I'M TERRY MOODY WITH THE NCI CENTER FOR CANCER TRAINING. THIS IS A CLASS ON COMPLIMENTARY AND INTEGRATIVE MEDICINE. TRADITIONALLY, THINGS LIKE CANCER, WE HAVE FOUR MODES OF THERAPY. IF THE TUMOR IS LOCALIZED, YOU COULD SURGICALLY REMOVE IT, TREAT IT WITH RADIATION. YOU COULD TREAT IT WITH CHEMOTHERAPY, AND IMMUNE CHECK-POINT INHIBITORS IS THE NEWEST THING. WITH CANCER IN THE TERMINAL STAGES, THEY USE COMPLIMENTARY MEDICINE, THEY USE OPIATES TO RELIEF THE PAIN AND THAT IS ONE OF THE LECTURES WE WILL DEAL WITH TODAY, IS ABOUT OPIATES. SO I WOULD LIKE TO INTRODUCE THE DIRECTOR OF THE CLASS, DAN. >> THANK YOU VERY MUCH. HI. I'M THE PROGRAM DIRECTOR AT NCI. YOU PROBABLY KNOW ME FROM THE FALL CLASS, SO THIS IS THE SECOND TERM, A CONTINUATION OF THE -- FOR THE FALL OF 2019. YOU CAN SEE HERE, WE HAVE COMMITTEE MEMBERS. WE HAVE TARI AND DR. DAVID. THIS IS THE CONTACT INFORMATION WITH TARI AND ME, IN CASE YOU HAVE QUESTIONS ABOUT THE COURSE OR YOU WANT THE HANDOUT, JUST CONTACT US. WE ALSO HAVE THE LISTSERV HERE AND I HOPE YOU HAVE TIME TO SUBSCRIBE. PROBABLY FROM TIME TO TIME WE WILL HAVE SOME INFORMATION ABOUT THE RESEARCH AND RESOURCES. YOU ALREADY HAVE THIS IN YOUR E-MAIL. I WON'T GO OVER IT ONE BY ONE, BUT THIS TERM, WE WILL HAVE LOT OF TALK ABOUT PAIN, THEN WE TALK ABOUT THE CANNABIS. WE WILL TALK ABOUT PHYSICAL ACTIVITIES, THEN WE ALSO HAVE A TALK RELATED TO SAFETY AND PRODUCT WHICH YOU USE. HERE JUST BRIEF, THE COURSES FOR CERTIFICATION, YOU CAN SEE HERE, AFTER YOU ARE PASSING THE COMPUTER, SUCH EXAM, YOU ARE SURE TO GET IT. SO HERE'S THE BACKGROUND, VERY BRIEF. MORE THAN 40% OF CANCER PATIENT, THEY WILL USE SOME FORM OF COMPLIMENTARY AND INTEGRATIVE FOR MANAGEMENT OF THE CANCER SYMPTOMS AND IMPROVEMENT FOR THE QUALITY OF LIFE. AND PERHAPS THEY HAVE PERCEIVED IMPROVEMENT. SO THE MOST COMMON USED MODALITY, THE PATIENT DISCUSS WITH THE PHYSICIAN, LIFESTYLE INTERVENTION AND NATURAL PRODUCT SO EVIDENCE-BASED KNOWLEDGE, BROADENS THE SCOPE OF THE DISCUSSION, THE CONCERN OF THE PATIENT. SO THERE IS A NEED FOR THE OBJECTIVE AND FOR ASSESSMENT IN FACT SPECIFIC INTERVENTIONS, WHICH INCLUDE SAFETY AND EFFECTIVENESS OF VARIOUS MODALITY, RESEARCH INTO SCIENTIFIC MECHANISMS OF ACTIONS, WITH THE GOAL OF ACHIEVING SUCH EVIDENCE-BASED INFORMATION, WE USE SCIENTIFIC BACKGROUND OF SAFETY AND ADVOCACY FOR PATIENT AND THE PRACTITIONERS. SO HERE IS THE OBJECTIVE FOR THE COURSE. WE WILL INTRODUCE ALL KINDS OF INTERVENTION AND MODALITIES, THEN THE TEACHER WILL TELL YOU FOR SUCH EVIDENCE-BASED, OR MAYBE THE LACK OF SUCH EVIDENCE-BASED PRACTICE AND USAGE. THE LAST IS MOST IMPORTANT, WE WANT TO SEE THE RESEARCH, THE CURRENT STATE OF THE RESEARCH FOR THAT PARTICULAR MODALITIES. SO HERE'S A DEFINITION. SO WHAT IS COMPLEMENTARY AND WHAT IS ALTERNATIVE, AND INTEGRATIVE MEASURES. I WANTED TO MENTION, THE COURSE, THE APPROACH, TO COMBINE TREATMENT OF INTERVENTION, CONVENTIONAL MEDICINE FOR WHICH THERE IS SOME, OKAY, MAYBE HIGH QUALITY OF EVIDENCE FOR THE SAFETY AND EFFECTIVENESS IN COORDINATED MANNERS. SO NOW WE TALK ABOUT TODAY'S LECTURES -- I'M SORRY, TODAY IS FEBRUARY 27. SO WHY WE HAVE SUCH -- I THINK EVERYBODY KNOWS THERE IS INCREASING OF EXPLORING SUCH INTEGRATIVE MEDICINES APPROACH, FOR INTERVENTIONS FOR PAIN. WE HAD THE TALK LAST FALL. THE FIRST TALK WAS FOR ACUPUNCTURE. ALSO, PEOPLE SEARCH FOR MEDITATIONS. FOR TODAY, WE DID NOT REALLY TOUCH ON OPIOIDS IN DEPTH, SO TODAY, WE ARE VERY FORTUNATE, HAVE TWO SPEAKERS I WILL INTRODUCE LATER. THEY WILL TALK ABOUT IN-DEPTH ON THIS TOPIC. IN-RUING RESEARCH OVERVIEW AND THE BIOLOGY OF THE PAIN. SO THE FIRST SPEAKER IS DR. WALTER KOROSHETZ, DIRECTOR OF NATIONAL INSTITUTE OF NEUROLOGICAL DISORDER AND STROKE. WE ARE FORTUNATE TO HAVE HIM. HE IS VERY BUSY, YOU CAN IMAGINE. HE WAS SELECTED DIRECTOR FOR NIDS IN 2015. HE JOINED NIDS IN 2007 AS THE DEPUTY DIRECTORS, AND LATER RETURNED 2014 AND 2015, HE WAS ACTING DIRECTER. HE HAS CHAIR AND LEAD MANY ROLES, A NUMBER OF -- THE PROGRAM INCLUDING THE INITIATIVE, HUGE, VERY IMPORTANT, COLLABORATIVE EFFORT BETWEEN NIH INTRAMURAL PROGRAM AND HOUSE SERVICE UNIVERSITY AND MULTIYEAR WORK TO DEVELOP AND ESTABLISH NIH OFFICE OF EMERGENCY CARE RESEARCH. SO HE WILL GIVE THE OVERVIEW FOR NIH RESEARCH ON THIS TOPIC. THEN WE ARE VERY FORTUNATE TO FOLLOWED BY THE EXPERT, HE WILL GIVE US THE DETAIL ABOUT THE PAIN BIOLOGY -- NEUROBIOLOGY OF PAIN. HE IS THE PROGRAM DIRECTOR FOR SOMATOSENSATION AT NIDS. HE JOINED NIDS IN 2019 AND HE RECEIVED HIS B.S. IN THE BIOLOGY CHEMISTRY IN INDIA. AND LATER ON, HE GOT MASTER IN BIOCHEMISTRY FROM INDIA TOO. THEN HE BECAME TENURE TRACKED ASSISTANT PROFESSOR AND LATER ASSOCIATE PROFESSOR IN THE DEPARTMENT OF PHARMACOLOGY. LATER IN 2015, HE MOVED TO THE WASHINGTON UNIVERSITY SCHOOL OF MEDICINE, BECOME THE PROFESSOR. SO LET'S FIRST WELCOME DR. CORE CORE. >> THANK YOU SO MUCH. IT IS A PLEASURE TO BE HERE. I'M THE DIRECTOR OF NIDS AND TOGETHER, WE LEAD THE HEAL INITIATIVE, CALLED HELPING TO END ADDICTION LONG TOMORROW, SO WE'LL TALK ABOUT THAT AND GIVE YOU A LITTLE OVERVIEWED OF PAIN, OPIOIDS AND THEN WE WILL GO INTO THE BIOLOGY OF PAIN. I THINK THE RELEVANCE IS THAT PAIN IS A CIRCUIT DISORDER, AND SO NO MATTER WHAT THE THERAPY IS GOING TO BE, YOU ARE -- WHAT YOU WILL SEE IS THE CIRCUITS THAT WILL HAVE TO BE MODULATED TO REDUCE PAIN. OPIOIDS, HOW DID THESE THINGS COME? WELL, OPIOIDS ARE FIRST USED ABOUT 8,000 YEARS AGO, SO THIS IS A REALLY OLD DRUG FROM THE POPPY PLANT, AND IT WAS BEGUN USED FOR MEDICINAL PURPOSES IN 1805, WHEN MORPHINE WAS ISOLATED AND PRIOR TO THAT, PEOPLE WOULD SPOKE OPIUM. THERE WERE WARS ABOUT OPIUM. THE