIBIT
MACROPHAGE ACTIVATION AND B
CELLS AND CAN DOWNREGULATE
INFLAMMATORY CYTOKINE DIRECTION.
UPREGULATION WOULD CAUSE REDUCED
LEVELS OF TGF-BETA, THIS MAY BE
AN IMPORTANT HUB FOR LOCAL AND
WIDESPREAD PAIN.
ESTROGEN IS IMPORTANT FOR
SUPPORT, PREDICTED TO BE BLUNTED
IN WOMEN WITH VBD.
THE MIR-449 HAS PREVIOUSLY BEEN
SHOWN IN ANOTHER STUDY TO BE
IMPLICATED IN ENDOMETRIOSIS AND
IN BLADDER PAIN, THIS REGULATES
NEUROKIND 1 RECEPTOR, IMPORTANT,
SO MIR-449B MAY PLAY A ROLE IN
PATHOPHYSIOLOGY OF PELVIC PAIN.
AND THERE WERE SEVEN MIRs
DYSREGULATED IN WOMEN WITH VBD
AND COPCs, THAT INCLUDES
microRNAS THAT REGULATE
INTEGRIN B1, ALSO KINASES SUCH
AS P30 MAP KINASE, IMPORTANT FOR
INTEGRIN B1 AND OTHER MEMBERS OF
THE EXTRACELLULAR MATRIX PATHWAY
WHERE STRUCTURE AND FUNCTION OF
NERVES, IMMUNE CELLS AND NERVES,
P38 MAP KINASE SIGNALING IS
IMPORTANT FOR CENTRAL
SENSITIZATION, PROMOTING PAIN
THROUGH UPREGULATION, AND
microRNA ASSOCIATED WITH IL-8
LEVELS IN THE COHORT.
TOGETHER DATA IMPLICATE MORE
SEVERE DYSREGULATION IN PATHWAYS
REGULATING IMMUNE AND SENSORY
PROCESSING, POSSIBLY LINKED TO
CENTRAL SENSITIZATION.
TO DETERMINE POTENTIAL
EFFECTIVENESS OF PERIPHERAL
VERSUS CENTRALLY TARGETED
TREATMENTS, WE COLLABORATED WITH
DR. RAPPKIN AT UCLA TO CONDUCT A
PILOT STUDY MEASURING
SELF-REPORTED PAIN IN A Q-TIP
TEST FOR 50 WOMEN AND FOLLOWING
TREATMENT IN THE CLINIC.
WE FOCUSED ON COMMONLY
PRESCRIBED TREATMENT AND TO SEE
WHICH ONES MAY WORK BETTER IN
WHICH OF THE GROUPS, WITH
LOCALIZED VBD OR THOSE WITH
OVERLAPPING PAIN.
TO THE TREATMENTS WE FOCUSED ON
WERE TOPICAL TREATMENTS SUCH AS
LIDOCAINE WHICH PREVENTS
TRANSDUCTION AND TRANSMISSION OF
PAIN,ES ESTRADIOL CAN REDUCE
INFLAMMATION, CENTRALLY TARGETED
TREATMENTS THAT PROMOTE
DESCENDING INHIBITION, ALL THE
WOMEN WERE FIRST GIVEN TOPICAL
LIDOCAINE TREATMENT AND THOSE
WHO DIDN'T RESPOND MOVED TO THE
CENTRALLY TARGETED TREATMENT.
WHAT WE FOUND WAS THAT TOPICAL
TREATMENTS ALLEVIATED PAIN IN
65% OF WOMEN WITH LOCALIZED VBD,
ONLY AS SMALL AS 36% OF WOMEN
WITH OVERLAPPING PAIN.
OF THOSE THAT FAILED TO RESPOND,
TO THE PERIPHERALLY TARGETED
TREATMENT, CENTRALLY ACTING
TRICYCLIC SSRIS, SUGGESTING
RESPONSE CENTRAL TARGETED
TREATMENT.
I DIDN'T PRESS THAT BUTTON SO
YOU CAN SEE THE GRAPH.
SO IN SUM FROM THIS PART OF THE
TALK WE HAVE DETERMINED THAT
WOMEN WITH OVERLAPPING PAINS
COMPARED TO THOSE WITH VBD HAVE
WIDESPREAD CENTRAL
SENSITIZATION, SUCH THAT THEY
HAVE GREATER PAIN AT THE SITE OF
CHIEF COMPLAINT, WIND UP AT
SITES REMOTE FROM THE SITE OF
CHIEF COMPLAINT, AND POOR AFFECT
AND PERCEIVED HEALTH.
TWO SUBTYPES, WOMEN WITH VBD
ALONE HAVE INCREASED LEVELS OF
IL-8 AND IR 1RA.
THOSE WITH COPCs HAVE
DYSREGULATION LINKED TO IMMUNE
FUNCTION.
OUR EARLY PILOT DATA SUGGESTS
THESE WOMEN MAY BENEFIT FROM
DIFFERENT TYPES OF TREATMENT.
REALLY WE NEED LARGER CONTROLLED
TRIALS TO DETERMINE OPTIMAL
TREATMENT STRATEGIES FOR THESE
AND POSSIBLY OTHER SUBTYPES.
SO THIS LEADS ME TO THE FINAL
SEGMENT OF MY TALK, WHERE I'D
LIKE TO SHARE OUR ONGOING
EFFORTS THROUGH THIS
COLLABORATION.
WE'RE CONDUCTING A CLINICAL
TRIAL FOR VESTIBULODYNIA,
UNDERSTANDING PATHOPHYSIOLOGY
AND DETERMINING APPROPRIATE
TREATMENT, THE UPDATE STUDY,
CONNECTIONING THIS IN AN EFFORT
TO GUIDE OPTIMAL TREATMENT
STRATEGIES IN AND EVIDENCE-BASED
WAY.
AND SO THE PURPOSE IS TO FIRST
COMPARE THE EFFICACY OF
PERIPHERAL LIDOCAINE AND
ESTRADIOL TREATMENT, CENTRALLY
TARGETED TREATMENTS OR COMBINED
TREATMENTS, ALLEVIATING PAIN AND
IMPROVING PATIENT OUTCOMES AND
NORMALIZING CYTOKINES AND RNAs
HOPING TO DETERMINE BIOMARKERS
IN THE SUBTYPES.
WE'RE ENROLLING FEMALES AGE 18
TO 50, WITH VAGINAL PAIN FOR
THREE MONTHS.
WE PLAN TO ENROLL 400 WOMEN, 200
AT EACH OF THE TWO SITES FOR
24-WEEK STUDY.
PARTICIPANTS WILL BE ASSIGNED TO
RECEIVE EITHER COMBINED
COMPOUNDED LIDOCAINE ESTRADIOL
CREAM WITH PLACEBO PILL, PLACEBO
CREAM WITH ACTIVE PILL,
ACTIVE-ACTIVE OR PLACEBO-PLACEBO
TREATMENT.
PARTICIPATION INCLUDES FOUR
STUDY VISITS TO EVALUATE VBD AND
OVERLAPPING PAIN TO MEASURE PAIN
AND SELF-REPORTED HEALTH, AND
ALSO TO PLOT BIOLOGIC SAMPLES,
INCLUDING LOCAL AS WELL AS
CIRCULATING BLOOD.
>> ONE MINUTE LEFT.
SORRY.
>> OKAY.
I'M ALMOST TO THE END.
SO THIS WILL INCLUDE DATA AND
SAMPLES INCLUDED, COLLECTED AT 8
WEEKS, 16 WEEKS, AND WEEKS AFTER
TREATMENT IS DISCONTINUED.
WE'LL BE MEASURING A NUMBER OF
PRIMARY AND SECONDARY VARIABLES,
WHICH ARE SHOWN HERE, INCLUDING
PAIN, EXPERIMENTAL PAIN,
SELF-REPORTED PAIN,
PSYCHOLOGICAL MOOD, OTHER
SELF-REPORTED HEALTH VARIABLES,
AND IMPORTANTLY BIOMARKERS,
COLLECTED AGAIN AT FOUR TIME
POINT, I THINK THIS IS PRETTY
POWERFUL.
AND SO IN THE INTEREST OF TIME
I'LL JUST HIGHLIGHT THAT
ENROLLMENT IS ONGOING AND IF
YOU'D LIKE TO LEARN MORE OR
REFER A PARTICIPANT OUR WAY, YOU
CAN CHECK OUT THE WEBSITE, OR
CHECK US OUT ON FACEBOOK OR
INSTAGRAM.
IN CONCLUSION, I'D LIKE TO
HIGHLIGHT THAT WOMEN WITH
LOCALIZED VBD EXHIBIT MODERATE
PERIPHERAL SENSITIZATION, AND
MAY BENEFIT FROM PERIPHERALLY
TARGETED THERAPIES.
NOT ONLY PHARMACOLOGIC BUT ALSO
SUCH AS PHYSICAL THERAPY.
THESE WOMEN, THEIR PAIN MAY STAY
THE SAME OR WORSEN, SUSTAINED
PERIPHERAL INFLAMMATION IN THE
CASE OF THOSE WHERE THE PAIN
WORSENED COULD RESULT IN
AMPLIFIED CENTRAL RESPONSES TO
PERIPHERAL STIMULI.
SO WOMEN WITH VBD ARE AT RISK
FOR OTHER CHRONIC PAIN
CONDITIONS AND HEALTH DISORDERS
THAT AFFECT OTHER BODY SITES
AND SYSTEMS.
IT'S IMPERATIVE WE EXPLORE
BEYOND THE PELVIS AND LOOK AT
OTHER HEALTH CONDITIONS ASIDE
FROM JUST PAIN.
WE FOUND WOMEN WITH OVERLAPPING
PAIN EXHIBIT PERIPHERAL
SENSITIZATION, SHIFT TO IL-8
MARKERS, CHANGES IN
microRNAs LINKED TO PAIN AND
INFLAMMATION.
THEY MAY BENEFIT FROM CENTRALLY
TARGETED OR COMBINED THERAPIES.
AND ULTIMATELY WHICH OF THESE
TWO OR MORE PATHS ON WHICH A
WOMAN FIND HERSELF IS DUE TO
INTERACTIONS BETWEEN GENETIC AND
ENVIRONMENTAL FACTORS, WE'RE
JUST BEGINNING TO SCRATCH THE
SURFACE, SO HOPEFULLY THROUGH
OUR WORK AND PARTNERSHIPS WITH
OTHER COLLEAGUES, WE'LL BE ABLE
TO IDENTIFY MECHANISMS AND
TREATMENTS FOR THESE WOMEN.
WITH THAT I WOULD LIKE TO THANK
MY COLLEAGUES IN MY LAB AND
THOSE AT UNC AND UCLA AND
ESPECIALLY LATE BILL MAIXNER,
AND I THANK NICHD AND OTHER
INSTITUTES FOR FUNDING AND I'D
LIKE TO THANK THE AUDIENCE AND
TAKE ANY QUESTIONS IF WE HAVE
TIME.
>> THANK YOU, DR. NACKLEY.
CAN YOU SEE THE CHAT?
FIRST QUESTION IS FROM JUDY.
IN THIS MODEL WHAT GROUP DO
WOMEN WITH GENERALIZE DISCERN
FALL INTO, VBD WITH COP GROUP?
>> IN THE INTRODUCTION I POINTED
OUT HETEROGENEITY IN THE
POPULATION.
FOR THE PURPOSE OF THIS STUDY,
SMALLER STUDY, THAT I PRESENTED
DATA ON, WE PRIMARILY FOCUSED ON
THOSE WITH VESTIBULODYNIA ALONE,
INCLUDING GENERALIZEED PAIN.
WE FOCUSED ON TMD, FIBROMYALGIA
AND HEADACHE.
ONGOING CLINICAL TRIALS WE'LL BE
ABLE TO LOOK IN A MORE DETAILED
WAY AT GENERALIZED PAIN AS WELL.
WE'RE CAPTURING PAIN IN A MORE
DETAILED WAY. .
>> CAN YOU SEE THE QUESTION ON
THE CHAT?
>> I'VE GOT MY SLIDE OPEN.
LET'S SEE.
>> WHERE DOES (INDISCERNIBLE)
FALL INTO THIS OR IS THAT THIS
NOT PART OF VDB.
>> YOU HAVE A PATHOLOGY, THERE
MIGHT BE SOME LINKS.
THAT WOULD BE AN EXCLUSIONARY
CRITERIA FOR PARTICIPATION.
WE'RE LOOKING MORE AT THIS
PRIMARY NOCIPLASTIC PAIN, NOT
PAIN ATTRIBUTABLE TO
ABNORMALITY.
>> NEXT QUESTION FROM STEVE
WALKER.
WHAT TISSUE WAS THE microRNA
PERFORMED IN?
>> THE PROFILING IN THE DATA
THAT I SHOWED WAS FROM BLOOD,
THIS IS CIRCULATING
microRNAs, WE CAN ONLY
EXTRAPOLATE WHAT WE KNOW ABOUT
CENTRAL TARGET.
IN OUR ONGOING STUDY WE'RE
COLLECTING VAGINAL SWAB SAMPLES
AND CAPTURING OR COLLECTING
VAGINAL LAVAGE FLUID TO MEASURE
LOCAL CYTOKINES.
AND WE'RE LOOKING AT
microRNAs AND CYTOKINES
CIRCULATING IN BLOOD AS WELL.
>> THANK YOU.
WE HAVE MORE QUESTIONS IN THE
CHAT BUT WE WOULD LIKE -- DUE TO
THE TIME LIMIT WE WOULD LIKE TO
HAVE THE BREAK NOW.
SO WE WILL HAVE A BREAK.
ENJOY YOUR BREAK.
PLEASE COME BACK AT THREE FIVE.
LET'S START WITH INTRODUCING DR.
JERRY LOUDER, ASSOCIATE
PROFESSOR OF OB/GYN AT
WASHINGTON UNIVERSITY IN
ST. LOUIS.
HE HAS COMPLETE THE FELLOWSHIP
AT UPMC AND MASTER'S DEGREE,
CLINICAL RESEARCH, THE
INSPIRATION FOR AREAS OF
CLINICAL RESEARCH INTERESTS
INCLUDING CLINICAL EFFECTIVENESS
RESEARCH FOCUSING ON THE
UTILIZATION OF APICAL SUPPORT
PROCEDURES IN PELVIC ORGAN
PROLAPSE SURGERY.