BRITISH STARTED A WAR WITH CHINA WHEN THE CHINESE TRIED TO STOP THE SPREAD OF OPIUM, WHICH WAS MARKETED BY ENGLAND. SO OPIUM HAS BEEN THERE A LONG TIME, BUT ITS MEDICINAL USE CAME WITH MORPHINE, AND THIS IS A RECURRENT THEME, WHERE PHYSICIANS BELIEVE OPIUM HAD BEEN TAMED, THATMORPHONE WAS GOD'S OWN MEDICINE, BECAUSE THEY THOUGHT IT WAS SO SAFE, WHEREAS OPIUM WAS KNOWN TO BE TERRIBLY ADDICTIVE. THAT TURNED OUT NOT TO BE TRUE. IN 1827, MERCK STARTED COMMERCIAL MANUFACTURE OF MORPHINE. THEY LEARNED INJECTION WAS MORE POWERFUL ADD QUICK. THEN PROBLEMS STARTED TO COME WITH ADDICTION TO MORPHINE. IT WAS USED PREDOMINANTLY IN WOMEN, USED FOR PAIN, BUT AT ONE POINT, THERE WAS AN EPIDEMIC OF MORPHINE ADDICTION IN THE U.S., WHICH AFFECTED MORE PEOPLE THAN IS CURRENTLY AFFECTED AND ALMOST ALL WOMEN. MORPHINE WAS GIVEN TO WOMEN FOR ALMOST ANY COMPLAINT THAT THEY MIGHT HAVE. REAL COMMON ONE MIGHT BE MENSTRUAL PAIN. SO CAUSED A REAL PROBLEM IN THE LATE 1800S. THEN, THE STORY REPEATED ITSELF, WHEN HEROIN WAS PURIFIED, BECAUSE THEY THOUGHT THAT WOULD BE A GOOD WAY TO WEAN PEOPLE OFF MORPHINE. SO THAT, AS YOU KNOW, DIDN'T WORK OUT SO WELL. HEROIN IS STRONGER AND MORE ADDICTIVE THAN MORPHINE. SO IN 1905, U.S. CONGRESS BARRED OPIUM, AND THEN IN THE 1914, THE U.S. REQUIRED DOCTORS WHO WERE PRESCRIBING NARCOTICS TO REGISTER. THEN WHAT HAPPENED IS THAT IN THE '90S, OXYCONTIN CAME ON THE MARKET. IT WAS A SLOW-ACTING MORPHINE-LIKE DRUG AND IT WAS MARKETED AS NONADDICTIVE BECAUSE IT WAS SO SLOW ACTING THAT PEOPLE COULDN'T GET HIGH FROM IT. THAT TURNED OUT, AGAIN, NOT TO BE TRUE. PEOPLE WERE BREAKING INTO PHARMACIES TO STEAL IT, SELLING IT ON THE STREET. IN ADDITION, THERE WAS A FAIRLY LARGE MARKETING EFFORT IN THE U.S. TOFFYITIONS AGGRESSIVE HIS TREAT PAIN, SO WHAT YOU CAN SEE HERE ON THE LOWER GRAPH IS PRESCRIPTIONS FOR OPIOIDS, OXY CODON WENT UP DRAMATICALLY. THEY TRIPLED BETWEEN THE EARLY '70S AND EARLY 2000S. THAT LED TO A LOT OF USE, BUT ALSO IT LED TO PEOPLE BECOMING ADDICTED TO THESE DRUGS THAT WERE GIVEN FOR THE PURPOSE OF TREATING PAIN. IN ADDITION, THERE WAS SO MUCH OF THIS STUFF AROUND THAT PEOPLE HAD THEM IN THE MEDICINE CABINET, KIDS STARTED GRABBING IT, SO IT WAS DIVERSION OF MEDICINES. WHEN YOU LEAVE THE HOSPITAL, YOU WOULD GET A WHOLE BUNCH OF OXY CODON AND IT WOULD STAY IN YOUR CABINET AND FELL IN THE WRONG HANDS MANY TIMES. THAT LED TO OVERDOSES DUE TO PRESCRIPTION MEDICATIONS AND THAT WAS THE REAL CRISIS WE WERE FACING AROUND 2012 TO 2015 OR '16 OR SO. THEN PEOPLE RECOGNIZED WHAT THE& PROBLEM WAS AND YOU YOU CAN SEE ON THE RIGHT, THE TRENDS IN OPIOID PRESCRIPTIONS STARTED TO DROP AFTER 2012, BUT IT'S STILL WAY ABOVE WHERE IT WAS IN THE 1980S, AND IT IS NOT CLEAR THAT PAIN IS MORE OF AFTER PROBLEM NOW THAN IT WAS IN THE 1980S, SO WE STILL HAVE A LONG WAY TO GO TO REDUCING PRESCRIPTION MEDICATIONS. THE OTHER PROBLEM THAT HAPPENED IS PEOPLE GOT ADISTRICT TO THE PRESCRIPTION MEDICATIONS AND THERE WERE OVERDOSES DUE TO THAT, BUT THE OTHER THING THAT HAPPENED IS ONCE PEOPLE GET ADDICTED TO OPIOID, THEY DEVELOP TOLERANCE, SO THEY ALWAYS NEED A STRONGER DOSE TO GET THE SAME KIND OF EUPHORIC EFFECTS. YOU CAN TRY TO GET THE PRESCRIPTION MEDICINES, BUT THAT IS NOT EASY, EVEN IN THE OLD DAYS, BUT YOU CAN GET HEROIN ON THE STREET. SO PEOPLE STARTED TO MOVE FROM PRESCRIPTION OPIOIDS TO HEROIN. THEN, WHEN DOCTORS STARTED CLAMPING DOWN ON PRESCRIPTION OPIOIDS, THAT PUSHED MORE PEOPLE TO HEROIN BECAUSE PEOPLE COULDN'T GET THE OPIOIDS. THAT LED TO A HUGE DEMAND FOR HEROIN, SO ILLEGAL NETWORKS STARTED TO FILL THE AREAS WHERE THERE WAS PRESCRIPTION OPIOIDS, NOW FILLED THOSE AREAS WITH HEROIN. AND THESE ARE CRIMINALS, PEOPLE DOING THIS ARE TOTAL CRIMINALS, BUT THEY WERE SUCCESSFUL, BECAUSE WE CREATED A DEMAND. THEN WHAT HAPPENED IS THIS GROUP OF CRIMINALS BECAME SO EFFECTIVE, THAT THEY STARTED TO HOOK PEOPLE ON HEROIN STRAIGHT OUT OF HIGH SCHOOL, WHO WEREN'T EVEN TAKING PRESCRIPTION OPIOIDS. SO FIVE YEARS AGO, 75% OF THE PEOPLE WHO HAD OVERDOSE DEATHS RELATED TO PRESCRIPTION OPIOIDS, EITHER PRESCRIPTIONS THEMSELVES OR PRESCRIPTIONS THAT LED TO HEROIN. MOST OF THE DEATHS NOW ARE ACTUALLY PEOPLE HAVE GONE STRAIGHT TO HEROIN, SO WE CREATED A NIGHTMARE SCENARIO. THE OTHER THING THAT HAPPENED IS THE HEROIN IS BEING LACED WITH FENTANYL. IT WAS AN ANSWER THETIC. ANESTHESIOLOGISTS GET PAID FOR WAKING YOU UP. WITH FENTONAL, YOU DIE FROM RESPIRATORY ARREST. IT IS A POWERFUL SUBSTANCE, AND THE CHANGE IN YOUR CIRCUITS THAT OCCUR IN PEOPLE WHO ARE ADDICTED TO HEROIN ARE SO STRONG THAT THEY ARE ALWAYS LOOKING FOR A STRONGER MEDICINE. SO THE WEIRDEST THING IS, WHEN THERE'S A REALLY STRONG DRUG THAT KILLS PEOPLE ON THE STREET, IT ACTUALLY DRIVES HEROIN USERS TO GET THAT DRUG, BECAUSE THEY THINK IT IS REALLY STRONG. THAT'S HOW BIZARRE THAT WHOLE PROCESS HAS BECOME. IN TERMS OF THE DEATHS, WHAT HAPPENED OVER TIME, THE HEROIN DEATHS SINCE 2011, IT WAS MOSTLY PRESCRIPTION MEDS, BUT AFTER 2011, HEROIN EXCEEDED PRESCRIPTION MEDS AND FENTONAL DEATHS EXCEEDED EVEN HEROIN. IT IS USUALLY FENTANYL MIXED WITH HEROIN. WHY ARE WE IN THIS MESS? IT IS BECAUSE OF THE BIOLOGY OF PAIN AND BIOLOGY OF REWARD. THEY ARE INTERSECTING. SO PHILOSOPHER SAID NATURE PLACED MANKIND UNDER THE GOVERNANCE OF TWO MASTERS, PAIN AND PLEASURE. SO SIMPLIFIED, YOU ARE TRYING TO GET AWAY FROM PAIN, TRYING TO GO TOWARDS PLEASURE, WHETHER IT'S THE^CREAM CONE YOU ARE TRYING TO GET, OR AWAY FROM A SUNBURN, BECAUSE IT'S PAINFUL AND THE INTERSECTION IS BASICALLY INTEGRATED IN THE ANATOMY OF THE AREAS THAT ARE RELATED TO PAIN AND THE AREAS RELATED TO REWARD ARE ACTUALLY INTERCONNECTED AND OVERLAPPING IN MANY INSTANCES, SO JUST THINK OF THE GANGLION CELLS, WHICH ARE THE FIRST CELLS -- CELL BODIES FOR YOUR PERIPHERAL NERVOUS SYSTEM, THEY HAVE OPIOID RECEPTORS ON THEM. THEY DON'T CAUSE REWARD, BUT THEY INVOLVE RELIEVING THE PAIN. SO THAT IS REALLY THE PROBLEM THAT YOU CAN'T REALLY SEPARATE VERY WELL THE REWARD SYSTEM FROM THE PAIN SYSTEM WHEN YOU ARE DEALING WITH OPIOIDS. THE GOOD NEWS IS THAT THERE ARE THINGS THAT ARE NOT OPIOID-MEDIATED, SO THERE ARE MOLECULAR AND THERE ARE LOCATIONS YOU CAN INTERVENE IN THE PAIN CIRCUIT THAT HAS NOTHING TO DO WITH THE REWARD SYSTEM. THAT'S REALLY WHAT WE ARE TRYING TO DO NOW, AND -- BUT THEY ARE VERY MUCH INTEGRATED, SO IF YOU STUDY ANIMALS AND YOU LOOK AT THEIR REACTION TO WHAT THEY WILL DO TO GET A REWARD, YOU GIVE THEM SOMETHING THAT BLOCKS OPIOID REACTION, THEY HAVE LESS REWARD. IF YOU GIVE AN OPIOID, LESS AVERSIVE TO A PAIN STIMULUS. SO WE HAVE TO TRY TO GET AWAY FROM THIS AS MUCH AS WE CAN. THE OTHER AREA PEOPLE ARE INVESTED IN IS TRYING TO GET AWAY FROM THE TOLERANCE PROBLEM, WHERE THE REWARD SYSTEM CERTAINLY, MORE AND MORE OF THE OPIOID TO GET THE SAME REWAR, AND THAT'S BECAUSE OF THIS DUAL FUNCTION OF THE G PROTEIN RECEPTOR THE OPIOIDS BIND TO, THAT THE BETA ARREST PORTION ACTUALLY CAUSES THE TOLERANCE. SO A LOT OF EFFORTS TO TRY TO GET THE ANALGESIA SIDE WITHOUT THE BETARY RESTER SIDE AND SEPARATE THE RESPIRATORY DYSFUNCTION, SEPARATE THAT FROM THE ANALGESIA, BUT NO ONE'S BEEN TOTALLY SUCCESSFUL IN DOING THAT AS OF YET. THERE ARE A LOT OF PLACES THE PAIN SYSTEM COULD BE INTERVENED WITH, SEPARATE FROM THE REWARD SYSTEM AND YOU WILL HEAR MORE ABOUT THIS FROM DP, BUT IT GOES FROM THE NOSE RECEPTORS, PERIPHERAL NERVE, GANGLION AREAS IN THE SPINAL CORD, AND THEN PARTICULAR AREAS IN THE RAIN AS WELL. ONE OF THE BEST EXAMPLES IS PEOPLE WHO HAVE A TERRIBLE INJURE ACIN WAR, THEN THEY RUN TO GET BACK INTO THEIR FOX HOLE WITHOUT FEELING ANY PAIN, UNTIL THEY -- THEIR BRAIN KIND OF CALMED DOWN FROM THE EXCITEMENT OF SURVIVING, THEN THE PAIN SETS IN. SO THERE ARE SYSTEMS THAT GO DOWN INTO THE SPINAL CORD TO SUPPRESS PAIN, SO SPINAL CORD STIMULATERS ARE USED TO TRY TO ACTIVATE THE DESCENDING PATHWAYS, AND THOSE ARE CERTAINLY EFFECTIVE IN SOME INSTANCES AND ACTUALLY, THE FIRST USE WAS IN CANCER PAIN, WHEN THEY WERE FIRST DEMONSTRATED TO BE USEFUL. THEN THERE'S MULTIPLE MOLECULAR SIGNALING THAT GOES ON AT ALL THE DIFFERENT STAGES IN PAIN, AND THESE -- SOME ARE OPIOID-MEDIATED, BUT A LOT ARE NOT. IF YOU CAN MIMIC THE ACTION OF THE OPIOID ON THE FIRING PATTERN OF A CELL, THE OPIOIDS ARE AFFECTING THE FIRING PATTERN IN THE CIRCUIT, THAT'S HOW THAW DEPRESS THE PAIN. SO IF YOU CAN MIMIC THAT WITHOUT GOING WILL YOU THE OPIOID RECEPTOR, THEN YOU COULD GET THE SAME EFFECT POTENTIAL LIVE AS THE OPIOIDS CAUSE, BUT NOT GIVEN THE DRUGS SYSTEMATICALLY THAT WOULD GET TO THE REWARD SYSTEM AND CAUSE ADDICTION. COUPLE OF EXAMPLES OF NEW PAIN THERAPY, SO CJRP IS CALCIUM GENE-RELATED PROTEIN, AND IT IS AN -- AN ANTIBODY HAS BEEN APPROVED FOR MIGRAINE AND PEOPLE FOUND DURING THAT MIGRAINE, THIS PEPTIDE IS RELEASED, YOU CAN MEASURE IT IN THE JUGULAR VEIN, YOU INJECT THE PEOPLE WITH THE DRUG, THEY GET PAIN, SO THE ANTIBODY ACTUALLY HAS A GOOD RATIONALE AND IT WORKS AND IT WAS APPROVED BY THE FDA, SO IT IS GOING TO THE PAIN SYSTEM THROUGH NON-OPIOID FASHION. VAGUEFALL STIMULATERS, ALSO SHOWN TO BE BENEFICIAL AND INITIALLY IN CLUSTER HEADACHE AND ALSO NOW IN COMMON MIGRAINE, AND THIS IS INTERACTING WITH THE BRAIN CIRCUS BY CAUSING THE VAGUS NERVE TO -- NONFORMLOGICAL NOW, THE ONE -- COUPLE THINGS GOING ON THAT ARE EXCITING, ONE IS THE BRAIN INITIATIVE. IT IS NOW A MASSIVE PROJECT BY NIH. IT IS A $500 MILLION A YEAR PROJECT TO TRY TO MAP OUT THE CIRCUITS OF THE BRAIN, SPECIAL CALL FOR GRANTS TO PAP OUT THE PAIN CIRCUITS, AND ALSO THE TECHNOLOGY. THE BRAIN IS DEVELOPING TECHNOLOGY WHERE YOU CAN MA NAME LATE THE PAIN CIRCUS FOR HEALTH, WOULD BE A GREAT OUTCOME FROM THE BRAIN INITIATIVE. AND THEY HAVE TOOLS NOW THAT NOBODY COULD IMAGINE WOULD EXIST FIVE YEARS FROM NOW. SO JUST ONE EXAMPLE. THIS IS AN EXAMPLE FROM THE STANFORD LAB. WHAT THEY DID IS DEVELOPED A PAIN MODEL IN A RAT, AND THAT IS CALLED NEURO PATHIC AND THIS, THEY PUT THE RAT IN A CAGE WHERE ONE SIDE, THE PLATE IS CODE AND THE RAT DOESN'T LIKE IT, AND THE OTHER SIDE, THE RAT -- THE TEMPERATURE IS FINE FOR THE RAT, SO AS YOU MIGHT IMAGINE T RAT WILL SPEND -- I'S A MOUSE. SORRY. SPEND ALL THEIR TIME THEY ARE COMFORTABLE ON. WHAT THEY WERE ABLE TO DO IS IDENTIFY A GROUP OF NEURONS IN THE BASAL LATERAL MA LIGDA AND TURN ON JUST THOSE NEURONS. THEY INJECT A VIRUS THAT CARRIERS A GENE. THAT GENE GOES INTO THE NEURONS, CAUSES EXPRESSION OF A CHANNEL THAT DOES NOTHING EXCEPT IF YOU GIVE THE ANIMAL A PARTICULAR CHEMICAL CALLED CNO, AND THEN THAT CHANNEL WILL BE ACTIVATED AND THE CELLS WILL SHUT OFF. THIS IS A TECHNOLOGY CALLED CHEMOGENETICS. DID NOT EXIST FIVE YEARS AGO, BUT JUST IMAGINE NOW, WITH THIS TECHNOLOGY, YOU CAN FIND AND YOU CAN SPECIFICALLY TURN ON OR TURN OFF ANY CELLS YOU WANT IN THE BRAIN PRETTY MUCH. IN THIS INSTANCE, WHAT THEY FOUND WAS, IF THEY TURNED THE CELLS OFF, THE ANIMALS DETECT PAIN PERFECTLY NORMALLY, BUT THEY DON'T CARE. SO WHEN YOU -- THERE ARE LOTS OF EXPERIMENTS THEY DIDN'T SHOW, BUT THEY DETECT THE PAIN, BUT WHEN YOU PUT THEM ON THIS WARM PLATE, THEY DON'T CARE. THEY CAN TELL COLD, THEY KNOW IT IS A NATURAL STIMULUS, BUT NO NEGATIVE CONNOTATIONS TO IT, SO THIS WOULD BE LIKE THE PERFECT THING YOU WOULD -- THEY WOULD STILL BE ABLE TO FEEL PAIN IF THEY DRANK HOT COFFEE, BUT THEY