NEXT DR. DIAZ, WHO IS A
PRINCIPAL RESEARCH SCIENTIST AND
CO-FOUNDER AT HILL MED, INC.,
UNDERGRADUATE AND Ph.D.
DEGREES IN BIOMEDICAL
ENGINEERING, RESEARCH HAS
UTILIZED NOVEL HIGH DENSITY
ELECTROPHYSIOLOGIC TOOLS TO
ASSESS NEURAL PROPERTIES AND
INNERVATION OF MUSCLES INVOLVED
IN URINARY, YOU NEED A Ph.D.
TO SAY ALL THAT.
CURRENT RESEARCH COMBINES
MULTI-DISCIPLINARY EXPERIENCE IN
PELVIC FLOOR ANATOMY AND HIGH
DENSITY SURFACE EMG TO DEVELOP
HIGH DENSITY SURFACE EMG AND
INNERVATION SYSTEM.
DR. SUSAN EVANS, IN
COLLABORATION WITH DR. MARK
HUTCHINSON FOUNDED ALIRA
BIOTECH, THEY ARE
COMMERCIALIZING INTRAUTERINE
NEUROIMMUNE MODULATION TO TREAT
WIDE RANGE OF CENTRALLY MEDIATED
NEUROIMMUNE SYSTEMS IN WOMEN.
WE WELCOME AND THANK ALL THREE.
DR. LOWDEW, IT'S YOUR SHOW.
>> EXCELLENT.
GOOD AFTERNOON.
I'D LIKE TO THANK THE NIH FOR
INVITING ME TO PARTICIPATE IN
THIS WEBINAR.
I'M HONORED TO BE PART OF THIS
ESTEEMED PANEL.
SO, THESE ARE MY DISCLOSURES.
AND TODAY I'D LIKE TO FOCUS ON
TERMINOLOGY, THEORIES OF
EPIGENESIS, RELATION WITH PELVIC
FLOOR DISORDER SYMPTOMS,
EXAMINATION OF THE PELVIC FLOOR,
RESULTS OF TREATMENTS FOR
MYOFASCIAL PAIN AND IMPACT ON
DISORDER SYMPTOMS.
MANY TERMS HAVE BEEN USED TO
DESCRIBE DYSFUNCTION OF THE
PELVIC FLOOR, MOST CONVEYING
MUSCLE SPASTICITY AND PAIN.
A WIDE VARIETY OF TERMS MAY BE
CONFUSING IN 2005 STANDARDIZED
TERMINOLOGY WAS PUBLISHED,
INCLUDING CONTRACTION AND
RELAXATION WHICH INCLUDE
VOLUNTARY AND INVOLUNTARY
COMPONENT.
FOR EXAMPLE, VOLUNTARY PELVIC
FLOOR MUSCLE CONTRACTION ON
DEMAND, CLASSIFIED AS STRONG,
NORMAL, WEAK, ABSENT.
INVOLUNTARY PELVIC FLOOR MUSCLE
RELAXATION WHEN STRANGE WITH
DEFECATION, CLASSIFIED AS A
ABSENT OR PRESENT.
DYSFUNCTION NON-CONTRACTING,
NON-RELAXING, NON-CONTRACTING
NON-RELAXING.
THEY DEFINED CONDITIONS WHICH
REQUIRES CHARACTERISTICS
SYMPTOMS AND SIGNS, NORMAL WHERE
VOLUNTARY AND INVOLUNTARY
CONTRACTION AND RELAXATION ARE
PRESENT.
OVERACTIVE DO NOT RELAX OR
CONTRACT WHEN RELAXATION IS
NEEDED.
NON-FUNCTIONING HAVE NO PALPABLE
MUSCLE ACTION, WOULD BE
NON-CONTRACTING, NON-RELAXING.
IN 2017, JOINT REPORT, AUTHORS
IDENTIFIED NEED FOR EXTENSIVE
DESCRIPTION OF PELVIC FLOOR
MUSCLE DYSFUNCTION, SYMPTOMS
SECTIONS DEFINED MYALGIA AS
MUSCLE PAIN, MAY BE PRESENT WITH
OR WITHOUT A CHANGE IN PELVIC
FLOOR MUSCLE TONE.
MYOFASCIAL PAIN CAUSED BY
PRESENCE OF TRIGGER POINTS.
RELEVANT DIAGNOSIS WAS CHRONIC
PELVIC FLOOR MYOFASCIAL PAIN
SYNDROME.
THERE'S BEEN AN UPDATED
DOCUMENT.
THE PATHOGENESIS OF PELVIC FLOOR
MYOFASCIAL PAIN IS INCLEAR,
PRIOR PRESENTER SET THE STAGE,
INCLUDING MICROTRAUMA,
IMBALANCE, CENTRALIZATION OF
PAIN, LIKELY WORK IN
COMBINATION.
ACUTE TRAUMA OR REPETITIVE
MICROTRAUMAS CAN LEAD TO CHRONIC
MUSCLE CONTRACTION, FORMATION OF
TRIGGER POINTS, METABOLIC
IMBALANCE BUILDING ELEVATED
LEVELS OF PAIN-PRODUCING
COMPOUNDS DEMONSTRATED IN THE
VICINITY OF TRIGGER POINTS.
CENTRALIZATION OF PAIN OCCURS
WHEN THE SENSORY PAIN
INFLAMMATION IS ABNORMALLY
PROCESSED, CENTRAL
SENSITIZATION, APPEARS TO RESULT
IN PAIN PERPETUATED BY THE CNS.
WOMEN GENERALLY PRESENT WITH
PAIN IN THE PELVIS, VAGINA,
VULVA, RECTUM OR BLADDER.
ASSOCIATED SYMPTOMS INCLUDE
ACHING, HEAVINESS, BURNING, OR
SYMPTOMS OF OVERACTIVE BLADDER,
CONSTIPATION.
I'D LIKE TO DISCUSS PELVIC FLOOR
DISORDER SYMPTOMS IN WOMEN WITH
PELVIC FLOOR MYOFASCIAL PAIN ON
PALPATION IT'S A CHRONIC PAIN
DISORDER, ARISING IN MUSCLE AND
FASCIA, PATIENTS HAVE CONTRACTED
BANDS OF SKELETAL MUSCLE, WITHIN
THESE BANDS DISCRETE PAINFUL
NODULES, TRIGGER POINTS, TENDER
POINTS.
PALPATION PRODUCES LOCAL AND
REFERRED PAIN, ACTIVE OR LATENT.
LATENT TRIGGER POINTS ARE TENDER
WHEN PALPATED.
THEY CAN REMAIN LATENT FOR YEARS
UNTIL REACTIVATED.
WHEN FIRM PRESSURE IS APPLIED
PATIENTS MAY HAVE AUTONOMIC
SYMPTOMS, PAIN IS DESCRIBED IN
THE NECK, UPPER BACK, FACE AND
JAW, IN THE PELVIS MYOFASCIAL
PAIN OFTEN ARISESES IN MUSCLES
AND CONNECTIVE TISSUE OF HIP,
AND HAS BEEN DESCRIBED IN THE
COXIGEUOS AND PYRAFORMIS.
I'D LIKE TO TOUCH ON THE
HYPERTONICITY.
CLINICALLY WE ADD ANATOMIC
PROXIMITY, SO WHILE CENTRAL
SENSITIZATION UNDERLIES PAIN
DISORDERS, LARGE DRIVER OF THE
FINDING OF PELVIC FLOOR
MYOFASCIAL PAIN, CONVERGENCE MAY
EXPLAIN RELATIONSHIP BETWEEN
PELVIC FLOOR MYOFASCIAL PAIN AND
SYMPTOMS IN WOMEN WITHOUT
CHRONIC PELVIC PAIN.
AFFERENT FIBERS FROM THE PELVIC
FLOOR MUSCLES, THE SAME DORSAL
HORN BEFORE ASCENDING FOR
CORTICAL INTERPRETATION, BECAUSE
OF PROXIMITY OF FIBERS
CROSS-TALK CAN LEAD TO
PERCEPTION OF PAIN FROM ONE OR
BOTH STRUCTURES.
ANATOMIC PROXIMITY MAY EXPLAIN
CONCURRENT SYMPTOMS, WITH
BLADDER FILLING, BLADDER COMES
TO REST ON THE MUSCLES, ONE
COULD IMAGINE THE TRIGGER POINTS
OR TINDER POINTS WHICH WE CAN
PALPATE AND ACTIVATE
TRANSVAGINAL PALPATION COULD BE
ACTIVATED WHEN THE BLADDER COMES
IN CONTACT LEADING TO
STIMULATION OF THE TRIGGER
POINTS WHICH MAY MANIFEST AS
PAIN WITH BLADDER FILLING, OR
SENSATION OF URGENCY OR
FREQUENCY.
MUSCLE ACTIVATION WITH FULL
BLADDER COULD ACTIVATE TRIGGER
POINTS IF PRESENT.
PREVALENCE ESTIMATES FOR PAIN
VARY WIDELY IN LITERATURE
DEPENDING ON POPULATION STUDIED,
FROM 17% OF PAIN-FREE PATIENTS,
TO AS HIGH AS 87% IN POPULATION
OF PATIENTS WITH INTERSTITIAL
CYSTITIS, MANY CONTRIBUTORS TO
DATA.
DYSFUNCTION IS BEING RECOGNIZED
IN SIGNIFICANT PROPORTION OF
PATIENTS PRESENTING FOR
EVALUATION OF OTHER NON-PAIN
PELVIC FLOOR DISORDERS, APPEARS
TO INFLUENCE SEVERITY OF THEIR
SYMPTOMS.
THESE PATIENTS REPORTED GREATER
SYMPTOMS RELATED TO PROLAPSE,
URINARY SYMPTOMS COMPARED TO
PATIENTS WHO DID NOT HAVE
LEVATOR MYALGIA.
PATIENTS REFERRED TO ANOTHER
UNIVERSITY-BASED PROGRAM, PAIN
WAS FOUND IN 32%, THESE PATIENTS
HAD A GREATER DEGREE OF SYMPTOM
DESPITE LOWER IMMUNE STAGE OF
PROLAPSE WITHOUT PAIN, DRIVING
THE SYMPTOMS IN THIS GROUP.
THE STUDY, WE HAD SIMILAR
FINDINGS, PELVIC FLOOR
MYOFASCIAL PAIN WAS HIGHLY
PREVALENT, AND PAIN SCORE
DISTRIBUTIONS WERE EXAMINED IN
THE FULL SAMPLE, STRATIFIED BY
PAIN AS PRESENTING COMPLAIN
USING BOX PLOTS, LEFT SIDE
REPRESENTS WITHOUT PAIN AS CHIEF
COMPLAINT.
WOMEN WITHOUT COMPLAINT HAD MEAN
PELVIC PAIN SCORES ONE POINT
LOWER THAN WITH CHIEF COMPLAINT
OF PAIN.
PAIN WITH PALPATION IS COMMON
AND SHOULD BE SCREENED FOR AS
MAYBE PLAYING A ROLE IN OTHER
PELVIC FLOOR SYMPTOMS.
HERE WE LOOKED AT CORRELATION.
OF NOTE ONLY 27% OF THIS SAMPLE
HAD STAGE 2 OR GREATER PROLAPSE
OF THE ORGAN PROLAPSE
QUANTIFICATION EXAM, MAJORITY
HAD STAGE ZERO OR 1 SUPPORT AND
SHOULD BE ASYMPTOMATIC,
CORRELATED WITH PRESSURE AND
LOWER ABDOMEN, PELVIC HEAVINESS,
HAVING TO PUSH.
THE CONVERSE, WE CREATED
OBJECTIVE SYMPTOM SUMMARY SCORE
INCLUDING QUESTIONS RELATED TO
BULGE SEEN OR FELT, NEED TO PUSH
TO COMPLETE URINATION,
CORRELATED WITH LEADING EDGE BUT
NOT PELVIC FLOOR MYOFASCIAL PAIN
SEVERITY.
SEVERITY EACH SIDE EXAMINED
OVERALL WAS SIGNIFICANTLY
CORRELATED WITH TOTAL SCORE AS
WELL AS SUBJECTIVE SUMMARY
SCORE, WE FOUND SIMILAR FINDINGS
WITH LOWER URINARY TRACT
SYMPTOMS, ASSESSED BY URINARY
DISTRESS INVENTORY SIX SCALE.
WE FOUND NOT ONLY DO WE SEE
ASSOCIATION BETWEEN PRESENCE OF
PELVIC FLOOR MYOFASCIAL PAIN AND
SYMPTOMS, WE ALSO FOUND
SIGNIFICANT CORRELATION BETWEEN
SEVERITY OF PELVIC FLOOR
MYOFASCIAL PAIN, ON EXAMINATION,
AND DEGREE OF PELVIC FLOOR
SYMPTOM SUCH AS THOSE WITH MORE
SEVERE PELVIC PAIN REPORTED
GREATER SYMPTOM BOTHER FROM
THESE PELVIC FLOOR SYMPTOMS.
WE DEVELOPED A PROTOCOL TO
ASSESS THIS.
IMPORTANT COMPONENTS INCLUDING
ORIENTING PATIENT TO PRESSURE
THAT WE APPLIED INTERNALLY AT
FIRST OR BY FIRST DEMONSTRATING
EXTERNALLY ON MID-THIGH,
PROVIDES REFERENCE FOR PRESSURE
PALPATION AND DEMONSTRATES
PRESSURE NOT PAIN, USED
NUMERICAL RATING SCORE TO SCORE
DEGREE OF COMFORT, AND FOR
MUSCLE, CENTER OF THE MUSCLE
BELLY AS PALPATED AND THEN IN
SWIFT MOTION ALONG THE LENGTH OF
THE MUSCLE IN DIRECTION OF THE
ORIENTATION OF THE MUSCLE, EXAM
STARTS WITH THE RIGHT, LEFT.
LET'S TRANSITION TO TREATMENT
STRATEGIES AND MANY OF THESE
PELVIC FLOOR SYMPTOMS RESOLVE OR
IMPROVE WHEN PAIN IS ADDRESSED.
MANY THERAPIES WORK WELL WHEN
COMBINED, AND PAIN IS OFTEN A
CHRONIC CONDITION THAT CAN
MANAGE, BUT MAY FLARE, THEORIZED
FLARES INVOLVE REACTIVATION EVER
LATE TRIGGER POINTS.
I WANT TO FOCUS ON NOVEL
FINDINGS WITH PELVIC FLOOR P.T.