DON'T CARE. IT DOESN'T CAUSE ANY SUFFERING. SO THIS IS ONE OF THE THINGS, AN EXAMPLE FROM THE BRAIN INITIATIVE. AND THE TECHNOLOGY, THIS IS BEING DONE HERE AT NIH, YOU CAN SEE THE CELLS FIRING. SO THEY ARE TOUCHING THE WHISKERS OF -- I GUESS THAT IS A MOUSE. THE MOUSE HAS A GENE IN IT, WHERE THE NEURONS LIGHT UP WHEN THE NEURONS FIRE. THEY LIGHT UP BECAUSE THERE'S A GENE IN THERE THAT DETECTS CALCIUM AND GIVES A FLUORESCENT SIGNAL WHEN THE CALCIUM FLOWS IN THE CELL. AN EXAMPLE, BEING NOW TO ACTUALLY SEE CIRCUITS IN ACTION, YOU CAN SEE THE NEURONS FIRING, AND THEY HAVE BEEN ABLE TO ARC OUT DIFFERENT PARTS OF THE NUCLEUS AFFECTING CERTAIN TYPES OF PAIN SENSATION, SO REALLY AMAZING TECHNOLOGIES TO STUDY PAIN NOW. AT NIH, THERE'S ALMOST ALL THE INSTITUTES ARE INVOLVED IN PAIN. THERE'S A PAIN CONSORTIUM THAT'S BEEN IN EXISTENCE AS LONG AS I HAVE BEEN HERE, YEARS BEFORE PROBABLY AS WELL. THEN THERE'S THE HEAL INITIATIVE. THE HEAL INITIATIVE IS A PROJECT, $500 MILLION A YEAR. $250 MILLION CAME TO NIDS. 250 TO NIDA, DRUG ABUSE INSTITUTE. NIDS IS A BANK, BUT IT'S THE TRANSNIH EFFORT, SO ALMOST ALL THE INSTITUTES ARE INVOLVED, INCLUDING NCI. FOR THE PAIN PROJECT, WE SEND THE MONEY OUT TO THE OTHER INSTITUTES TO MANAGE PAIN PROJECTS. SO TWELVE INSTITUTES AND CENTERS CURRENTLY LEADING 26 RESEARCH PROJECTS, AND THERE'S TWO COMPONENTS. THE BIGGEST COMPONENT IS IMPROVING TREATMENTS FROM OPIOID MISUSE AND ADDICTION. THERE IS NO REALLY GOOD TREATMENT FOR ADDICTION, UNFORTUNATELY. 'S A PARTIAL AGONIST THAT DECREASES THE CRAVING, BUT EVEN IN THE BEST OF ALL POSSIBLE SCENARIOS, MY UNDERSTANDING IS 70% OF THE PEOPLE WILL BECOME -- ONCE THEY ARE CLEAN, THEY WILL GO BACK TO HEROIN AGAIN. IT'S JUST SUCH A STRONG REWIRING SIGNAL FOR THE GRAIN. SO WE HAVE TO REALLY STOP PEOPLE FROM GETTING ON IT. ONCE YOU ARE ON IT, YOU GAVE YOURSELF A CHRONIC DISEASE BASICALLY. THE OTHER PART IS PAIN MANAGEMENT. SO IN THE PAIN MANAGEMENT SPACE AND THE HEAL INITIATIVE, WE HAVE PROJECTS THAT GO ALL THE WAY FROM TRYING TO UNDERSTAND PAIN, HOW TO PREVENT PAIN, SO LOOKING AT PEOPLE WHO HAVE A PAINFUL, TRAUMATIC EVENT, TRYING TO UNDERSTAND WHICH ONES DEVELOP PAIN AND WHICH DON'T. THAT'S ACUTE TO CHRON I BE PAIN SIGNATURES. WE HAVE BASIC SCIENCE TO FIND NEW TARGETS FOR NONADDICTIVE PAIN MEDICINES, WE HAVE PRECLINICAL SCREENING PLATFORM, WHERE INDUSTRY OR ACADEMIES CAN SEND THEIR DRUGS AND DIVIDES TO BE TESTED ON ANIMAL MODELS THEY CAN BELIEVE IN. WE HAVE A NETWORK TO DO EARLY PHASE NEW NONADDICTIVE PAIN THERAPIES, WE HAVE BIOMARKER STUDIES TO HELP IN UNDERSTANDING IF A DRUG OR DEVICE DOING THAT THEY HOPE TO BE DOING WHEN IT GOES INTO HUMANS. THERE'S A HEAVY EMPHASIS ON BACK PAIN, AND THEN AT THE END, THERE'S TWO NETWORKS. ONE IS FOR COMPARATIVE EFFECTIVENESS STUDIES IN MANAGING DIFFERENT PAIN CONDITIONS, AND THIS HAS BEEN HEAVILY USED TO GET GRANTS TO STUDY NON-PHARMACOLOGICAL MANAGEMENT OF DIFFERENT PAIN CONDITIONS. THEN THERE'S A NETWORK TO DO EFFECTIVENESS IN HEALTH SYSTEMS. THAT IS EVEN MORE FOCUSED ON NON-PHARMACOLOGICAL TREATMENTS AND SO ONE EXAMPLE IS STUDY OF ACUPUNCTURE AND BACK PAIN, WHICH IS DONE IN COORDINATION WITH MEDICARE, SO THAT'S THE STORY IN TERMS OF WHERE WE ARE NOW. OPIOIDS, A LITTLE ABOUT PAIN, AND THE HEAL INITIATIVE. NOW I WOULD LIKE TO TURN IT OVER TO DP TO TALK TO YOU ABOUT THE BIOLOGY PARTICULARLY OF CANCER PAIN. >> THANK YOU, WALTER, FOR THAT BIG OVERVIEW. WE DECIDED TO MAYBE GIVE AN OVERVIEW OF WHAT'S THE BIOLOGY OF PAIN OF THE SO WHAT IS PAIN ACTUALLY? AS PER THE INTERNATIONAL ASSOCIATION FOR STUDY OF PAIN, THE PAIN IS DEFINED AS AN UNPLEASANT SENSORY AND EMOTIONAL EXPERIENCE. SO YOU CAN SEE THERE ARE TWO COMPONENTS. ONE IS SENSORY, WHERE YOU DETECT THE SIGNAL OR DETECT THE PAINFUL SIGNAL, AND THE OTHER IS EMOTIONAL EXPERIENCE, WHICH IS PROCESSED IN THE BRAIN, AND THAT'S WHAT BASICALLY IS PAIN. THESE EXPERIENCES, WHEN ASSOCIATED WITH ACTUAL OR POINT DAMAGE, OR IN A CONDITION WHERE IT CAN BE DESCRIBED AS DAMAGE OR POTENTIAL DAMAGE. SO THAT OVERALL CONTRIBUTE AS -- CONSTITUTES AS A PAIN. SO YOU CAN SEE IN THE PICTURES THERE, THERE ARE MULTIPLE WAYS HUMANS, WE ALL FEEL PAIN, AND MANY TIMES, PAIN IS BUILT SO THAT WE CAN AVOID A NOXIOUS STIMULI, BUT MANY TIMES, IT'S JUST ONGOING CHRONIC PAIN WE FEEL IN MULTIPLE WAYS AT MULTIPLE AREAS IN OUR BODY AND WITH MULTIPLE DIFFERENT MECHANISMS. SO THEN THE QUESTION COMES, LIKE WHEN WE KNEW ABOUT PAIN, IT WAS HISTORICALLY FIRST IN 16TH CENTURY. THE FRENCH PHILOSOPHER DESCARTES. HE POSTLATED THAT OUR BRAIN SOMEHOW DETECTS ANY KIND OF NOXIOUS STIMULUS AND THAT SIGNAL GOES TO DETECT THAT AS A PAIN. AND IN THE LAST FIVE CENTURIES, SO TREMENDOUS ADVANCEMENT HAS BEEN MADE TO UNDERSTAND THE VERY NITTY-GRITTIES WITHIN THAT RED INITIAL SIGNAL, WE POE THERE ARE MULTIPLE PATHWAYS GOING FROM THE PERIPHERY TO THE BRAIN AND ALSO PATHWAYS COMING DOWN FROM THE BRAIN, SO FROM ONE EXAMPLE, LIKE IF YOU WERE DOING EXERCISE, SO THERE ARE A LOT OF MUSCLE CONDITIONS HAPPENING THERE, BUT WE DO NOT FEEL THE PAIN, BECAUSE OUR BRAIN RELEASES ENDORPHINS, LIKE OPIOIDS, INDIGENOUS OPIOIDS AND THEY BIND WITH THOSE RECEPTORS IN THE PATHWAYS. THAT'S HOW IT LIKE BLOCKS THE PAIN SIGNAL. IT DOESN'T -- OUR BRAIN DOESN'T TELL IT IS PAIN, SO WE KEEP ON DOING EXERCISE. SO A LOT OF PROGRESS HAS BEEN MADE, BUT STILL, WE DO NOT UNDERSTAND A LOT IN TERMS OF PAIN MECHANISMS ASSOCIATED WITH DIFFERENT DISEASES. WE ALL COULD ASK, WHY DO WE NEED PAIN AND WHY NATURE DESIGN PAIN? BECAUSE IT IS ACTUALLY NECESSARY. IT IS A PROTECTIVE MECHANISM, ALARM SYSTEM IN OUR BODY, WHICH TELLS US LIKE HEY, YOU ARE GOING TO FACE THIS AVERSIVE CONDITION OR THIS DANGEROUS CONDITION, SO IT IS AN ALARM TELL US HEY, TAKE CARE OF, OTHERWISE YOU COULD FEEL A VERY UNPLEASANT SITUATION. SO TALKING ABOUT PAIN IN SCIENTIFIC TERM, WE COME UP WITH TWO DIFFERENT PHENOMENON. ONE IS CALLED THE PROCESS WHERE THE ACTIVATION OF SPECIALIZED GROUP OF RECEPTORS OR NERVE FIBERS, AND THEY CAN LIKE SENSE THIS NOXIOUS STIMULI. NOXIOUS STIMULI, WHEN THEY ARE SENSED BY THE RECEPTORS, WHICH ARE NOTHING BUT SENSORY NEURONS THAT RESPOND TO THESE NOXIOUS STIMULI OR CELL DAMAGING OR TISSUE-DAMAGING CONDITIONS, SO NOT EVERY TIME A NOXIOUS STIMULI WILL BE PERCEIVED AS PAIN IN OUR BRAIN. SO A PAIN ALWAYS HAS A -- AN INITIAL COMPONENT. SO THE PERCEPTION OF THOSE SIGNALS FROM THE PERIPHERY BY THE BRAIN, THAT IS WHAT WE CALL IT AS PAIN. TALKING ABOUT PAIN, THERE ARE DIFFERENT CLASSES OF PAIN. MAINLY, THERE ARE THREE. SO WHERE THE PAIN IS ORIGINATING ACTUALLY FROM AN ACTIVE RECEPTOR, WHERE IT DETECTS ANY INJURY OR DAMAGING SIGNALS. SO THAT RESPONSE, WHEN IT IS LIKE SENT TO THE BRAIN, AND OUR BRAIN DETERMINES THAT IT IS PAIN, SO THAT TYPE OF PAIN IS RECEPTIVE PAIN. THEN WE HAVE NEURO PATHIC PAIN, WHERE THERE'S NO TISSUE DAMAGE, BUT IT IS PAIN ORIGINATING DIRECTLY FROM THE DAMAGE OF LESION OR DAMAGE OF THE NERVOUS SYSTEM. SO IT COULD BE A NERVE FIBER JUST GETTING DAMAGED, GETTING COMPRESSED AND IT CAN EITHER HAPPEN IN THE SYMPATHETIC NERVOUS SYSTEM OR CENTRAL NERVOUS SYSTEM. WHENEVER THERE IS A DIRECT LINK OR DAMAGE TO THE NERVES. THOSE TYPE OF PAIN ARE NEUROPATHIC PAIN. THESE ARE THE TWO TYPES OF PAIN WHICH WAS THERE UNTIL 2017, WHEN ISD CAME ONE A THIRD TYPE. THERE WERE CERTAIN TYPES OF PAIN THEY COULD NOT BE CLASSIFIED BASED ON THOSE MECHANISMS OR THOSE CLASSIFICATIONS, SO THAT GAVE RISE TO WHERE THE PAIN CAN ORIGINATE FROM ALTERED DAMAGE CAUSING A NOXIOUS STIMULI, BUT THERE'S NO CLEAR EVIDENCE THERE IS TISSUE DAMAGE. CLASSICAL EXAMPLES ARE LIKE FIBROMYALGIA. IN THIS TYPE OF PAIN THERE'S NO DIRECT EVERYDAY OF STRONG TISSUE DAMAGE GOING ON, BUT THERE IS ONGOING PAIN. THERE ARE OTHER EXAMPLES, LIKE COMPLEX PAIN SYNDROME. THE DAMAGE COULD BE SOMEWHERE ELSE, BUT IT IS A GENERALIZED PAIN. SO THE BOTTOM LINE THERE IS THESE ARE THE CONDITIONS WHERE THE NERVE FIBERS, SENSORY NERVE FIBERS GET ALTERED IN THE LONG-TERM, AND THEY THEMSELVES START LIKE REGULAR ACTION-POTENTIAL NOW BECOMES PAIN. THAT IS THE TYPE OF PAIN CATEGORIZED. TALKING ABOUT CANCER PAIN BECAUSE OF NCI MOSTLY, CANCER PAIN FALLS INTO THE FIRST TWO TYPES. AND SO FAR, THERE'S STILL NO DIRECT EVIDENCE OF ANY TYPE OF CANCER PAIN WOULD FALL INTO THE THIRD CATEGORY, BUT THIS IS REALLY EVOLVING FIELD. IT MIGHT CHANGE. TALKING ABOUT THE CANCER PAIN, I JUST WANTED TO AGAIN, REVISIT -- I'M SURE YOU ALL KNOW ABOUT THESE NUMBERS AND NUMBER OF CANCER CASES COMING UP, SO IT IS GROWING EVERY YEAR. SO NEARLY 1.5 TO 2 MILLION PEOPLE A YEAR GET CANCER IN THE UNITED STATES. IF WE LOOK INTO ALL TYPES OF CANCERS, MAJORITY OF THEM, VAST MAJORITY OF THEM, THEY HAVE ISSUES WITH QUALITY OF LIFE WITH ADVANCED CANCERS, AND PAIN HAPPENS TO BE ONE OF THE MAJOR ONES THERE. SOMETIMES IT IS NOT ONLY THE PRIMARY CANCERS, BUT ALSO AT THE TIME STATIC CANCERS, LIKE THE ONES HIGHLIGHTED, THEY METASTASIZE TO BONES AND CAUSE SEVERE PAIN FOR A LONG TIME. THAT IS WHERE THE MANAGEMENT OF PAIN IS NOT THAT EFFECTIVE, EVEN WITH STRONG DRUGS WITH OPIATES. WITH THE NUMBERS OF NEW PATIENTS, WHO CAME ONE A GUIDELINE LAST YEAR ABOUT CANCER PAIN. THE DATA SHOWS ALMOST 66% OF THE CANCER -- ADVANCED CANCER PATIENTS WILL HAVE CHRONIC PAIN GOING ON. WE ALL KNOW, MORE THAN 100 MILLION AMERICANS FACE PAIN EVERY DAY ALMOST, BUT ALMOST 55% OF PATIENTS UNDERGOING TREATMENT FOR CANCERS, AND THE TREATMENTS COULD BE CHEMOTHERAPY TREATMENT OR OTHER TYPES OF TREATMENT, BUT MOSTLY CHEMOTHERAPY, THAT LEADS TO STRONG PAIN ALSO. MOST OF THOSE PAINS ARE KIND OF CATEGORIZED AS NEURO PATHIC, BECAUSE THEY ARE DIRECTLY TRYING TO DAMAGE THE -- THE CHEMOTHERAPY AGENTS DAMAGE THE NERVES. ELEPHANTS, I WOULD SAY. IN TERMS OF MECHANISTIC-WISE, SO CANCER PAIN IS DIVIDED INTO THESE TWO, SO MOSTLY, THE BONE METASTASES CASES. YOU CAN IMAGINE, AT THE VICINITY OF TUMOR, WHERE THEY ARE GROWING, WHETHER IT'S PRIMARY OR METASTATIC, THEY HAVE A STRONG INFLAMMATORY SIGNAL SURROUNDING THE TWO. THAT PROVIDES ENOUGH STIMULATION FOR THESE SENSORY NERVES TO GET ACTIVATED CONSISTENTLY. SO THAT'S WHY THOSE ARE LIKE CLASSIFIED AS RECEPTIVE TYPE OF PAIN, BUT WHEN THERE ARE TUMORS, WHICH ARE METASTASIZEING -- SO IN HERE, YOU CAN SEE, THE SPINAL CORD. THAT ALSO PRODUCES NEURO PATHIC-TYPE PAIN. THERE ARE OTHER CONDITIONS WHERE THE TOMB SIR INFILTRATING INTO THE BRACHIAL PLEXUS, SO IT DAMAGES THE SENSORY NERVES OR COMPRESSES THOSE, SO IT CAUSES NEUROPATHIC PAIN. THERE ARE OTHER TYPES OF CONDITIONS WHERE IT IS A MIXED TYPE OF -- THERE ARE SOME TISSUE DAMAGES, BUT DIRECTLY CONVERGING ON THE SENSORY NERVES OR IN THE SPINAL CORD, SO THE NEUROPATHIC TYPE IS MORE AND MORE EMPHASIS, BECAUSE THE EVIDENCE IS GROWING MORE AND MORE. BUT IN TERMS OF BONE -- INFLAMMATORY TYPE OF PAIN. TO GIVE YOU AN OVERALL -- OVERVIEW OF HOW THE PAIN REALLY IS PROCESSED, IF YOU IMAGINE, THIS IS -- THESE ARE SENSORY NERVE FIBERS COMING FROM THE DORSAL ROOT GANGLIA, WHICH CONNECTED TO SPINAL CORD AND BRAIN. THESE PERIPHERAL NERVE FIBERS ARE ON THE SKIN, BRANCH OUT IN THE SKIN OR THE VISCERAL ORGANS, THEY HAVE MULTIPLE TYPES OF RECEPTORS. A VAST MAJORITY OF THESE RECEPTORS ARE REALLY CHANNELS. THE CHANNELS RESPOND TO VARIOUS STIMULI, WHETHER IT'S TEMPERATURE CHANGE, TO THE WARM SIDE OR COLD SIDE, OR TO ANY MECHANICAL STIMULI, OR TO A