TYPE, VAGINAL CRYOTHERAPY
ALLUDED TO EARLY IN
PRESENTATIONS, DIFFERING METHODS
OUT THERE.
PELVIC FLOOR P.T. IS THE
CORNERSTONE, MAINSTAY OF
TREATMENT.
AGAIN APPROACH IS HIGHLY
VARIABLE, DEPENDING ON THERAPIST
TRAINING AND BACKGROUND.
AND SOME P.T.s, MYOFASCIAL
RELEASE BASED TECHNIQUE, OTHERS
USE MOVEMENT BASED, IDENTIFY AND
TREATMENT MOVEMENT IMPAIRMENT
DISORDERS.
STRETCHING OF AFFECTED MUSCLES,
STRENGTHENING USED BY BOTH,
SUCCESS VARIES BY THERAPIST
TRAINING.
CLINICAL I TELL PATIENTS IF THEY
ARE DOING KEGEL TO STOP UNTIL
THEY SEE THEIR P.T.
TRADITIONAL P.T. CAN IMPROVE
LEAKAGE.
THE LESS INFORMATION IS KNOWN,
SPECIFICALLY TYPES OF P.T.
A STUDY IN WOMEN WITH OVERACTIVE
BLADDER AND PAINFUL SYMPTOMS
WITH OR WITHOUT INCONTINENCE,
10-WEEK COURSE OF MYOFASCIAL
RELEASE BASED P.T., STRESS
INCONTINENCE AND HAD BEEN ON
ANTICHOLINERGIC MEDICATIONS WERE
EXCLUDED.
THERE WAS A SIGNIFICANT DECREASE
IN TOTAL PFDI 20 SCORES ASSESSED
AND URINARY SYMPTOMS IN BOTH OAB
GROUP AND PAINFUL BLADDER GROUP.
BOTHER IMPROVES WITH MYOFASCIAL
RELEASE BASED P.T., FOCUSING ON
MYOFASCIAL PAIN AND DYSFUNCTION,
NOT SIMPLY STRENGTHENING OF THE
MUSCLES.
THE PELVIC FLOOR P.T.s USE OF
AT OUR INSTITUTION UTILIZE
MOVEMENT BASED.
SCORES OF 4 OR GREATER OUT OF
10, TWO OR MORE SITES, REFERRAL
WAS SPECIFICALLY WRITTEN TO
ADDRESS PELVIC FLOOR MUSCLE
DYSFUNCTION, NOT URINARY
INCONTINENCE.
OUTCOME WAS CHANGED IN THE
INVENTORY.
BASELINE NO DIFFERENCE IN TOTAL
OR SUBSCALE SCORES BETWEEN WOMEN
WHO DID OR DID NOT ATTEND P.T.
WOMEN WHO DID ATTEND MOVEMENT
BASED P.T. THERE WAS SIGNIFICANT
IMPROVEMENT COMPARED TO WOMEN
WHO DID NOT ATTEND.
THERE WAS SIGNIFICANT DECREASE
IN MEAN CHANGE OF TOTAL AND
SUBSCALES OF THE UVI.
REPORTING MYOFASCIAL PAIN WITH
PALPATION SCORES, WOMEN WHO
ATTENDED PELVIC FLOOR P.T.,
DECREASE IN PAIN SCORES IN ALL
MUSCLE GROUPS SHOWING
SIGNIFICANT CHANGE.
URINARY SYMPTOMS AND BOTHER
SYMPTOMS WITH MOVEMENT-BASED
P.T. IMPROVED.
AGAIN, THIS WAS P.T. FOCUSED ON
MUSCLE DYSFUNCTION, NOT JUST
STRENGTHENING.
P.T.S AT OUR INSTITUTION HAVE
BEEN USING CONCOMITANT VAGINAL
CRYOTHERAPY.
PATIENTS HAD TO WAIT SIX WEEKS
TO SEE P.T.
WE BEGAN INITIATING VAGINAL
CRYOTHERAPY CLINICALLY, PRIOR TO
PATIENTS GETTING IN TO SEE THE
PHYSICAL THERAPIST, REPORTING
IMPROVEMENTS IN PELVIC FLOOR
SYMPTOMS WITH ICING ALONE.
WE DECIDED TO FORMALLY STUDY
THIS, ENROLLED 163 PATIENTS.
PARTICIPANTS IN CRYOTHERAPY ARM
WOULD ICE VAGINALLY FOR TEN
MINUTES DAILY FOR TWO WEEKS.
PLACEBO ARM PARTICIPANTS WOULD
PLACE ROOM TEMPERATURE TUBE
DAILY, BOTH COMPLETED A DIARY
AND RETURNED FOR EXAMINATION
PRIOR TO STARTING P.T.
MEDIAN TIME TO FOLLOW-UP THREE
WEEKS.
AFTER TWO WEEKS, TYPICALLY
CLINICALLY WOULDN'T SEE PATIENTS
BACK FOR A MINIMUM OF SIX TO
EIGHT WEEKS, WOMEN IN THE
CRYOTHERAPY ARM SHOWED
STATISTICALLY SIGNIFICANT
DECREASE IN PELVIC FLOOR
MYOFASCIAL PAIN IN THE RIGHT AND
LEFT.
AT TWO WEEKS WOMEN PERFORMING
ICING SHOWED BORDERLINE
STATISTICAL SIGNIFICANT
IMPROVEMENT, P-VALUE OF .05.
WOMEN PERFORMING ICING HAD
GREATER IMPROVEMENT IN ALL
SYMPTOM SCALES, TOTAL OF 20,
SUBSCALE SCORES PROLAPSE SHOWING
STATISTICAL SIS CANS.
THERE'S NO BIOLOGIC PLAUSIBILITY
FOR WHY VAGINAL CRYOTHERAPY
SHOULD IMPROVE PROLAPSE
SYMPTOMS.
SYMPTOM IMPROVEMENT IS LIKELY
DUE TO EFFECT ON PELVIC FLOOR
MUSCLES.
SO THIS NEEDS FURTHER STUDY,
OVERALL PELVIC FLOOR MYOFASCIAL
PAIN SCORES APPEAR TO IMPROVE
WITH VAGINAL CRYOTHERAPY.
>> A MINUTE LEFT.
>> IN SUMMARY, PAIN WITH
PALPATION IS ASSOCIATED WITH
SYMPTOMS, SEVERAL PATHWAYS
EXIST.
IT'S COMMON AND APPEARS TO
RESPOND TO P.T. OF THE
MYOFASCIAL RELEASE BASED AND
MOVEMENT BASED APPROACHES,
APPEARS TO RESPOND TO VAGINAL
CRYOTHERAPY, AGAIN BOTH NEED
MORE STUDY, I THINK THE CONVERSE
OF THAT IS IMPORTANT TO STRESS
URINARY AND PROLAPSE SYMPTOMS IN
WOMEN WITH PAIN WITH PALPATION
IMPROVES WITH P.T. AND
CRYOTHERAPY.
WE NEED TO IMPROVE
IDENTIFICATION OF WOMEN WITH
PELVIC FLOOR MYOFASCIAL
PALPATION AND SYMPTOMS BY
EDUCATING PROVIDERS ABOUT
SCREENING, INCREASING AWARENESS
OF EDUCATION, AMONG PROVIDERS
AND PATIENTS, OPTIMIZING
TREATMENT ALGORITHMS AND
IMAGING, LOOKING FOR BEST
METHODS TO IDENTIFY TRIGGER
POINTS POSSIBLY FOR INJECTIONS,
FOR RESEARCH DEVELOPING
NON-INVASIVE SCREENING TOOLS TO
IDENTIFY WOMEN AT RISK, MAPP,
DR. ACKERMAN ARE WORKING ON
THOSE USING QUESTIONNAIRE AND
DATABASES.
OPTIMIZING TREATMENT ALGORITHMS,
USING ROBUST CLINICAL TRIALS AND
IMAGING ESPECIALLY WITH SOME
NEWER TECHNOLOGY OF MR
ELASTOGRAPHY WITHOUT REQUIRING
BIOPSIES.
I THANK MY LOCAL COLLABORATORS
AND LOOK FORWARD TO YOUR
QUESTIONS.
THANK YOU.
>> THANK YOU.
WE'LL MOVE TO THE NEXT
PRESENTATION AND WE CAN ADDRESS
THE QUESTIONS AT THE END,
HOPEFULLY.
>> SORRY FOR RUNNING OVER.
>> YOU'RE DOING OKAY.
WE COULD TAKE A COUPLE OF
QUESTIONS.
BUT WE'LL MOVE ON TO DR. DIAZ,
AND WE WILL DO ALL THE QUESTIONS
AT THE END.
DR. DIAZ, PLEASE FELL -- FEEL
FREE TO START.
>> THANK YOU FOR INVITING ME TO
SHARE ON ASSESSING TREATMENT.
WE'RE USING A FEW TECHNOLOGIES.
WE FOCUS ON OUR HIGH DENSITY
SURFACE EMG TECHNOLOGY IN THIS
PRESENTATION.
I'M A CO-FOUNDER AND SHAREHOLDER
OF HILLMED, A UNIVERSITY OF
HOUSTON SPIN-OUT, EARLY STAGE
START-UP COMPANY.
WE'RE WORKING ON PROVIDING
NEURAL ENGINEERING SOLUTIONS TO
IMPROVE CHRONIC PELVIC PAIN
MANAGEMENT, NEURAL
REHABILITATION AND PRECISION
BOTOX INJECTIONS, COMBINING
ENGINEERS WITH SOME
ENTREPRENEURIAL EXPERIENCE TO
BRING THIS DREAM TO FRUITION.
MY OBJECTIVES TO EXPLORE
POTENTIAL GAPS IN THE DIAGNOSIS
AND CARE OF PELVIC FLOOR MUSCLE
OVERACTIVITY, OVERVIEW OF
CURRENT TOOLS AND HOW WE'RE
AIMING TO IMPROVE THESE TOOLS BY
ACTUALLY GIVING YOU A 2D MAP OF
OVERACTIVITY, AND LOOK AT SOME
FUTURE APPLICATIONS OF THIS TOOL
TO GUIDE BOTOX INJECTIONS AND
IMPROVE THE CONSERVATIVE CARE OF
PELVIC FLOOR MUSCLE
OVERACTIVATING.
A VERY, VERY BRIEF OVERVIEW OF
SOME GAPS THAT WE'VE IDENTIFIED,
THERE'S A LACK OF OBJECTIVE
MUSCLE TONE DIAGNOSIS TOOL,
RIGHT NOW YOU USE DIGITAL
PALPATION AND ONE OPINION MAY
NOT BE THE SAME AS ANOTHER
DOCTOR'S UPON.
WE'D LIKE TO PROVIDE YOU WITH A
QUANTIFIABLE MEASURE OF THE
OVERACTIVITY OF THE MUSCLE.
THERE'S A LACK OF ADAPTIVE
AT-HOME TREATMENT AND LACK OF
PERSONALIZED INJECTION TOOL.
INTRAMUSCULAR EMG HAS BEEN USED,
PALPATION OF TRIGGER POINTS, NO
CONSENSUS OF A GOOD TOOL FOR
INJECTION OF BOTOX.
THERE'S A PIECE FROM DR.
LOWDER'S PRESENTATION AND I
COMBINED PAPERS TO MAKE THIS
FLOWCHART.
THERE'S A VISCERAL PAIN
GENERATOR IN THE PELVIS, IN THE
CASE OF OUR STUDIES WE'VE LOOKED
AT ICBPS, THE BLADDER, LEADING
TO MUSCLE PAIN.
ONCE THE MUSCLE BECOMES PAINFUL
THERE'S PATHWAYS THAT CAN LEAD
TO HYPERTONICITY.
ONCE THE PELVIC FLOOR MUSCLE IS
HYPER CLONIC, LOOPS OCCUR.
TRIGGER POINTS FORM LEADING TO
PAIN AND FEEDS BACK INTO ITSELF.
MORE PAIN IN THE MUSCLE LEADS TO
MORE HYPERTONICITY, INCREASE THE
SEXUAL DYSFUNCTION, FEEDING INTO
THE VISCERAL PAIN WITH LOOPS
EVERYWHERE, YOU NEED TO BREAK
LOOPS.
IC - BPS IS THE CENTRAL
GENERATOR, AND AFFECTS 7 TO 9
MILLION WOMEN IN THE U.S.
ON MRI THIS LOOKS LIKE A
SHORTENED PELVIC PAIN MUSCLE, A
STUDY COMPARED 15 WOMEN WITH 15
CONTROLS, WITH SIGNIFICANTLY
SHORTER PELVIC FLOOR MUSCLES
COMPARED TO THOSE WITH NO
IC/BPS, UP TO 85% OF PATIENTS
WITH IC OR CHRONIC PAIN SYNDROME
EXHIBIT HYPERTONIC OR OVERACTIVE
PELVIC FLOOR MUSCLES.
THERE'S TOOLS OUT TO ASSESS THE
PELVIC FLOOR MUSCLE ACTIVITY, IN
ALL SHAPES AND SIZES.
YOU GET ONE MEASURE OF PELVIC
FLOOR MUSCLE ACTIVITY, YOU CAN
USE THIS FOR BIOFEEDBACK BUT
THERE'S NO LOCALIZATION THAT CAN
BE DONE WITH THESE TOOLS.
WE'RE DEVELOPING A TECHNIQUE,
ESSENTIALLY A HIGH DENSITY ARRAY
OF SURFACE EMG ELECTRODES,
ALLOWING US TO MAP ACTIVITY
INSIDE THE VAGINAL LUMEN USING
SINGLE SIGNAL ACQUISITION.
SO IT'S NOT LIKE NEEDLE EMG
WHERE YOU POKE AROUND AND GET
MULTIPLE MEASURES TO MAP THE
ACTIVITY OR SURFACE PROBE, YOU
GET ONE MEASURE OF THE PELVIC FLOOR.
.
THIS IS THE MOTOR UNIT TRAVELING
DOWN THE MUSCLE FIBER, YOU CAN
TRACK IN TIME AS IT'S TRAVELING
DOWN THE MUSCLE FIBER, PROVIDED
YOU HAVE A DIFFERENTIAL SIGNAL
SET UP.
THIS FIGURE B OVER HERE, MOTOR
UNIT TRAVELS DOWN THE MUSCLE
FIBER.
YOU CAN TRACK THIS BACKWARDS,
THIS IS WHERE THE MOTOR UNIT
EXPONENTIAL ORIGINATED FROM.