VARIETY OF CHEMICAL STIMULI. A VAST MAJORITY OF THESE RECEPTORS RESPOND TO A LOT OF NATURAL CHEMICALS, WHICH HUMANS ALWAYS TRY TO AVOID. BUZZ AT THE SAME TIME, MANY OF THOSE CHEMICALS HUMANS LOVE EATING THOSE, BECAUSE THEY ALSO PRODUCE REWARD. WHEN YOU EAT CHILIS, IT FEELS HOT, BUT THERE'S SOMETHING THAT TELLS YOU LET ME EAT MORE BECAUSE I LIKE THEM. SO THOSE COMPONENTS PLAYED A BIG ROLE IN IDENTIFYING THE RECEPTORS. SO THE CHANNELS WHEN THEY ACTIVATE, THEY CHANGE THE MEMORY POTENTIAL, SO IT FIRES ACTION POTENTIAL, AND THOSE ACTION POTENTIAL ARE ELECTRICAL SIGNALS, TRAVEL TO THE CELL BODY AND ALL THE WAY TO THE BRAIN. THE BRAIN DECIDES YES, IT IS PAIN. AND THERE ARE EXAMPLES OF THESE TYPE OF PAINS, LIKE POSTOPRATIVE PAIN OR ARTHRITIS-TYPE PAIN, INFLAMMATORY BOWEL DISEASE AND SICKLE CELL DISEASE AND PRIMARY AND METASTATIC BONE TUMORS, THEY FALL INTO THIS. SO YOU CAN IMAGINE THE TUMOR GROWING, AND ALL THE RECEPTORS ON THE SENSORY NERVES WHICH ARE SURROUNDING THE TUMOR, EITHER PRIMARY OR METASTATIC TUMORS, THEY GET ACTIVATED BY THAT, AND THAT LEADS TO THE PAIN SENSATION SO A PART OF THAT PAIN, INFLAMMATORY PAIN, SO THE WAY IT HAPPENS IS DURING ANY OF THE INJURY, TISSUE INJURY, INFLAMMATION OR IN TERMS OF THE BONE TUMOR GROWING INSIDE THE BONES. SO THEY PRODUCE INFLAMMATORY -- ATTRACT A LOT OF THE IMMUNE CELLS. THOSE CELLS PRODUCE A VARIETY OF SECOND MESSENGERS OR MEDIATORS. THOSE SECOND MESSENGERS OR MEDIATORS, THEY HAVE RECEPTORS ALSO ON THE SENSORY NERVES, AND THAT'S HOW SENSORY NERVES ACTIVATE AND THEN -- THEY CAN ALSO MODIFY THE FUNCTION OF THESE CHANNELS, WHICH ARE SHOOTING ACTION POTENTIAL. THAT'S HOW THE SIGNAL GOES TO THE BRAIN. AND BECAUSE OF THESE INFLAMMATORY NATURE, THE WAY ANALGESICS FOR THIS TYPE OF PAIN WAS IDENTIFIED AS LIKE N-SAIDS. SO THEY ARE KIND OF BLOCKING THE SYNTHESIS OF SOME OF THESE MEDIATORS, BUT THEY ARE NOT ALWAYS EFFECTIVE, BECAUSE THERE COULD BE SEVERAL TYPES OF THESE INFLAMMATORY MEDIATORS. SO THE OTHER DRUGS LIKE OPIOIDS, THEY WOULD BLOCK THE ENTIRE CENTRAL PATH WAIVE. THAT'S HOW THEY ARE MORE EFFECTIVE, BUT AGAIN, AS WALTER TODAY, OPIATES COME WITH OTHER UNWANTED ROLES. THEN WE HAVE NEUROPATHIC PAIN, WHERE THE PREDOMINANT SOURCE OF THE PAINFUL STIMULUS IS NOTHING BUT NERVE INJURY AND THERE ARE SEVERAL TYPES OF NEUROPATHIC PAIN, EITHER INJURY TO A PERIPHERAL NERVOUS SYSTEM NERVES OR SPINAL CORD, OR EVEN LIKE IN A CONDITION OF STROKE. SO THEY LEAD TO KIND OF CHRON I BE PAIN CONDITION BECAUSE OF DIRECT LESION TO THE NERVOUS SYSTEM. THERE ARE MULTIPLE TYPES OF THESE NEUROPATHIC PAIN, LIKE NEUROPATHY OR CHEMOTHERAPY-INDUCEED -- ALL THESE CANCER THERAPEUTIC DRUGS INDUCE NEUROPATHY. NOT ALWAYS NECESSARILY INVOLVES NEURODEGENERATION. MANY TIMES IT COULD BE A DEGENERATION OF THE NERVE FIBERS. AND SINCE THE NEUROPATHIC PAIN HAS MORE INVOLVEMENT OF THE CENTRAL CIRCUIT, THAT'S WHY THE DRUGS WHICH WOULD REDUCE THE ANXIETY OR DRUGS LIKE ANTI-CONSULTANTS, THEY ARE THE ONES GIVE SOME LEVEL OF RELIEF. OF COURSE, OPIOIDS GIVE SOME LEVEL OF RELIEF, BUT MORE AND MORE NOW, IT IS CLEAR THAT OPIOIDS DO NOT PROVIDE GOOD MANAGEMENT FOR THESE NEUROPATHIC PAIN CONDITIONS. SO THIS IS A NEW PAIN TYPE WHERE EXAMPLES LINE FIBROMYALGIA, WHERE SENSORY NERVES ARE GETTING ACTVATED SYSTEMATICALLY, IRRESPECTIVE OF WHERE THE DAMAGE OR INJURY WAS. SO THIS IS A COMPLEX PAIN CONDITION, WHERE SOMEONE WHO HAS A BACK PAIN, BUT DID NOT HAVE ANY VISIBLE INJURY TO THE BACK, SO MORE AND MORE NEW STUDIES ARE COMING UP WITH THIS, BUT IT'S REALLY EARLY FOR THIS TYPE OF PAIN. GOING INTO THE RECEPTORS, THIS IS AN EXAMPLE OF HOW THE NERVE FIBERS, FOR EXAMPLE, IN SKIN, SO WE HAVE SPECIFIC NERVE FIBERS FOR TEMPERATURE, SPECIFIC FIBERS FOR MECHANICAL, AND SOME RECEPTORS -- SOME CAN CONDUCT SLOW, SOME CAN CONDUCT REALLY FAST, AND THESE FIBERS ARE LIKE BRANCHED IN THE SKIN OR IN DIFFERENT ORGANS, SO THEY CAN SENSE THE CHANGE OR SENSE ANY DISEASE OR INJURY CONDITION AND SEND INFORMATION TO THE SPINAL CORD AND THEN GOES ALL THE WAY TO THE BRAIN. WITH MUSCLES, A LITTLE DIFFERENT TYPE. WE HAVE SOME SENSORY FIBERS FOR DETECTING -- A LOT OF ONES, THE SENSORY FIBERS, WHICH DETECT STRONG TOUCH OR STRONG MECHANICAL FORCE. SO THAT IS HOW, IMAGINE UNDERGRAD PHYSIOLOGY, THE REFLEX ARC, HOW IT WORKS. YOU HAD A MECHANICAL FORCE GIVEN TO -- APPLIED, SO THE MUSCLES STRETCH AND THE BONE WILL STRETCH, THE MUSCLE WILL STRETCH. THAT SENDS INFORMATION, YES, IT IS A STRONG MECHANICAL PAIN. THEN THE BRAIN SENDS SIGNAL BACK, AND SOMETIMES EVERYONE THE SPINAL CORD DIRECTLY SEND THE SIGNAL BACK TO THE MUSCLES TO CONTRACT, TO AVOID THE STIMULUS. SO MANY DIFFERENT PATHWAYS FROM MULTIPLE VISCERAL ORGANS, CONNECTED BY THE SENSORY FIBERS THROUGH DORSAL ROOT GANGLIA, BUT THEY ALL GO TO SPECIFIC AREAS WITHIN SPINAL CORD, AND THEN GO ALL THE WAY TO THE BRAIN, AND YOU CAN SEE THERE ARE SOME PATHWAYS REALLY FAST, LIKE THE RED ONES. SO THESE ARE LIKE MECHANICAL SENSORY FIBERS. SO THE SIGNAL GOES REALLY FAST, SO THAT IS HOW WE FEEL THE TOUCH MUCH FASTER, WHEREAS THE PAIN GOES RELATIVELY SLOW, BECAUSE IT HAS TO GO THROUGH MULTIPLE CONNECTIVITY THERE, FOR THE CIRCUIT. TALKING ABOUT THE FIBERS, HOW WE HAVE MULTIPLE TYPES BASED ON THE MYELINATION THICKNESS. SO ALPHA OR BETA TYPE ARE HEAVILY MYELINATED FIBERS. DELTA AND -- C IS UNMYELINATED. THAT'S HOW THESE FIBERS SENSE TOUCH. THE OTHERS ARE SENSE OF PAIN. HOW IT HAPPENS, IF YOU RECORD THE FIBER, YOU CAN SEE A DELTA AND A BETA FIBER, SHOOT MUCH FASTER. THE C FIBERS, THEY GO REALLY SLOW. SO YOU CAN SEE IN A PAINFUL STIMULUS, SO A DELTA AND C FIBERS ARE ACTIVATED, BUT -- PRODUCE IT IS FIRST STRONG PAIN FOR EXAMPLE YOU PINCH VERY STRONGLY WITH LIKE A PIN, YOU FEEL THE INITIAL PIN PRICK BECAUSE A DELTA GOING REALLY FAST CHANNEL, WHEREAS IN THE C TYPE, IT FOLLOWS THE SECOND PAIN BECAUSE IT IS SLOW. IT IS UNMYELINATED, SO TAKES TIME TO TRANSFER THE ELECTRICAL SIGNAL TO THE BRAIN. AND BASED ON THE DIFFERENT TYPES OF THESE RECEPTORS, A DELTA OR C, SO THEY ARE CLASSIFIED TO DETECT WHAT TYPE OF SIGNAL THEY CAN DETECT, LIKE WARM, COLD. JUST ONE FIBERS, ONLY C FIBERS. SO WE TAKE TIME TO DETECT NOXIOUS HEAT. BUT IT IS COLD, WE TAKE A LITTLE LESS TIME. WE FEEL COLD MUCH FASTER THAN HEAT, SO THAT IS CONTRIBUTED BY THE A DELTA FIBERS. THE SAME WAY, LIKE DEPENDING ON WHAT TYPE OF MODALITIES WE HAVE, DIFFERENT FIBERS. AGAIN, AT A MOLECULAR LEVEL, THERE ARE MULTIPLE RECEPTORS, LIKE THIS IS IN THE SKIN, SO THEY DETECT MULTIPLE PHYSIOCHEMICAL STIMULI. ACTIVATED BY COLD OR -- WHAT ALL THESE RECEPTORS -- ACTIVATED BY MECHANICAL FORCE. SO WHAT ALL OF THEM DO IS DEPOLAR RISE THE MEMBRANE. THEY DEPOLARIZE IT TO SUFFICIENT EXTENT WHERE SODIUM CHANNELS CAN OPEN. THEN SODIUM CHANNELS OPEN. SO THESE LIKE TWO LINES OF THESE PAIN TRANSDUCER. ONE IS PRIMARY ONES. AND THEN CLASSIC -- AGAIN, WE HAVE MULTIPLE CHANNELS, BASED ON THEIR TEMPERATURE OF ACTIVATION. YOU CAN SEE BASED ON WHAT TYPE OF NATURAL COMPOUNDS THEY ACTUALLY ACTIVATE. FOR EXAMPLE, WE HAVE THE COLD CHANNEL. YOU EAT ANYTHING MINT OR MENTAL, YOU FEEL THE COOLNESS. ACTIVATED BY TEMPERATURE, LIKE HIGH TEMPERATURE. SO THAT IS KIND OF NATURE'S DESIGN TO HAVE ALL THESE AREA OF THESE RECEPTORS. AT A VERY BASIC LEVEL, HOW IT HAPPENS, THE ACTION POTENTIAL, SO WHEN THE PRIMARY TRANSDUCER ACTIVATE, THEY DEPOLARIZE THE MEMBRANE AND THAT IS WHEN THE RED ONES, THE SODIUM CHANNELS OPEN, THEN THEY FULLY DEPOLARIZE, THEN CALCIUM CHANNELS OPEN IN THE THE BLUE. DEPOLARIZE, THEN CHANNELS OPEN AT THE END TO BRING IT BACK. SO THIS ACTION POTENTIAL KEEPS ON GOING AND MOVING ACROSS, LIKE FROM THE PERIPHERAL FROM THE NERVE ENDING, ALL THE WAY TO THE GANGLIA AND THEN TO THE SPINAL CORD AND BRAIN. IN THE SPINAL CORD, THERE ARE MULTIPLE DIFFERENT FIBERS. THEY SYNAPSE ON DIFFERENT LEVELS OF SPINAL CORD AND DIFFERENT TYPES OF NEURONS, SO A BETA FIBER, SYNAPSE NEURONS WHICH DIRECTLY CONNECT ALL THE WAY TOWARDS THE BRAIN, SO IT GOES MUCH FASTER, WHEREAS THE A AND C PIKERS HAVE MULTIPLE NEURONS IN BETWEEN, SO THAT IS WHY THE SIGNAL GOES SLOWER. MASSIVE SIGNALING OF A LOT OF NEUROTRANSMITTERS AND DIFFERENT MEDIATORS, WHICH BASICALLY TRANSMIT THE SIGNAL THERE. FROM SPINAL CORD, IT GOES ALL THE WAY TO THE BRAIN, AND THERE ARE MULTIPLE AREAS WITHIN THE REGIONS IN THE BRAIN, LIKE SINGULAR CORTEX OR THE INSULAR CORTEX, SO THESE ARE THE MAIN AREAS INVOLVED WHERE THE PAIN PERCEPTION IS PROCESSED. AT THE SAME TIME, THE BRAIN SENDS SIGNAL BACK, SO THAT IS BASICALLY THE SENDING PATHWAYS. THOSE PATH WAIVES CAN BE INHIBITED. THESE ARE THE PATHWAYS WHERE OPIOID RECEPTORS ARE HEAVILY EXPRESSED, AND THE INDIGENOUS OPIATES IN THE BODY, THEY ACTIVATE THE DESCENDING PATHWAYS, SO THEY CAN BLOCK THE PAIN SIGNAL. HOW DO WE ASSESS PAIN IN HUMANS? NORMALLY, IT IS A QUESTION-BASED STRATEGY, WHERE THE PATIENT IS GIVEN, EXPRESS WHAT TYPE OF PAIN AND WHAT LEVEL OF PAIN, EXCUSE ME. LIKE MILD WORK THEY DO NOT HAVE ENOUGH PAIN, OR LIKE CANCER PAIN PATIENTS -- AND THEN WITHIN THE DIFFERENT SCORING SYSTEM, SO THERE ARE EXAMPLES GIVEN LIKE WHAT KIND OF PAIN YOU HAVE, SO THEY CAN SCORE. THIS IS ONE WAY OF ASSESSING, BUT THIS IS -- THAT DIFFERENCE ABSOLUTELY ON PATIENT SELF-REPORTING. BUT THERE ARE OTHER WAYS TO ASSESS PAIN BY ASSESSING -- DOING QUANTITATIVE SENSORY TESTING. HOW IT IS DONE, IS A SET OF FILAMENTS, MECHANICAL FILAMENTS, THEY ARE POINTED TO THE PATIENT'S SKIN -- GO BACK. >> USING A SET OF -- AS PRESCRIBED BY -- IN 2006. ASSESSMENT MAY BE DONE AT THE SITE OF THE PAIN. THE FILAMENT IS PRESSED AT A 90-DEGREE ANGLE TO THE SKIN AND IS HELD THERE APPROXIMATELY 1.5 SECONDS. THE FILAMENTS ARE -- >> YEAH, SO THEY ARE 1K-D WHETHER THEY CAN FEEL IT AND WHETHER THE FEELING IS PAIN OR NOT. YEAH. SO AS THE FILAMENT SIZE INCREASES, THE WEIGHT INCREASES, THEY FEEL MUCH MORE PAIN. SO THIS IS A WAY TO QUANTIFY LIKE HOW MUCH PAIN THEY FEEL. SO IF THERE IS A CERTAIN ONE TYPE OF FILAMENT WHERE THEY HAVE A NON-PAINFUL AREA IN THE SKIN, THEY DO NOT FEEL THAT PAIN, BUT THE SAME FILAMENT IS FELT -- THEY REPORT AS PAIN ON THE PAINFUL SIDE, SO THAT MEANS YES, THEY HAVE A MUCH MORE STRONGER PAIN PERCEPTION. AND THAT IS KIND OF ACTUALLY THE PRINCIPLE BEHIND THAT, WHEN YOU PUT THIS BLUNT OBJECT, PEOPLE DO NOT FEEL, BECAUSE WE HAVE ROPE RECEPTION GOING, BUT -- WHEN YOU PUT THE PIN PRICKS, THEN YOU HAVE MUCH MORE FIRING, SO YOU INCREASE THE PIN PRICK THRESHOLD OR THE SIZE OR THE WEIGHT THAT GOES MUCH STRONGER. SO THAT WAS ONE TYPE OF PAIN. ANOTHER TYPE OF PAIN MEASUREMENT -- YEAH, I WILL LET THIS PLAY. YEAH. WITH THAT, THERE IS A DIRECT MEASUREMENT OF HOW MUCH PRESSURE IS NEEDED FOR THEM TO PERCEIVE THAT AS PAIN. SO UNDER INJURY CONDITIONS OR DISEASE CONDITION, SO THEY DESCRIBE PAIN AT MUCH LOW -- AS COMPARED TO -- THEN THERE ARE OTHER METHODS WHERE -- I WILL FORWARD THIS A LITTLE BIT TOWARDS THE END. SO YOU CAN SEE, IT IS A PIN PRICK -- YOU CAN SEE IN THE PIN PRICK -- SO YEAH, THAT'S LIKE WHERE INITIALLY, IF YOU TOUCH THE -- IT WON'T BE PAINFUL, BUT THE MOMENT IT IS A VERY SLOW MOTION GOES, THAT HYPER-ACTIVATES THE DAMAGED FIBERS. USUALLY IF YOU TOUCH, YOU WILL NOT SENSE IT. BUT YOU BRUSH IT, IT HYPER-ACTIVATE. SO THESE ARE SOME EXAMPLES HOW PAIN IS ASSESSED. IN ANIMAL WORLD, I THINK SCIENTISTS HAVE ALWAYS LOOKED INTO HOW THEY CAN USE INFORMATION IN