THAT'S CONSIDERED THE
INNERVATION ZONE AND THAT'S
WHERE NEUROMUSCULAR JUNCTIONS
ARE MOST DENSELY DISTRIBUTED.
THIS ALLOWS UNDER -- ALLOWS US
TO TAKE THIS, PUT IT THROUGH A
DECOMPOSITION ALGORITHM FOR THE
INDIVIDUAL MOTOR UNITS CAPTURED
AND LOOKS LIKE THIS FIGURE OVER
HERE ON THE RIGHT, YOUR TYPICAL
PLOT OF A NEURAL SIGNAL, ONCE
YOU HAVE THESE INDIVIDUAL MOTOR
UNIT FIRINGS, YOU CAN USE THEM
TO TIME LOCK THAT ORIGINAL MESSY
SURFACE INTERFERENTIAL PATTERN.
THAT IS SHOWN ON THE RIGHT.
YOU HAVE THAT -- YOU START WITH
THE FILTERED MESSY SURFACE
PATTERN, PUT IT THROUGH THE
ALGORITHM, WE USE THE CLUSTERING
CONVOLUTION COMPENSATION
ALGORITHM, TIME LOCK THE SIGNALS
IN EACH CHANNEL WITH RESPECT TO
EACH OF THOSE SPIKE TIMINGS
OBTAINED FROM THE DECOMPOSITION
TO GET THE OUTPUT OF THE MOTOR
UNIT TERRITORY FOR THAT
IDENTIFIED MOTOR UNIT.
FROM THERE YOU CAN DO THE
INNERVATION ZONE LOCALIZATION,
CLEAR TO SEE THAT IN THE BICEP,
ALSO DONE IN THE PELVIC FLOOR
MUSCLES ON THE OVERLAP HERE.
ONE APPLICATION OF THIS ZONE
IDENTIFICATION TECHNIQUE IS TO
POTENTIALLY USE IT TO GUIDE THE
INJECTION OF BOTOX TOWARDS THE
INNERVATION ZONE WHERE THEY ARE
DENSELY DISTRIBUTED.
THESE BOTULISM TOXIN INJECTIONS
FOR PELVIC FLOOR PAIN HAVE GROWN
INTEREST, TRIALS HAVE SHOWN
INCONSISTENT OUTCOME, SOME SHOW
GREAT RESULT, SOME NO BETTER
THAN PLACEBO.
ONE EXPLANATION COULD BE THEY
ARE NON-TARGETED INJECTIONS.
TEMPLATES WITH USED, EVERY
PATIENT IS GETTING A 5:00 AND
7:00 INFECTION WHICH MAY NOT BE
ACTUALLY HITTING THAT
NEUROMUSCULAR JUNCTION OF THE
INNERVATION ZONE REGION
SUFFICIENTLY.
OR THEY ARE BEING INJECTED INTO
THE MYOFASCIAL TRIGGER POINTS
SHOWN DRY NEEDLING CAN HELP.
YOU DON'T NEED TO INJECT THE
BOTOX.
POTENTIALLY THERE'S A BETTER
TARGET FOR THESE INJECTIONS.
SO FIRST WE DEVELOPED THE PELVIC
FLOOR HYPERTONICITY TECHNIQUE
COMPARED 15 HEALTHY VOLUNTEERS
AND 15 WITH PELVIC PAIN.
THE PATIENTS FILLED OUT A SLEW
OF SURVEYS, UNDERWENT PHYSICAL
ASSESSMENT, COULD THEY RELAX,
LOWER IT, CONTRACT IT?
ALL OF THAT.
THEY MOVED INTO ENG ASSESSMENT
WITH ONE MINUTE BASELINE
FOLLOWED BY VOLUNTARY
CONTRACTION, REST AND
CONTRACTION, SO FORTH.
MORE DETAILS, PALPATED FOR
PRESENCE OF MYOFASCIAL TRIGGER
POINTS AND PAIN.
ELEMENTS OF CONTROL WERE
EXAMINED.
HOW IS THE PELVIC FLOOR ALIGNED
AT REST, SHORTENED, LENGTHENED,
NORMAL?
COULD THE SUBJECT RELAX THE
PELVIC FLOOR AFTER CONTRACTION
AND LOWER THE PELVIC FLOOR, ONCE
AT REST WERE THEY ABLE TO LOWER
THE PELVIC FLOOR AS IF TO USE
THE RESTROOM.
80% OF SUBJECTS EXHIBITED
SHORTENED PELVIC FLOOR MUSCLE
UPON EXAM, 80% OF THE I.C.s
WERE ABLE TO RELAX AFTER
CONTRACTION, ALL OF THE HEALTHYS
COULD.
40% OF PATIENTS COULD LOWER THE
PELVIC FLOOR MUSCLES WHEN
REQUESTED COMPARED TO 73%.
WE SAW SIGNIFICANTLY INCREASED
RESTING RMS, THIS IS THE
AMPLITUDE OF THE EMG SIGNAL AT
REST COMPARED TO CONTROLS.
WE WANTED TO LOOK AT HOW THIS
RELATED TO KIND OF THE
ACTIVATION CAPACITY OF THE
MUSCLES, SO WE NORMALIZED THE
RESTING ACTIVITY WITH RESPECT TO
THE MAXIMUM AMPLITUDE REACHED
DURING MAXIMUM VOLUNTARY
CONTRACTION TO GIVE US THIS RMS
RATIO MAPPING WHICH THESE
COLORFUL MAPPINGS ARE SHOWN
HERE.
AND WE SAW A MUCH MORE
SIGNIFICANTLY INCREASED
INTENSITY OF THESE RATIO
MAPPINGS IN THE I.C. PATIENTS
COMPARED TO CONTROL PATIENTS.
THIS CORRELATED WITH SCORES AS
WELL AS BASELINE PAIN.
FURTHERMORE IT WAS SIGNIFICANTLY
INCREASED IN THE PATIENTS WITH
SHORTENED PELVIC FLOOR MUSCLE
UPON EXAM, WHEN COMPARED TO
PATIENTS WITH NORMAL LENGTH
PELVIC FLOOR MUSCLE ON EXAM.
AND WE ALSO TOOK THIS ONE STEP
FURTHER AND DECOMPOSED ALL OF
THOSE HIGH DENSITY SURFACE ENG
SIGNALS INTO POTENTIALS AND
DEVELOPED INNERVATION ZONE MAPS
FOR SUBJECTS AND OVERLAID THESE
ON THE RESTING RMS HEAT MAPS
SHOWN HERE.
WE CAN SEE NOT EVERY INNERVATION
ZONE WAS IDENTIFIED AS
CORRESPOND BE TO HYPERTONIC
ZONE.
WE CAN IDENTIFY HYPERTONIC
INNERVATION ZONES AND THOSE ARE
SHOWN HERE, LET ME PULL UP THE
LASER POINTER IF I CAN.
I WON'T MESS WITH THAT.
THE CIRCLE WITH THE BLACK ARMS
EXTENDING, THAT RECOMMENDS ONE
INNERVATION ZONE IDENTIFIED
THROUGH DECOMPOSITION.
WE CAN TAKE AN AVERAGE OF THESE
TO GIVE A PHYSICIAN A TARGET FOR
THE BOTOX INJECTION, THAT'S THE
SAME THING SHOWN IN FIGURE C AND
D, THIS IS A POLAR
REPRESENTATION, SO WHICH CHANNEL
DOES THE INNERVATION ZONE AND
HOW DEEP INTO FROM THE VAGINAL
INTROITUS DOES IT FALL.
MY COLLEAGUES AT THE UNIVERSITY
OF HOUSTON AND UT HEALTH
CONDUCTED A CLINICAL TRIAL
LOOKING AT ABILITY OF THIS
INNERVATION ZONE TARGETED BOTOX
INJECTION TECHNIQUE IN STROKES
PLASTICITY PATIENTS, LOOKED AT
SIX CONTROLS, SIX -- NO, SIX
PATIENTS, I'M SORRY, TWELVE
PATIENTS, GROUPED SIX INTO THE
CONTROL GROUP, SIX INTO
EXPERIMENTAL GROUP.
CONTROLS RECEIVED YOUR OF
ROUTINE INJECTION, EXPERIMENTAL
GROUP RECEIVED IZ-GUIDED
INJECTION, BOTH SAW DECREASE IN
AMPLY FEUD -- AMPLITUDE.
THE GUIDED GROUP SAW
SIGNIFICANTLY REDUCED COMPOUND
MUSCLE POTENTIAL COMPARED TO
CONTROL GROUP.
SIGNIFYING GREATER REDUCTION IN
MOTOR UNIT ACTIVITY IN GUIDED
GROUP.
FUTURE WORK APPLYING TO PELVIC
FLOOR MUSCLE.
WE'RE WE DEVELOPING THE PROBE
INTO A COMMERCIALLY VIABLE
DESIGN WITH LESS ELECTRODES,
GROUPING IN A MORE DENSE
ARRANGEMENT TO HIT THE PELVIC
FLOOR MUSCLES, WITH NO
ELECTRODES READING FROM THE
PELVIC FLOOR MUSCLING, MOVING IN
THE DEVELOPMENT PROCESS.
ONCE WE GO THROUGH VERIFICATION
TESTING WE'LL GO INTO IN VIVO
STUDY LOOKING AT 15 CONTROLS, 46
WOMEN WITH IC OR WITH CHRONIC
PELVIC PAIN.
IT WILL BE A SIMILAR SETUP TO
THE STUDY I JUST PRESENTED.
MORE SUBJECTS USING THE NEW
DEVICE.
AFTER THAT THE WOMEN WITH
CHRONIC PELVIC PAIN WILL MOVE
INTO CLINICAL FEASIBILITY STUDY
LOOKING AT GUIDED INJECTIONS
VERSUS TEMPLATE INJECTS, ONCE
THE DRUG WASHES OUT WE'LL HAVE A
CROSSOVER AND THEY WILL RECEIVE
THE ALTERNATE INJECTION TYPE.
ANOTHER THING WE'RE WORKING ON
IS PERSONALIZATION OF THE PELVIC
FLOOR MUSCLE PHYSICAL THERAPY.
AND WE'RE WORKING TO DEVELOP AN
AT-HOME TECHNIQUE TO HELP TREAT
CHRONIC PELVIC PAIN USING
INTRAVAGINAL PROBE, THERE'S
NOTHING NEW ABOUT THAT BUT WE'LL
BE INCLUDING THE ABILITY TO
MEASURE SIGNAL FROM THE TRUNK,
THE LEG, HIP AND ABDOMINAL
MUSCLES, HELPING US TACKLE THAT
POSTURAL COMPONENT, THE MOVEMENT
COMPONENTS LACKING IN THESE EMG
TECHNIQUES IN THE PAST.
THE PAST, BIOFEEDBACK TECHNIQUES
HAVE BEEN A VAGINAL PROBE,
HOWEVER WE'RE GOING TO INCLUDE A
MUSCLE NETWORK TECHNIQUE IN
CONCURRENCE TO GUIDE CONTRACTURE
OF PELVIC FLOOR.
THIS IS MY -- I'D LIKE TO THANK
OUR CLINICAL COLLABORATORS,
WE'RE A TEAM OF ENGINEERS, WE
NEED COLLABORATORS TO HELP WITH
THESE PRODUCTS.
DR. LAI AND SPITZNAGLE AND OTHERS.
THAT'S IT.
>> THANK YOU.
I'D LIKE TO OPEN IT UP TO THE
AUDIENCE IN GENERAL FOR THE
QUESTIONS.
I'M GOING TO GO THROUGH SOME OF
MY OWN AS WELL AS SOME IN THE
CHAT.
>> RECORDING IN PROGRESS.
>> SO WE'LL START WITH DR.
LOWDER.
IF YOU WOULDN'T MIND COMMENTS
AGAIN, CRYOTHERAPY PROTOCOL.
>> SURE.
SO, ONE THING I MENTIONED IN THE
CHAT WE DO HAVE PATIENTS ICE
LONGER THAN IN THE PROTOCOL,
THAT WAS JUST TO KEEP IT IN LINE
WITH THE IMMEDIATE ICING STUDY
THAT WE DID IN CLINIC.
AND GO OVER THOSE RESULTS.
PROTOCOL BASICALLY WE BUY THE 15
ML TUBES, CENTRIFUGE, HAVE
PATIENTS FILL THEM WITH 3 MLs
OF ALCOHOL, 12 MLs OF TAP
WATER, SCREW CAP ON, PLACE IN
FREEZER.
THEY DON'T FREEZE SOLID, SO WE
THEN HAVE PATIENTS ICE, ONE TUBE
AT A TEAM, LEAVE ONE IN THE
FREEZER, BECAUSE THEY COULD
POTENTIALLY GET TO ROOM TESTIFY
BEFORE THEY GET DONE ICING WITH
THE FIRST TUBE.
MOST SAY IT WILL STAY COLD FOR 7
MINUTES, SO A 15-MINUTE PROCESS.
THEY WASH THEM WITH SOAP AND
WATER, DRY THEM, PUT THEM IN A
DIFFERENT BAG SO THERE'S NO
CONTAMINATION, PUT THEM BACK IN
THE FREEZER.
WE TYPICALLY HAVE THEM ICE, YOU
KNOW, AS LONG AS THEY ARE
CONTINUING TO HAVE SYMPTOMS.
AND THEY CAN KEEP THOSE TO ICE
FOR FLARES.
I DIDN'T GET A CHANCE TO TALK
ABOUT, WHEN WE DESIGNED THE
STUDY WITH OUR FELLOWS, AND WITH
COLLABORATION WITH PHYSICAL
THERAPIST, WHO DR. DIAS
COLLABORATES WITH AS WELL, WE
WANTED A PLACEBO, THE BEST WE
COULD REALLY DO WAS WE THOUGHT
WOULD BE A ROOM TEMPERATURE
TUBE.
BUT IF YOU HAD A CHANCE TO LOOK
AT SOME OF THE SYMPTOMS WE SAW
SOME IMPROVEMENT WITH JUST THE
ROOM TEMPERATURE TUBE SO THE
ROOM TEMPERATURE TUBE MAY NOT
HAVE BEEN A TRUE PLACEBO.
AND TALKING WITH P.T.s,
DEPENDING HOW YOU MANIPULATE A
MUSCLE YOU CAN CAUSE IT TO
CONTRACT OR RELAX.
ONE THING TO LOOK AT IN THE
FUTURE IS THE ROLE OF THE ROOM
TEMPERATURE TUBE BECAUSE FOR
FOLKS THAT EXPERIENCE PAIN WITH
ICING, THAT MAY WORK AS WELL.
FUTURE WORK TO BE DONE THERE.
DOES THAT ANSWER YOUR QUESTION?
>> FOR THAT ONE.
SO ONE OTHER FOLLOW-UP QUESTION
TO WHAT YOU JUST MENTIONED, DO
YOU THINK THAT THERE'S A PLACEBO
EFFECT OR DO YOU THINK THAT
MAYBE IT'S JUST THE GENERAL
PRESSURE THAT THE ROOM
TEMPERATURE TUBE MIGHT HAVE --
IS THERE SOME SORT OF
STIMULATION OF THE MUSCLE?
>> I THINK THAT NEEDS FUTURE
WORK, ALSO TO DETERMINE WHAT
KIND OF MINIMALLY IMPORTANT
DIFFERENCE IN PAIN SCORES.
TYPICALLY WE DON'T SEE PATIENTS
BACK FOR 6 TO 8 WEEKS, IF THEY
ARE JUST DOING ICING ALONE.
AND I THINK WE'VE ANECDOTALLY
SEEN AND HEARD, NOT SURE I HEARD
A RESPONSE, SO I THINK THIS ALSO
NEEDS TO BE TESTED FOR A LONGER
PERIOD.
BUT SINCE WE WERE SENDING
PATIENTS TO P.T. DID NOT WANT TO
SLOW THEIR GETTING INTO PHYSICAL
THERAPY.
AND SO WE CHOSE TWO WEEKS AS A
FIRST TIME POINT.
SO I MEAN THAT NEEDS TO BE
ASSESSED BUT AGAIN THIS IS
ANECDOTAL, BUT CLINICALLY SEEING
PATIENTS WHO REPORT ALMOST
COMPLETE RESOLUTION OF THEIR
SYMPTOMS, I THINK IT IS MORE
THAN -- ICING IS MORE THAN
PLACEBO, WE HAVE TO FIND OUT
ABOUT THE ROOM TEMPERATURE.
>> SO, ALONG THE LINES, WE HAD A
QUESTION THAT COULD STATISTICAL
DIFFERENCE IN THE PELVIC FLOOR
ASSESSMENT NOTED ON THE RIGHT
SIDE BE BASED ON THE FACT THE
EXAM STARTED ON THE RIGHT SIDE
OF THE MUSCLES?
>> YEAH, I MEAN, WE'VE
STANDARDIZED WITHIN THE PROTOCOL
OUR PALPATION, LIKE THE DEPTH
AND PRESSURE THAT WE USED.
BUT WHEN WE LOOKED, WE FOUND
ASSOCIATION WITH PEOPLE THAT ARE
RIGHT-HANDED, OFT FINANCE YOU
WATCH PEOPLE STAND, P.T.s OR
PHYSIATRIST TO SPEAK TO THIS
BETTER THAN I CAN, PEOPLE OFTEN
STAND ON ONE HIP MORE THAN THE
OTHER.
AND SO WE THINK IT MAY HAVE BEEN
ASSOCIATED WITH THAT.
THAT ALSO NEEDS FURTHER
EVALUATION.
>> I HAD A QUESTION, MYSELF,
JUST ABOUT THE PATIENTS THAT YOU
DID NOTE HAD MORE BOTHER FROM
THEIR PROLAPSE, THEIR URINARY
INCONTINENCE SYMPTOMS IF THEY
HAD THE MYOFASCIAL COMPONENT.
IN YOUR PRACTICE, MAYBE AN AREA
TO ASK, SHOULD WE BE ADDRESSING
THAT FOR EVERYBODY AND MAYBE
TRYING TO ADDRESS THAT PRIOR TO
ANY OTHER INTERVENTIONS FOR
OTHER PELVIC FLOOR DISORDERS?
>> WE DO AS PART OF STANDARD
INTAKE EXAM PRETTY MUCH ON
EVERYBODY THAT COMES THROUGH, WE
DO THAT EXAM AND WE REPORTED, WE
HAVE SUCH A LARGE NUMBER WHEN WE
DID OUR RETROSPECTIVE STUDY, WE
COULD LOOK AT.
WHAT I -- EVEN MORE WITH
PROLAPSE, I THINK WHEN PATIENTS
HAVE PRESSURE HEAVINESS, YOU SEE
POP Q IT'S NOT EVEN THROUGH THE
INTROITUS, I ENCOURAGE PATIENTS
TO TRY P.T. FIRST, TO ADDRESS
THAT MYOFASCIAL PAN IF THEY HAVE
IT CONCOMITANTLY.
A LOT OF TIMES PRESSURE GOES
AWAY, THEY DON'T NEED OR DESIRE
SURGERY BUT A LOT OF TIMES THEY
HAVE BEEN TOLD ON INITIAL
COMPASSION, OH, PRESSURE
HEAVINESS, A LITTLE BIT OF
CHANGE THAT IS VERY COMMON IN
WOMEN THAT HAD PREGNANCIES AND
DELIVERIES, THAT THEY HAVE
PROLAPSE, THEY CAN COME IN
SAYING, OH, I NEED SURGERY.
I'M A BIG FAN OF IT.
WHAT WE ALSO TYPICALLY DO IS,
THERE'S USUALLY A WAIT FOR
SURGERY, THAT ENCOURAGE THEM TO
DO THE P.T., DO THE ICING, AND
WE REASSESS AT FOLLOW-UP PRE-OP
VISIT.
IF SYMPTOMS RESOLVED, THEY MAY
NOT NEED SURGERY.
I DO ENCOURAGE INCORPORATING
THAT EXAM AS PART OF A STANDARD
INTAKE EXAM IN WOMEN WITH PELVIC
FLOOR DISORDER SYMPTOMS.
>> THANK YOU SO MUCH.
I'M GOING TO SOME QUESTIONS FOR
DR. DIAS.
>> THANK YOU.
>> IF YOU HAVE OTHER QUESTIONS
FOR DR. LOWDER PUT THEM IN THE
CHAT SO WE CAN BOTHER HIM AGAIN
LATER, NOT GIVE HIM FREE TIME.
THERE WAS A QUESTION THE STROKE
SPASTICITY HYPERTONICITY IS
DIFFERENT.
DO YOU ANTICIPATE BETTER UTILITY
OF THE DEVICE IN ONE GROUP OVER
ANOTHER AND COULD YOU PLEASE
EXPLAIN WHY?
>> SURE.
THE SIMPLE EXPLANATION, IF WE
CAN SHUT DOWN THE MUSCLE, TARGET
INNERVATION, WE'LL SEE SIMILAR
OUTCOMES IN BOTH.
THE MUSCLE IS SHORT SO YOU HAVE
TO FIND ANOTHER WAY TO TREAT IT.
I WOULD EXPECT SIMILAR OUTCOMES
FROM BOTH PATIENT GROUPS.
AS LONG AS WE CAN HIT THE
NEUROMUSCULAR JUNCTION WITH
BOTOX AND SHUT THE MUSCLE DOWN.
>> FANTASTIC.
AND I BELIEVE THIS WAS PROBABLY
THE NEXT QUESTION, DIRECTED
TOWARDS DR. EVANS SO WE CAN GO
THERE.
DOES ANYBODY ELSE HAVE ANY
QUESTIONS FOR DR. DIAS?
WE MAY COME BACK TO YOU.
I WANT TO MAKE SURE WE HAVE TIME
FOR EVERYBODY.
SOME MAY BE COMPLICATED AND TAKE
SOME TIME.
SO, DR. EVANS, IF WE COULD JUMP
TO YOU, THERE WAS A COMMENT
AGAIN TLR INNATE IMMUNE FAMILY
ARE QUITE INTERRELATED, REDONE
REDONANT IN FUNCTION.
ARE YOU LOOKING AT EFFECTING ONS
OTHER TOLL-LIKE RECEPTORS
BESIDES TLR 4.
>> TO VARYING DEGREES, YES.
WE'RE AWARE THERE TEN IN HUMANS,
THEY HAVE DIFFERENT ACTIVITIES.
AND SO WE'RE LOOKING AT A RANGE
OF TOLL-LIKE RECEPTORS BUT I
DON'T HAVE THINGS I CAN SHARE
WITH THAT AT THE MOMENT.
>> WAS THERE A COMMENT FROM
SOMEBODY?
I'LL GIVE THEM ANOTHER MINUTE.
IF NOT, SORT OF ON THE SAME
LINES OF THAT TLR 4 HAS MANY
FUNCTIONS, ACTUALLY CONNECTED TO
UTERINE DISORDERS SUCH AS
PRE-TERM LABOR, ANY SPECULATION
OF LOCAL DELIVERY FOR INHIBITORS
ON MYOMETRIAL OR PREEXISTING
DISORDERS ASIDE FROM EXPECTED
EFFECT ON PAIN?
>> THEY HAVE LOTS OF POTENTIAL,
AS YET UNDERDEVELOPED.
CERTAINLY THERE'S BEEN PAPERS
COMING OUT SUGGESTING THAT
EXCESS TLR 4 ACTIVATION
DISINCREASE PRE-TERM LABOR,
QUITE A BUSINESS FROM SARAH
ROBINSON, ROBINSON RESEARCH
INSTITUTE HERE.
I THINK - -- I DON'T THINK I CAN
SAY AT THE MOMENT BUT I THINK
THAT DR. HENDI IS THINKING WELL
IN THIS AREA.
>> AS HE USUALLY DOES.
I WOULD LIKE TO INVITE THE
PANELISTS IF THERE ARE NO MORE
QUESTIONS FROM THE AUDIENCE IN
THE CHAT.
I THINK THE TOPICS WERE A LITTLE
BIT OVER OUR HEADS.
MINE INCLUDED.
WE DO THANK YOU.
THESE ARE EXCELLENT
PRESENTATIONS.
AND ONE OF THE THINGS THAT WE
ARE HOPING TO ACCOMPLISH WITH
THIS IS GETTING THE DISCUSSION
GOING, AND TALKING AMONGST THE
DIFFERENT EXPERTISE TO SEE WHERE
THINGS CAN GO.
AND SO ONE OF THE QUESTIONS I
WOULD HAVE TO ALL OF OUR
PRESENTERS WOULD BE DO YOU HAVE
ANY THOUGHTS ON WHAT THE ISSUES
WITH HEALTH DISPARITY AND
DIVERSITY IN THE FIELD OF
GYNECOLOGIC PAIN RESEARCH ARE?
WITH RELATIONSHIP TO WHAT YOU'RE
DOING SPECIFICALLY.
>> CAN I TALK ON THAT ONE?
>> YES.
SINCE WE HAVE YOU UP.
>> MY OTHER HAT OF COURSE IS
RUNNING A PELVIC PAIN CENTER OF
AUSTRALIA, WE'VE ASKED
THROUGHOUT ALL THE STATES OF
AUSTRALIA NOW ON PAIN,
ENDOMETRIOSIS, PELVIC PAIN
PERIODS, AND I THINK WE HAVE TO
GET BACK TO THE EARLY STAGES OF
HOW ALL THIS STARTED.
AND WE HAVE TO GET AWAY FROM THE
SORT OF LINEAR CONCEPT WITH
THINGS THAT YOU HAVE A HEALTHY
CHILD, GETS A PERIOD, RETROGRADE
MENSTRUATION, DEVELOPS
ENDOMETRIOSIS LESION, GETS PAIN,
AS IF THEY ARE ALL CAUSAL AND
ALIGNED.
GIRLS SAY MY FIRST PERIOD WAS
DREADFUL, OR SOON THEREAFTER.
CENTRAL MECHANISMS, THEY START
YOUNG.
AND WE NEED TO START YOUNG AND
LOOK AT THE BIG PICTURE, NOT
JUST WHAT WE CAN SEE DOWN THE
LAPAROSCOPE IF WE'RE GOING TO
MAKE MAJOR CHANGE IN THIS AREA.
>> THAT'S AN EXCELLENT POINT.
THAT WAS BROUGHT UP IN OUR
PREVIOUS SESSION 2, TRYING TO
EXAMINE THIS PRIOR TO THE PAIN
EVEN STARTING, MAYBE LOOKING
YOUNGER.
DR. EVANS, COULD YOU GIVE US --
I WANTED TO ASK SINCE WE HAVE A
FEW MINUTES, CURIOUS ABOUT THIS
PROGRAM THAT YOU DO HAVE IN
AUSTRALIA, IF YOU COULD GIVE US
A BACKGROUND.
>> IT'S JUST FANTASTIC.
SO, I CO-WROTE THE PROGRAM
MYSELF.
I TRAIN ALL THE EDUCATORS.
SO WE HAVE GOVERNMENT FUNDING
TO -- WE'VE BEEN THREE YEARS IN
MY STATE HERE, TWO YEARS IN
ANOTHER ONE, WE GOT FUNDING TO
EXTEND TO EVERY STATE IN
AUSTRALIA.
SO WE HAVE TRAINED EDUCATORS WHO
TALK TO GIRLS ABOUT HOW THEY CAN
RECOGNIZE IF THEIR PAIN IS
NORMAL OR ABNORMAL.
WE DON'T WANT TO FEARMONGER
EVERYBODY, JUST WANT TO HELP
THEM WORK AT WHAT'S NORMAL,
WHAT'S NOT NORMAL, SIMPLE THINGS
THEY CAN DO THEMSELVES, HOW THE
OTHER SYMPTOMS FIT IN, THE BIG
PICTURE, AND WHEN THEY --
WHETHER THEY ARE SOMEONE WHO
SHOULD GO LOOKING FOR HELP
EARLY.
AND HOW TO DO THAT.
WE HAVE OUR PRE-PRESENTATIONS,
FOR THE ONES WHO HAVEN'T GOT
MUCH HEALTH LITERACY AND POST
PRESENTATIONS, IF YOU HAVE PAIN
WHAT TO DO NEXT.
WE ALSO ACTUALLY ARE BRINGING IN
OUR PROGRAM FOR -- MODIFIED
PROGRAM FOR BOYS TO HELP THEM BE
MORE COMFORTABLE UNDERSTANDING
AND TALKING ABOUT THESE ISSUES,
AND ALSO TEACHING THEM HOW TO
SUPPORT THE WOMEN IN THEIR LIFE
WITH PAIN.
SO IT'S GOING REALLY WELL.
IT'S CALLED THE PEP TALK
PROGRAM.
AND IT'S SO POPULAR.
100% OF SCHOOLS WANT US BACK.
>> FANTASTIC.
CONGRATULATIONS ON BEING ABLE TO
DEVELOP SUCH A GREAT PROGRAM.
>> THANK YOU.
>> AND INCORPORATING MEN.
>> YES, WE LOVE EVERYBODY.
>> IT'S ALWAYS A BRILLIANT
THING.
DR. DIAS, IN CLINICAL PRACTICE A
LOT OF PATIENTS GET BORED OF
TRAINING, MORE IMPORTANTLY
FORGET TRAINING, EVEN MAYBE
PROVIDERS WHO TALK ABOUT THAT
SORT OF TRAINING ALL DAY LONG
DON'T EVEN REMEMBER TO DO THEIR
OWN TRAINING.
DO YOU HAVE ANY WORDS OF WISDOM?
>> SURE.
SO I CAN SPEAK.
THERE'S BEEN SOME PUSH TO TRY TO
GAMIFY PELVIC FLOOR MUSCLE
THERAPY.
YOU'VE SEEN THE BIOFEEDBACK
DEVICES IN THE CLINIC NOW,
RIGHT?
IT'S A SCREEN THAT MAYBE SHOWS A
SIGNAL OR MAYBE A LIGHT THAT
YOUR MUSCLE IS ON, MAY NOT SHOW
A SIGNAL AND VAGINAL PROBE.
THERE'S BEEN SOME WORK TO TRY TO
GAMIFY THIS INTO A CELL PHONE
APP, DETAILED SIGNAL, GIVE
ACHIEVEMENTS AS YOU PROGRESS
THROUGH YOUR TREATMENT.
AND THEN TRY TO LOOP THE CLOUD
INTO IT AND LOOP THE CLINICIAN
IN WHO HELP TRACK THE TREATMENT.
THERE'S A LOT OF WAYS.
IT'S A HUGE ISSUE THOUGH, THESE
AT-HOME TREATMENTS, PATIENTS
FORGET TO DO THEIR TREATMENT OR
GET BORED.
JUST AS YOU SAID.
SO IF THERE'S SOME WAY BRINGING
ON THE CELL PHONE, GAMIFY IT,
GIVE BENCHMARKS AS THE PATIENT
MOVES ALONG.
>> REWARDS.
>> YEAH.
AND IT LOOPS BACK IN HOW DO WE
MAKE SURE WE'RE HITTING ALL OUR
POPULATIONS.
IF YOU PUT THE CELL PHONE APP,
MAYBE YOUR OLDER PATIENTS MAY
NOT BE AS GOOD WITH THE CELL
PHONE OR DOWNLOADING AN APP,
CONNECTING TO BLUETOOTH, RIGHT?
YOU HAVE TO MAKE SURE THE OLDER
ONES ARE TRAINED AS WELL.
>> WHAT IS THE SAFE TLR 4
INHIBITOR IN THE MARKET?
TO YOU, DR. EVANS.
>> THERE'S A LOT CURRENTLY
AVAILABLE.
THE POSTER ONE IS CALLED TAC2
42, A FEWER SELECTIVE TLR4,
INHIBITOR, TRIALS IN SEPSIS, AND
SO THE THING IS WITH ALL OF
THEM -- OH, THERE'S NUTRITIONAL
SUBSTANCES WITH SOME INHIBITOR
ACTION, FOR EXAMPLE CURCUMIN,
PALMITOL ETHANOLAMID, SOME ARE
ORAL MEDICATIONS THAT REDUCE
INFLAMMATION.
QUITE A FEW.
OURS IS VERY DIFFERENT BECAUSE
WE'RE DOING IT JUST IN THE
UTERUS, AND WE'RE NOT -- WITH
MINIMAL SYSTEMIC ANYTHING.
SO OURS IS WORKING ON THAT
UTERUS CNS CIRCUIT, WHEREAS IF
YOU THINK OF A LOT OF THINGS
THAT PEOPLE HEAR ABOUT THAT ARE
GOOD FOR THEM THEY SAY, OH, THIS
IS GOOD FOR ME, YOU'LL FIND IT'S
GOT AN ANTI-INFLAMMATORY EFFECT.
AND QUITE A BIT OF THAT IS
THROUGH TOLL-LIKE RECEPTORS.
>> COULD YOU ELABORATE WHAT THE
SIDE EFFECTS WOULD BE WHEN GIVEN
MORE SYSTEMIC ALLY?
>> IT DEPENDS ON THE DRUG, AND
THE COMPOUND.
I DON'T HAVE ALL OF THOSE HERE.
BUT I THINK QUITE -- THERE'S
SOME -- QUITE A FEW THINGS.
I DON'T THINK I CAN TODAY, TO
OUTLINE ALL THE SIDE EFFECTS AND
THINGS.
SOME DRUGS ORALLY DO HAVE THOSE
EFFECTS.
BUT NOT ALWAYS WELL TOLERATED BY
HUMANS WHEN USED ORALLY.
>> WE HAD ANOTHER QUESTION IN
THE LAST MINUTE.
I'LL DIRECT THIS TO ANY OF THE
PANELISTS, BUT MANY WOMEN WILL
RECEIVE ORAL CONTRACEPTIVES AS
FIRST LINE THERAPY FOR CHRONIC
PELVIC PAIN BEFORE SEEN MY
RESEARCH ORIENTED SPECIALIST
CLINICIANS.
HOW DOES PRIOR EXPOSURE TO ORAL
CONTRACEPTIVES IMPACT YOUR
ASSESSMENT OF PAIN?
>> YES, YOU'RE ASKING ME?
OR ANYBODY?
>> IT WAS A GENERAL QUESTION SO
I'LL PUT IT OUT TO ANYBODY WHO
IS WILLING TO ANSWER.
GO FOR IT, DR. EVANS.
>> I CAN THINK OF ONE MAJOR
THING THAT'S OFTEN OVERLOOKED.
I PRESENTED THIS AT THE WORLD
ENDOCONGRESS IN 2021, I THINK
ONE OF THE THINGS THE PILL DOES,
IT'S GOT UNDOUBTED BENEFITS BY
REDUCING MENSTRUATION, BLOOD
LOSS, BUT ALSO DRAMATICALLY
REDUCES ANDROGENS, INCREASES SEX
HORMONE BINDING GLOBULIN.
YOU PUT SOMEONE ON THE PILL
YOU'RE DRAMATICALLY REDUCING HER
ANDROGEN EFFECT, THE LOWER THAT,
THE MORE DAYS OF PELVIC PAIN.
TWO-EDGED THING.
THERE'S BENEFITS TO THE PILL AND
THERE'S DOWN SIDES TO THE PILL.
AND THIS IS ANOTHER REASON WHY
IF WE CAN DO OUR BEST AS
CLINICIANS TO SOMETIMES MOVE
MORE TO THE INTRAUTERINE DEVICE
AND ALLOW NATURAL CYCLES WE'RE
AT LEAST REDUCING ONE FACTOR
THAT DIMINISHES ANDROGENS, SO
ANDROGENS AND PELVIC PAIN IS MY
OTHER INTEREST IN RESEARCH.
>> THANK YOU VERY MUCH.
THANK YOU SO MUCH TO THE THREE
SPEAKERS.
GO AHEAD.
>> I WOULD JUMP IN AND SAY
THOUGH, I THINK IT'S PRETTY
COMPLEX ISSUE.
WE KNOW THAT MANY OF THESE
GYNECOLOGIC PAIN CONDITIONS LIKE
ENDOMETRIOSIS AND ADENOMYOSIS
ARE ESTROGEN DRIVEN AND ESTROGEN
DRIVES INFLAMMATION AS WELL AS
SOME OTHER PATHWAYS, AND
ESTRADIOL SUPPRESSION IS
CURRENTLY THE ONLY ONE APPROVED,
TO REDUCE ESTRADIOL BEFORE THEY
GET A DIAGNOSIS OF ENDOMETRIOSIS
AND WE DON'T KNOW ENOUGH YET
ABOUT ITS EFFECTS ON
TESTOSTERONE TO REALLY HELP US
GUIDE WHICH LIKE AMONGST THE
MANY DIFFERENT TYPES OF HORMONE
SUPPRESSION, WHAT THOSE EFFECTS
WOULD BE.
AND SO IT VARIES.
IT PROBABLY IS JUST UNCLEAR AND
I THINK THIS IS WHY THIS TYPE OF
DETAILED PHENOTYPING IS GOING TO
BE CRITICAL.
I WAS ACTUALLY JUST LOOKING UP A
REFERENCE FOR THIS, IN A BIG
HEALTH CLAIMS DATA ANALYSIS.
ANYWHERE BETWEEN 42 AND 60% OF
WOMEN ARE USING SOME METHOD OF
ESTROGEN PROGESTIN, IT GOES UP
AFTERWARDS, IT IS EFFECTIVE, I
DON'T WANT PEOPLE TO WALK AWAY
THINKING THAT WE SHOULD BE
TAKING AWAY HORMONE SUPPRESSION
AND FOR SPECIFIC TYPES OF
PATIENTS SOMETHING LIKE
PROGESTIN OR IUD-BASED TREATMENT
WILL ACTUALLY NOT BE E
EFFECTIVE.
WHERE OVULATION IS A BIG PART OF
THE PATHOPHYSIOLOGY, WE KNOW WE
DON'T GET ADEQUATE OVULATION
SUPPRESSION, WITH IUDs, SO WE
NEED TO THINK ABOUT IT IN A
MORE -- A NUANCED FASHION.
>> THANK YOU SO MUCH.
I'M GOING TO TURN THE PROJECTION
BACK TO DR. TING AND DR. AHN FOR
OUR FINAL DISCUSSION.
>> THANK YOU VERY MUCH FOR
MODERATING THIS SESSION 2.
I WILL MODERATE THE DISCUSSION
SESSION.
DR. TING, COULD YOU BRIEFLY
INTRODUCE YOURSELF?
>> OF COURSE, YES.
I KNOW A LOT OF PEOPLE ON THE
CALL FROM OVERSEEING THE
PORTFOLIO IN THE PAST.
I'M A PROGRAM OFFICER IN THE
GYNECOLOGIC DISEASE BRANCH, FOR
ABOUT SEVEN YEARS NOW.
HAVE OVERSEEN THIS, WE'RE SO
HAPPY TO HAVE A NEUROSCIENTIST
SPECIALIST AMONG US NOW THAT CAN
SPEAK TO THESE ISSUES.
>> TODAY DR. LISA HALVORSON
JOINS US, FORMER BRANCH CHIEF,
NOW SENIOR MEDICAL DIRECTOR.
WELCOME.
>> THANK YOU.
I'M HONORED TO BE ASKED TO SAY
HELLO TO THIS GROUP.
MANY FACES THAT ARE FAMILIAR TO
ME, IT'S TERRIFIC TO BE ABLE TO
SEE THIS MEETING COME TO
FRUITION.
I HAD THE HONOR OF BEING CHIEF
BRANCH FOR MANY YEARS, I WILL
USE THIS AS A PLUG TO TELL ANY
OF YOU OUT THERE IF YOU HAVE ANY
THOUGHTS OF WAYS IN WHICH PHARMA
COULD BE OF USE TO YOU, EITHER
IN THE THERAPEUTIC OR DIAGNOSTIC
SPACES, ALWAYS FEEL FREE TO
REACH OUT TO ME.
LISA.HALVORON@BAYER.COM OR TRACK
ME DOWN THROUGH THE BRANCH
MEMBERS.
I WANT TO SAY WE'VE TALKED ABOUT
WANTING TO HAVE A MEETING LIKE
THIS FOR A NUMBER OF YEARS,
BETWEEN COVID AND NOT HAVING THE
CORRECT PROGRAM OFFICER IT
WASN'T THE TIME TO DO IT.
I'M THRILLED TO SEE THIS COME TO
FRUITION, TERRIFIC, TERRIFIC
TALKS TODAY.
ONE OF THE ADVANTAGES OF
DELAYING IS THE FIELD HAS MADE A
REMARKABLE AMOUNT OF PROGRESS
WE'RE ABLE TO SEE PRESENTED TO
US.
CONGRATS TO THE INVESTIGATORS
AND PRESENTERS AND GHDB FOR
PULLING THIS TOGETHER, I TAKE
PRIDE EVEN THOUGH I HAD NOTHING
TO DO WITH IT COMING TOGETHER.
THANKS AGAIN.
>> VERY HAPPY TO SEE YOU AGAIN,
DR. HALVORSON.
CAN YOU PUT YOUR CONTACT
INFORMATION IN THE CHAT?
SO THERE ARE MANY QUESTIONS WE
HAVE NOT ADDRESSED DURING THE
MEETING.
IF YOU HAVE ANY QUESTIONS, YOU
WOULD LIKE TO ASK NOW, PLEASE
RAISE YOUR HAND SO YOU CAN
SPEAK.
OR COPY AND PASTE YOUR QUESTION
ON THE CHAT SO THAT WE CAN SEE
THEM EASILY.
>> I CAN MAKE A MODERATOR'S
PERSPECTIVE TO ASK A QUESTION?
>> SURE.
>> I WILL.
THIS QUESTION IS FOR DAN, SUSIE,
MAYBE FRANK, ANDREA TALKED ABOUT
THIS TOO.
THIS IDEA THAT THESE PHENOTYPES,
DIFFERENT PHENOTYPES BETWEEN
PERIPHERAL PAIN AND NOCIPLASTIC
PAIN, MAYBE INTERMEDIATE
PHENOTYPE FOR ENDO, AND THE FACT
WE NEED TO DISAGGREGATE BEFORE
THE STUDIES.
HOW DO WE PROPOSE THAT WE DO
THIS IN STANDARDIZED WAY?
DO WE NEED TO BE BEFORE WE EVEN
START HAVE fMRI OR ARE THERE
CERTAIN INCLUSION/EXCLUSION
CRITERIA APPLIED, A PAIN
QUESTIONNAIRE, SOME VERSION TO
HELP US SCREEN?
I DON'T SEE THAT DONE IN OUR
PROPOSALS.
REVIEWERS ARE CRITICAL ABOUT
INVESTIGATING HETEROGENEITY OF
ENDOMETRIOSIS IN THE SENSE OF
LESION TYPE, NOT NECESSARILY
PAIN PHENOTYPES WHICH SEEMS TO
BE PROBLEMATICALLY STILL
AGGREGATED.
ANY FEEDBACK HERE ABOUT AN
OBJECTIVE STANDARDIZED WAY TO
ADDRESS THAT?
>> I'LL TAKE A CRACK.
I THINK STARTING IN THE MAP
NETWORK WE SPEND A LOT OF TIME
IN THE DIFFERENT DOMAINS HOW TO
STANDARDIZE PHENOTYPING, THERE
WAS NO INCENTIVE FOR GROUPS TO
STANDARDIZE ACROSS SITES LIKE
QUANTITATIVE SENSORY TESTING OR
THINGS LIKE THAT.
THE NETWORK STARTING WITH THE
MAPP, NOW ALL THE NETWORKS THAT
US AND OTHERS ARE INVOLVED IN
HAVE REALLY LED TO A LOT OF
MATURITY IN A STANDARDIZED SET
OF PHENOTYPING TOOLS THAT LOOK
VERY SIMILAR, FOR EXAMPLE, WE'RE
A SITE IN THE ACUTE TO CHRONIC
PAIN NETWORK, AS WELL AS BACPAC
NETWORK, AND PROs WE'RE
GIVING, FUNCTIONAL IMAGING
PARADIGMS, QSD BATTERIES, REALLY
QUITE SIMILAR ACROSS THOSE
NETWORKS BECAUSE THERE'S BEEN A
BIG ATTEMPT TO HARMONIZE AS WELL
SO WE CAN LOOK AT OUR DATA AND
SAY, WELL, HOW DOES THIS
CONNECTIVITY DATA LOOK COMPARED
TO THE U.K. BIOBANK THAT HAS
IMAGES ON A COUPLE HUNDRED
THOUSAND PEOPLE.
SO JUST AS A PART OF -- AND
THERE'S ALSO THE EXERCISE IN THE
NIH THAT'S TRIED TO STANDARDIZE
PHENOTYPING NOW GOING INTO THE
PAIN SPACE.
IF PEOPLE JUST LOOK AT SOME OF
THE NETWORKS, "HEAL" NETWORKS,
WHAT IS BEING DONE THERE, THAT
REALLY PRETTY MUCH IS THE GOLD
STANDARD, YOU CAN DO A LOT WITH
PROs ALONE, YOU KNOW, AND A
BODY MAP.
PLEASE, EVERY STUDY THAT HAS A
CHRONIC PAIN PATIENT IN IT
THAT'S EVER FUNDED BY THE NIH,
IT SHOULD BE NEW RULE, IF I
COULD MAKE IT.
YOU HAVE TO PUT A BODY MAP IN.
THIS IS RIDICULOUS.
YOU LEARN SO MUCH FROM A BODY
MAP AS FAR AS WHAT SORT OF
SUBSET -- THERE'S A LOT MORE BUT
I'M SAYING START THERE AND MOVE
OUTWARD FROM SIMPLE THINGS THAT
MAKE A BIG DIFFERENCE IN
PHENOTYPING.
>> OKAY.
THAT'S PERFECT.
IMPLEMENTAL SUGGESTION.
>> I WANT TO JUMP IN.
I'D LIKE TO ECHO WHAT DAN WAS
SAYING IN TERMS IRRESPECTIVE OF
THE PAIN CONDITION, I WAS
WORKING IN TMD, WE SEE THESE
INDIVIDUALS WITH OVERLAPPING
PAINS ARE MORE LIKE ONE ANOTHER,
WHETHER INDEX CONDITION IS
ENDOMETRIOSIS OR TMD OR
VULVODYNIA.
AND ONE OF THE DIFFICULTIES IS
THEN THAT PHENOTYPING HAS BEEN
ORGAN CENTRIC AND WE HAVEN'T
REALLY DEVELOPED QST PROTOCOLS
THAT ARE SIMILAR IN DIFFERENT
RESEARCH ARENAS.
I THINK DEVELOPMENT OF THESE
PROTOCOLS TO CAPTURE MAYBE
GLOBAL PAIN AND STARTING WITH
THIS BODY MAP ARE REALLY
IMPERATIVE.
FOR CLINICAL TRIALS IT'S
ONGOING.
WE BEGIN WITH BODY MAP, TO
EVALUATE ALL OF THE PAINFUL
AREAS, AS WELL.
AND WE'VE DEVELOPED TOOLS,
STUDIES ARE ELECTRONIC AND ALL
OF OUR SURVEYS INCLUDING THE
BODY MAP ARE ELECTRONIC AND
DEVELOPED THROUGH REDCap.
THOSE SHOULD BE AVAILABLE TO
ANYONE ELSE THROUGH REDCap AS
WELL.
I THINK IT'S IMPORTANT THAT WE
SHARE RESOURCES.
THAT HAVE BEEN DEVELOPED.
AND WHAT ARE TO STREAMLINE
CURRENT AND FUTURE STUDIES.
>> ONE OTHER PLUG, LINDA PORTER
AS PART OF THE PAIN CONSORTIUM
HAD BILL AND DAVE DEVELOP COPC
SCREENER, THE LATE BILL MAIXNER
UNFORTUNATELY, SHOULD BE
AVAILABLE IN THE NEXT THREE TO
SIX DAYS, DAVE IS COMPLETING
THAT PROJECT.
LINDA PUT OUT A NOSI, HIGHLY
RECOMMENDING AND SUGGESTING THAT
PEOPLE INCORPORATE THAT INTO
STUDIES, ANOTHER PHENOTYPING
TOOL THAT'S USED.
AGAIN, BECAUSE ALL THE DIFFERENT
CATEGORICAL INSTITUTES FUND WORK
ON LIKE ONE LITTLE ORGAN.
>> RIGHT.
>> IF WE ALL SAID, OKAY, NIAMS,
IF YOU FIND FIBROMYALGIA
RESEARCH MAKE SURE EVERY
PARTICIPANT FILLED OUT COPC
SCREENER TO SEE WHAT SUBSET
MEETS CRITERIA FOR IRRITABLE
BOWEL, WHATEVER, WE'D LEARN MORE
ABOUT THAT.
SO THAT'S ANOTHER TOOL THAT I
THINK WILL BE COMING OUT SOON
THAT MOST I THINK CONTEMPORARY
PAIN RESEARCHERS WILL USE, IT
DOES START WITH BODY MAP AND
GIVERS PEOPLE ITEMS, FOR
EXAMPLE, FOR IRRITABLE BOWEL IF
THEY HAVE PAIN IN THE ABDOMEN,
DOES IT IN A FAIRLY RAPID WAY
WITH LOW PARTICIPANT BURDEN
USING SMART LOGIC IN THE
BACKGROUND.
>> OKAY, FANTASTIC.
SUSIE, DID YOU HAVE ANYTHING
EXTRA TO ADD?
>> NO, GREAT SUMMARY.
WE'RE JUST A BIT BEHIND IN THE
GYNECOLOGIC AND ENDOMETRIOSIS
WORLD, IT'S JUST TAKEN LONGER TO
MOVE AWAY FROM FOCUSING ON THE
LESION TO THE ENTIRE PATIENT
OVERALL.
>> RIGHT.
>> JUST KEEP PUSHING THIS
KNOWLEDGE AND AGENDA WILL BE
VERY HELPFUL.
>> FANTASTIC.
THANK YOU.
THAT WAS A REALLY GREAT
DISCUSSION OF THAT.
HELENA IS THE PERSON TO
INSTITUTE THAT RULE FOR NICHD
FUNDING.
THAT'S A GOOD PERSON TO HAVE THE
ERO.
THERE ARE A FEW QUESTIONS.
>> KATIE, WOULD YOU LIKE TO
SPEAK?
WOULD YOU LIKE TO -- WOULD YOU
LIKE TO ASK YOUR QUESTION?
>> YOU MAY WANT TO JUST READ IT.
>> I HAVE A BOLD QUESTION ABOUT
MENSTRUAL PAIN.
TO WHAT EXTENT DO WE EXPECT
ADDRESSING MECHANICAL MECHANISMS
IN THE UTERUS TO REDUCE PAIN?
DOES THIS REDUCE THE PAIN RELIEF
(INDISCERNIBLE) FROM TREATMENTS?
>> THIS IS FOR ANYONE WHO WANTS
TO ANSWER IT.
TALKING ABOUT CONTRACTALITY.
>> IT WOULD BE LIKELY THAT THEY
HAVEN'T DONE LARGE SCALE
STUDIES, CLINICAL EXPERIENCE IS
PATIENTS WHO HAVE MULTIPLE
COPCs ARE NOT GOING TO RESPOND
AS WELL TO NSAIDs AS DAN
ALLUDED TO IN ARTHRITIS, FOR
EXAMPLE.
IT WORKS IN 85% OF PATIENTS
PRETTY WELL.
THAT WAS ONE OF THE DRAMATIC
BREAKTHROUGHS IN THE '80s.
THE PRIOR MECHANISMS,
CONTRACTILITY AND INFLAMMATION.
IT GOES BACK TO SAYING THAT ANY
CHANGE EARLY SCREENING FOR
INDIVIDUALS WITH MULTIPLE
DIAGNOSES WIDESPREAD POSITIVE
SYMPTOMS SOMETHING MAY NOT WORK
THAT WELL, WHETHER FOR JOINT
PAIN OR PERIOD PAIN.
POSTOPERATIVE, WE TRY TO FOCUS
ON THAT AREA.
>> THERE'S ANOTHER QUESTION IN
THE CHAT, DO THE PANELISTS THINK
THERE'S AN MSKCPP PHENOTYPE
DEFINED NOT JUST BODY MAP PAIN
LOCATION BUT MOVEMENT INDUCED
PAIN, IS IT JUST THAT C OR IS
THAT JUST THE CPP REGIONAL
INTERMEDIATE PHENOTYPE?
>> I THINK THAT'S A GREAT
QUESTION.
I DON'T KNOW THAT WE KNOW.
I MEAN, IF YOU ASK ME
CLINICALLY, I WOULD TEND TO
THINK ABOUT MOVEMENT INDUCED
PAIN AS BEING MORE PERIPHERAL
VERSUS THOSE THAT HAVE
SPONTANEOUS PAIN, BEING MOVING
MORE ON THE NOCIPLASTIC AND
SOMETHING THAT DR. NACKLEY
PRESENTED MADE ME THINK ABOUT
THAT A LITTLE BIT MORE IN TERMS
OF THE PHENOTYPES OF PATIENTS
WITH PROMOTE VESTIBULEDYNIA, I'D
BE INTERESTED IN WHAT OTHER
PEOPLE THINK AS WELL.
>> I FEEL LIKE THE MOVEMENT PAIN
PATIENTS TEND TO RESPOND TO P.T.
A BIT BETTER THAN THOSE THAT
HAVE WIDESPREAD SPONTANEOUS PAIN
WITHOUT MOVEMENT.
>> THAT'S BEEN LOOKED AT IN
OSTEOARTHRITIS, THOUGHT THE
MOVEMENT INDUCED PAIN IS REALLY
A QUITE DIFFERENT MECHANISM THAN
THE SPONTANEOUS PAIN, AND AGAIN
IT IS MORE NOCICEPTIVE TYPICALLY
THAN MOVEMENT INDUCED PAIN.
>> I GUESS I WAS ASKING, IF WE
COULD PHENOTYPE THIS GROUP A
LITTLE BIT MORE, YOU KNOW,
MOVEMENT-BASED POPULATION, WE
MIGHT BE ABLE TO REALLY LOOK AT
THE PHYSICAL THERAPY RESULTS
MORE CLEARLY.
THAT'S WHY I ASKED.
SO THANK YOU.
>> THERE ARE SHADES OF GRAY,
IT'S NOT NECESSARILY THAT
THERE'S ONE TREATMENT FOR ONE
SUBTYPE BUT PROBABLY DIFFERENT
COMBINATIONS OF TREATMENT MAY BE
IMPORTANT, WE NEED TO GET PAST
THE TRIAL AND ERROR APPROACH
WHERE WE START WITH THE LEAST
INVASIVE AND JUST SLOWLY
PROGRESS TO MORE INVASIVE
TREATMENTS, AND REALLY NEED TO
INDIVIDUALIZE TREATMENT
APPROACHES, MAY NOT BE ONE SIZE
FITS ALL.
>> TO FOLLOW UP REALLY WELL ON
THAT POINT ABOUT WHEN TO WE USE
CERTAIN TREATMENTS, ONE QUESTION
FROM THE CHAT AND I WANT HELENA
TO ASK A QUESTION, ABOUT HEALTH
DISPARITIES THAT WE HAVEN'T
COVERED YET.
THIS IS FOR YOU, DR. TU, BUT
OTHERS CAN CHIP IN.
WHEN SHOULD WE THINK ABOUT USING
YOUR SOPHISTICATED CONTRACTILITY
METHODS, ONLY AFTER THEY FAIL
OTPs?
>> I APPRECIATE THE QUESTION.
DR. HELMAN HAS A ROBUST LINE OF
WORK TRYING TO DO ASSESSMENT OF
UTERINE ACTIVITY AND UTERINE
PHYSIOLOGY.
THIS IS WHAT HE'S REFERRING TO.
THAT GRANT, BASED ON A COUPLE
SMALLER PRELIMINARY STUDIES, IS
STILL EARLY, RECRUITING WAS
HAMSTRUNG BY COVID.
IT WILL BE A FEW YEARS BEFORE WE
CAN USE IT TO SUBTYPE
INDIVIDUALS.
IT'S A GREAT QUESTION
CLINICALLY.
WE HAD ONE RECENTLY, MASSIVE
WORKUP, CITY OF CHICAGO, PAIN
PROVOKED WITH ATHLETIC ACTIVITY
AND ORGASM, NEGATIVE WORKUP, THE
ONLY THING WE COULD THINK ABOUT
IS LOOK AT SOME SORT OF EQUATION
TO MODEL WHAT THEY ARE UTERINE
ACTIVITY IS THERE WOULD BE A
SIGNAL THAT MIGHT ALLOW US TO
ARGUE SHE HAS A DIFFERENCE, ALL
THE OTHER STRUCTURAL EVALUATION,
THE FACT THAT SHE'S PAIN FREE AT
REST DOESN'T SEEM TO HELP US
MUCH.
I THINK IN THE MEANTIME WE OF
COURSE DO WHAT HE SAID, TRY TO
SUPPRESS TO AVOID HORMONAL
CYCLING.
I WENT BACK TO EARLY LITERATURE
IN ADVANCE OF THE TALK, WE
UNDERUTILIZE DRUGS IN THE '80s
AND '90s FOR PERIOD PAIN,
MUSCLE RELAXANTS, INTERESTING
ENOUGH DAN HAS SAID SOME
NEUROMODULATORS WORK BADLY FOR
NOCICEPTIVE PAIN, SOME ARE NOT
NOCICEPTIVE, JUST LIKE LIKE THEY
ARE, WHEN YOU'RE FACED WITH AN
ACTUAL PATIENT WITH DEPUTY
OPERATION, OFF LABEL
NEUROMODULATORS FAMILIAR WITH
USING IN CHRONIC PAIN, OR AS DR.
EVANS POINTED OUT SOMETHING LIKE
PEA, A SMALL BIT OF DATA ON IT,
FOR ENDOMETRIOSIS, THE IMPORTANT
IS TO BE HONEST, I'LL WILLING TO
TRY THINGS TO MODULATE INSTEAD
OF SAYING, WELL, YOU JUST HAVE
TO LIVE WITH IT OR TAKE MORE
NSAIDs.
WE HAVE TO BE ON THE LOOKOUT FOR
BETTER OPTIONS.
>> HELENA, DO YOU WANT TO ASK
YOUR QUESTION?
>> YES.
THANK YOU.
WE'RE WONDERING, WHAT ARE THE
ISSUES WITH HEALTH DISPARITIES
IN THE GYNECOLOGIC PAIN
RESEARCH, HOW CAN WE ADVANCE
HEALTH EQUITY AND DIVERSITY?
THIS IS THE QUESTION FOR ALL THE
SPEAKERS.
>> I'LL TAKE A CRACK AT THIS.
YOU'RE PROBABLY AWARE OUR GROUP
HAS GOTTEN A LOT OF NIH FUNDINGS
UNTIL RECENTLY, DIDN'T TAKE
SERIOUSLY HAVING TO PUT MORE
TIME AND EFFORT, SPECIFICALLY,
INTO RECRUITING AND COMMUNITIES
OF COLOR.
AND BECAUSE THE NIH MADE
SUPPLEMENTS RECENTLY AVAILABLE
FOR SOME OF OUR GRANTS LIKE OUR
"HEAL" GRANTS, WE HAVE SORT OF
PERMANENTLY CHANGED THE WAY WE
DO BUSINESS WHETHER WE WILL HAVE
RESEARCH COORDINATORS IN
COMMUNITIES OF COLOR THAT ARE
AROUND US AND THAT WE WILL
FOREVER MORE BE RECRUITING
ADEQUATE NUMBERS OF PARTICIPANTS
FROM THOSE COMMUNITIES INTO OUR
STUDIES BUT I THINK MOST OF US
HAVE HISTORICALLY NOT TAKEN THIS
AS SERIOUSLY AS WE SHOULD HAVE.
TO BE FAIR, IT TAKES A LOT OF
MONEY AND EFFORT, PEOPLE THAT
ARE ACTUALLY TRAINED IN
COMMUNITY BASED PARTICIPATORY
RESEARCH TO DO THIS RIGHT AND
WELL.
WE HIRED A FACULTY MEMBER
FABULOUS WITH TRAINING IN THAT,
BUT PEOPLE THAT --
WELL-INTENTIONED RESEARCHERS CAN
CAUSE A MESS, RIGHT INTENTIONED,
DOING THE WRONG THINGS.
I'M HAPPY THE NIH HAS MADE SOME
SUPPLEMENTS AVAILABLE AND THAT
THEY SEEM TO BE TAKING THIS
SERIOUS, IT WILL ALLOW ALL OF US
INTO OUR FUTURE STUDIES TO HAVE
ADEQUATE PARTICIPATION FROM
PEOPLE IN COMMUNITIES OF COLOR.
THERE'S STARK DISPARITIES.
THERE'S GOT TO BE IN PELVIC
PAIN, THERE IS IN ALL PAIN
CONDITIONS, THERE ARE IN ALL
MEDICAL CONDITIONS.
I WANT TO SAY AGAIN I'M GLAD THE
NIH IS TAKING IT SERIOUSLY AND
SO ARE GROUPS OF INVESTIGATORS.
>> I WOULD ECHO DAN'S COMMENTS
ABOUT -- THERE'S THE UNIVERSITY
OF MICHIGAN TEAM THAT ARE
WRITTEN A NICE ARTICLE HOW TO
INTERFACE WITH COMMUNITIES THAT
WERE UNDERREPRESENTED.
THE PAPER IS QUITE A FEW YEARS
OLD BUT A RESEARCHER IN
PSYCHOLOGY FOUND IT, THEY HAVE A
NICE TABLE.
I CAN SHARE THE LINK, THIS IS
HOW YOU DO ENGAGED RESEARCH.
IT'S QUITE CHALLENGING.
YOU DON'T JUST DABBLE IN IT.
IT COMES TO THINGS LIKE YOU GO
TO THE COMMUNITIES AND YOU
BECOME PART OF THE PROCESS.
YOU VOLUNTEER AT THE FESTIVALS.
YOU ATTEND THE RELIGIOUS
SERVICES.
YOU IT AND FIND OPPORTUNITIES
FOR JOB TRAINING THAT ARE NOT
JUST SO YOU CAN MAKE YOUR TEAM
MORE ABLE TO DO IT BUT BECAUSE
YOU BELIEVE IN IT, IT SOUNDS
LIKE FROM WHAT I READ FROM THESE
SEASONED RESEARCHERS AT
MICHIGAN, IT'S A MULTI-YEAR
PROCESS, POSSIBLY
MULTI-GENERATIONAL PROCESS.
OUR OWN EXPERIENCES VERY NAIVELY
WE GOT MINORITY SUPPLEMENT
FUNDING IN THE PAST, VERY
HELPFUL, BUT TAUGHT US THAT IT
DOESN'T STOP WITH ONE HIRE.
YOU HAVE TO LOOK AT MIDDLE
SCHOOL CHILDREN WHO WANT GET
INTERESTED IN SCIENCE, EMBED
PROCESSES IN TEN YEARS AHEAD OF
TIME OR LONGER.
IT'S HARD TO GET THE LONG-TERM
VISION IF YOU DON'T HAVE
SUSTAINED INPUT OR FINANCES FROM
PARTICIPANTS AND FUND
ORGANIZERS.
YOU WON'T SEE ANSWERS UNTIL YOU
SEE IT ACROSS THE SPECTRUM IN
SCIENTIFIC INQUIRY AND TRAINING.
>> ALSO, DR. HINDY BROUGHT UP A
GREAT POINT FROM PATIENT
PERSPECTIVE THERE'S ALMOST
CERTAINLY BIAS IN DIAGNOSIS OF
CHRONIC PAIN CONDITIONS
ACCORDING TO RACE.
CERTAINLY AS WELL DOCUMENTED IN
ENDOMETRIOSIS, THE VERY FIRST
TIME THAT IT WAS DESCRIBED IN
THE LITERATURE WAS BY A
GYNECOLOGIST WHO SPECIFICALLY
SAID IN HIS ORIGINAL ARTICLE
THAT ENDOMETRIOSIS WAS A DISEASE
IN WOMEN OF -- OF WHITE WOMEN IN
HIGHER BRACKETS AND THAT IDEA
HAS BEEN PROPAGATED IN DIAGNOSIS
ANT ATTRIBUTION SINCE THEN.
THERE ISN'T MUCH EPIDEMIOLOGIC
DATA.
THERE'S A NICE PAPER OUT OF YOU
CANADA WITH DR. BOOUGIE, BLACK
WOMEN AND HISPANIC WOMEN WERE
HALF AS LIKELY TO BE DIAGNOSED
WITH ENDOMETRIOSIS COMPARED TO
CAUCASIAN WOMEN AND ASIAN WOMEN,
ALMOST 50% MORE LIKELY TO BE
DIAGNOSED.
PARTICULARLY WITH ENDOMETRIOSIS,
UNTIL MORE RECENTLY REQUIRES A
SURGICAL DIAGNOSIS, WE CANNOT
SEPARATE THAT FROM ISSUES OF
ACCESS TO CARE, ACCESS TO
SURGEONS, AND WE HAVE TREMENDOUS
HEALTH CARE DISPARITIES
PARTICULARLY IN THE U.S. WHETHER
WE DON'T HAVE GOVERNMENT FUNDED
INSURANCE AND SO PATIENTS JUST
DON'T HAVE ACCESS TO THE RIGHT
CARE.
IF THEY DON'T HAVE ACCESS
DOCTORS ARE NOT THINKING ABOUT
IT, THEY CONSIDER IT TO BE A
CONDITION OF WHITE WOMEN.
AS WELL AS THERE ALSO MIGHT BE
DIFFERENCE IN NORMALIZATION AND
STIGMATIZATION OF PAIN THAT VARY
ACROSS RACES, I THINK, WE HAVE A
LOT OF WORK TO BE DONE HERE.
>> YEAH, THANK YOU, SUSIE.
IT'S A STRONG POINT.
FROM THE FIBROID THERE IS
RESEARCH BEING DONE, WHEN PAIN
IS THE PRIMARY COMPLAINT THAT
THERE ARE DIFFERENCES IN
REFERRALS AND/OR TREATMENT
RECOMMENDED BASED ON RACE.
I THINK THAT IS CERTAINLY
SOMETHING TO THINK ABOUT.
HELENA, YOU HAVE A FEW MINUTES
LOAFORT.
I DON'T KNOW IF YOU WANT TO GET
INTO ANOTHER QUESTION OR OPEN IT
UP TO THE ROOM.
YOUR COVID QUESTION MIGHT BE
LENGTHY.
>> SO OUR NEXT QUESTION IS WHAT
IS THE EFFECT OF THE COVID
PANDEMIC ON GYNECOLOGY RESEARCH
AND TREATMENT?
>> WE KNOW IT HAS AFFECTED
RECRUITMENT IN STUDIES.
ARE WE SEEING DIFFERENCES IN
PAIN REPORTING, IN SOME OF THESE
QUESTIONS?
ANDREA, YOU UNMUTED.
>> I THINK WE ALL KNOW
DEVASTATING CONSEQUENCES OF
COVID-19, ON RECRUITMENT.
SO I THOUGHT I WOULD JUST PUT A
POSITIVE SPIN ON IT AND SAY
THAT, YOU KNOW, IN LIEU OF
COVID-19, WE DID DEVELOP SOME --
WE MOVED TOWARDS TELEVISITS FOR
FOLLOW-UP VISITS FOR
PARTICIPANTS ALREADY ENROLLED
AND ON MEDICATION.
THEY WERE PERMITTED TO COME BACK
FOR THE FOLLOW-UP VISITS, BUT I
DON'T THINK ANYONE CAME BACK
DURING THAT LOCKDOWN TIME.
YOU KNOW, FOR AN IN-PERSON
VISIT.
WE WERE ABLE TO KIND OF PIVOT
AND ADAPT OUR SURVEY FOR
ELECTRONIC, WE WERE ABLE TO GIVE
THOSE KIND OF LIKE A TELEVISIT
AND COMPUTER-BASED VISIT.
AND THEN WE WORKED WITH
PHARMACIES AND RESEARCH TEAM TO
MAIL OUT LIKE THE PREGNANCY
TEST, TAMPON TEST, THINGS LIKE
THAT.
WE DID EVERYTHING EXCEPT FOR
COLLECT BIOLOGIC SAMPLES.
AND SO ONCE THE STUDY
PARTICIPANTS RETURNED, IN-PERSON
VISITS, IF SOMEONE MOVED AWAY OR
SOMETHING LIKE THAT CAME UP, WE
WERE PREPARED TO HANDLE THAT
SITUATION WITH THIS COMBINATION
TELECOMPUTER VISIT.
IF ANYTHING, IT DID PROMOTE US
TO BE A LITTLE BIT MORE FLEXIBLE
AND HAVE MORE OPTIONS WITH STUDY
PARTICIPANTS.
BUT, YEAH, THAT WAS ONE SILVER
LINING THAT WE FOUND.
>> IT'S MADE CLINICAL RESEARCH
MORE EFFECTIVE IN A DISRUPTIVE
WAY, THAT WOULDN'T HAVE
OTHERWISE HAPPENED, PARTICIPANT
BURDEN IS WAY DOWN,
INTERVENTIONS WE DIDN'T THINK
COULD BE DELIVERED REMOTELY ARE
BEING DELIVERED.
LOOK WHAT HAPPENED TO CLINICAL
CARE, HOW MANY VISITS FLIPPED
OVER.
THERE'S A LOT OF REALLY GOOD
THINGS THAT HAPPENED TO CLINICAL
RESEARCH ENTERPRISE WITH RESPECT
TO TOTALLY RETHINKING HOW WE DO
THINGS.
I HAD GIVE A TALK FOR ISP,
PEOPLE THAT GET HURT THE MOST
ARE TRAINEES, PEOPLE THAT WERE
IN MORE VULNERABLE POSITIONS,
LIKE HEALTH DISPARITIES WITH
COVID.
WHAT WE'RE TALKING ABOUT IS THE
PEOPLE IN THE RESEARCH
ENTERPRISE, A LOT OF TRAINEES
SUFFERED BECAUSE OF COVID.
NOT HAVING THE KIND OF TRAINING
EXPERIENCES THEY WOULD OTHERWISE
GET.
>> RIGHT.
GOOD POINTS.
THANK YOU ALSO FOR OPTIMISM FROM
TWO OF YOU.
I THINK THAT'S THE TIME FOR YOUR
DISCUSSION SESSION.
I'LL TURN IT BACK OVER TO YOU
FOR CLOSING REMARKS.
>> THANK YOU.
THANK YOU VERY MUCH FOR YOUR
GREAT TALKS, EXCELLENT TALKS AND
GREAT DISCUSSION.
THANK YOU VERY MUCH FOR STAYING
WITH US AND PARTICIPATING IN THE
MEETING UNTIL NOW.
IT WAS MY GREAT HONOR AND
PLEASURE TO DISCUSS WITH YOU
ABOUT GYNECOLOGY PAIN RESEARCH.
THE RECORDING WITH SPEAKERS'
APPROVAL AND SUMMARY STATEMENT
WILL BE POSTED ON THE WEBSITE
AFTER THIS MEETING.
THEY MAY BE AVAILABLE PROBABLY
IN APRIL, SO IT WILL TAKE SOME
TIME.
IF YOU HAVE FURTHER QUESTIONS,
REGARDING THE GHDB OR QUESTIONS
FOR SPEAKERS, PLEASE DON'T
HESITATE TO CONTACT US.
WE WILL TRY TO ADDRESS ALL THE
QUESTIONS WE HAVE NOT BEEN ABLE
TO ANSWER.
THANK YOU.