ANIMALS WHICH CAN TELL US ABOUT WHETHER THERE'S PAIN OR NOT, SO HERE IS ONE OF THE EXAMPLES FROM TOM AND JERRY. YOU CAN EASILY SEE IT HITS THE NAIL, SO TWO THINGS. IT HAS ONE PHYSICAL RESPONSE, WHERE IT LIFTS ITS PAW, SO IT IS PAINFUL, SO A PHYSICAL OUTCOME. AND THEN VERBAL. HMM. EXACTLY. IT HAS TWO COMPONENTS. ONE IS INITIAL STIMULATION, BUT EVEN IF THE FAIL IS TAKEN OUT, THE PAIN STILL PERSISTS, AND THAT'S BECAUSE OF ALL THE INFLAMMATION AND ALL THE RECEPTOR PROCESS INITIATED, AND THAT WILL KEEP ON HAPPENING. AND THE BRAIN -- EVEN THE STIMULUS IS NOT THERE, BUT THE BRAIN STILL PERCEIVES ONGOING PAIN. IN ANIMALS, PEOPLE USE THE SAME FILAMENTS WHICH WERE USED IN HUMANS IN THE FIRST VIDEO I SHOWED YOU, TO DETERMINE HOW LONG IT TAKES FOR THEM TO WITHDRAW THEIR PAW. SO THAT IS ONE TYPE OF REFLEXIVE ASSESSMENT, WHICH IS THESE DAYS GETTING MORE AND MORE QUESTIONED, WHETHER IT HAS CORRELATION TO HUMAN PAIN OR NOT. IT COULD BE CONSEQUENCE OF PAIN, BUT IT MIGHT NOT BE A PREDOMINANT LIKE CAUSE OF PAIN CONDITION IN HUMANS BEFORE NORMALLY, WHAT HAPPENS WHEN YOU ASSESS PAIN, YOU GIVE THIS STIMULUS. AS YOU INCREASE THE STIMULUS, THE PAIN RESPONSE INCREASES, BUT WHAT HAPPENS DURING DISEASE OR PATHOLOGY, THIS ENTIRE GRAPH IS SHIFTED, RESPONSE. SO NORMALLY, THE STIMULI, WHICH ARE VERY LOW OR JUST STARTING TO BE NOXIOUS, CALL IT -- NOW IT'S PAINFUL. THAT'S THE TYPE OF PAIN, PARTICULARLY IN CANCER PAIN-TYPES, WHETHER IT'S BONE CANCER PAIN TYPE, AND THAT HAPPENS BECAUSE WE HAVE SURGE OF DIFFERENT MEDIATORS WHICH ARE CONSISTENTLY SENSITIZING THE NERVE FIBERS, AND A VARIETY OF MECHANISMS HAPPENING THERE, EITHER BY ACTIVATING A RECEPTOR OR INCREASING THE NUMBER OF RECEPTORS AND EVEN INCREASING THE NUMBER OF FIBERS, SO THERE ARE MULTIPLE OF THESE MECHANISMS HAPPENING, BUT THEN THE OTHER AREAS WHERE CHANGES HAPPEN IS LIKE THERE IS AN AREA WHERE THERE'S PAINFUL, SO IN THAT AREA, IF YOU RECORD BEFORE AND AFTER, THE PRIMARY AFFERENT AND SPINAL CORD DORSAL HORN, NERVE FIBERS ARE HYPEREXCITED. WHEREAS IN SECONDARY REGIONS SURROUNDING THAT INITIAL INJURY, THERE'S NO CHANGE IN THE PRIMARY AFFERENT THERE, BECAUSE THERE'S NO INJURY MEDIATORS OR DIRECT CONTACT WITH THE NERVE FIBERS, BUT IF YOU ARE RECORDING THE SPINAL CORD DORSAL HORN, THAT IS HIGHLY ACTIVATED. SO WHAT'S HAPPENING THERE IS NORMALLY, IN SPINAL CORD, FOR NORMAL STIMULUS, WHATEVER ELECTRICAL SIGNAL THEY RECEIVE, INFLAMMATORY CONDITIONS, SO THEY MAGNIFY THAT SIGNAL. SO THE PERIPHERAL STIMULUS ACTS AS A SWITCH. SO YOU SWITCH ON THE LIGHT AND HERE, IT ACTS AS A CONTROL, THE INTENSITY CONTROLS. SO IN THE CENTER OF THE SPINAL CORD, IT KIND OF TUNES IT OUT OR TUNES IT DOWN, DEPENDING ON WHAT IS THE CONDITION. AND IN THE SPINAL CORD, THERE IS ALSO OTHER WAYS, MULTIPLE CIRCUITS, LIKE A BETA FIBERS VERSUS RECEPTIVE FIBERS. IN DISEASE CONDITIONS, SOMETIMES THERE ARE MORE NUMBER OF THESE CONNECTIVITY, SO THE SIGNAL IS AMPLIFIED. SOMETIMES THERE ARE INHIBITORY NEURONS, BLOCKING THE PAIN SIGNAL. LIKE A CLASSIC EXAMPLE IS IF YOU ARE EATING THE HOT CHILI FOODS, YOU START DRINKING COLD WATER, YOUR PAIN GOES DOWN, BECAUSE THE NEURONS -- COLD-SENSING NEURONS ARE GETTING MORE AND MORE ACTIVATED, SO THEY DAMPEN IT, BUT IN DISEASE CONDITIONS, SOMETIMES THOSE INTERNEURON CONNECTIONS ARE LOST, SO THAT LEADS TO MORE AMPLIFICATION OF THE SIGNAL. THE SIGNALS GO ALL THE WAY TO THE BRAIN, BUT FROM BRAIN, THE DESCENDING MODULATION COMES WITH MULTIPLE OF THESE DIFFERENT FLAVORS, DIFFERENT CIRCUITS ARE THERE FOR DIFFERENT TYPES OF NEUROTRANSMITTERS. ONE EXAMPLE HERE, THESE ARE AT THESCENDING PATHWAYS COMING FROM THE BRAIN AND THIS IS CONNECTING TO THE BRAIN FROM SPINAL CORD AND THAT IS FROM PERIPHERY. THOSE DESCENDING PATHWAYS RELEASE MULTIPLE OF THE NEUROTRANSMITTERS, SO THAT IS WHERE -- AT THE SPINAL CORD, THEY CAN CONTROL WHAT MAGNITUDE AND WHAT TYPE OF SIGNALS SHOULD GO ALL THE WAY. SO THIS IS BODY'S OWN MECHANISM TO CONTROL OR DOWNPLAY OUR PAIN AT THE SPINAL CORD. SO WE HAVE MULTIPLE AREAS, STARTING FROM PERIPHERY TO THE BRAIN THAT ARE MULTIPLE PATHWAYS AND MULTIPLE CIRCUITS AND MECHANISMS WORKING TO CONTROL OUR PAIN PERCEPTION. IN TERMS OF PHARMACOLOGICAL MANAGEMENT OF CANCER PAIN, THIS IS JUST A LIST YOU CAN SEE IN THE GUIDELINES, WHICH WAS RELEASED LAST YEAR, SO THERE ARE NON-OPIOIDS, MAINLY NON-OPIOIDS, EITHER NSAIDS OR DRUGS JUST TO RELEASE THE INFLAMMATORY CONDITIONS, BUT THEY ARE NOT REALLY GOOD IN CHRONIC STAGE. OPIOIDS, THERE ARE WEAK AND STRONG OPIOIDS, MOSTLY UTILIZED FOR CHRONIC PAIN AND BONE CONDITIONS. STEROIDS REALLY ALSO USED. THAT IS EFFECTIVE IN PROSTATE CANCER, TO MANAGE THEIR PAIN. NOT NECESSARILY ALEAVING THE PAIN, BUT THEY ARE REDUCING THE EMOTIONAL COMPONENT. THAT'S HOW THEY ARE MANAGING THE PAIN. IN ADDITION, THERE ARE OTHER PSYCHOLOGICAL AND PHYSICAL WAYS TO MANAGE CANCER PAIN, INCLUDING LIKE ELECTRICAL STIMULATIONS AND EVEN YOGA, THERAPY. SO OTHER THAN INDUCING PAIN, ACTUALLY, THE SENSORY NERVE FIBERS ARE ALSO INVOLVED IN SOMETHING DIFFERENT, AND THESE ARE MORE KIND OF EVOLVED IN LAST TEN YEARS, AS A PHENOMENAL CALLED NEURAL INVASIONS. IT TURNS OUT CERTAIN TYPES OF CANCERS, LIKE PANCREATIC CANCERS, THEY INVADE THE SENSORY NERVES AND GO ALL THE WAY TO THE DORSAL ROOT AND SPINAL CORD, THEN THEY UTILIZE THE NEURONS TO RELEASE A LOT OF NUTRIENTS AT THE VICINITY OF TUMOR, SO THE TUMOR GROWS. AND THERE ARE SOME BEAUTIFUL STUDIES WHICH CAME OUT THE LAST ONE, ON THE PANCREATIC CANCERS, WHERE THE TUMOR CELLS ARE INVADING AND UTILIZING THE PAIN SENSORY NEURONS, SO THE NERVES IN UTERO, THE ONES THAT DID NOT DEVELOP THOSE DID NOT HAVE PANCREATIC CANCERS, SO THAT IS A NEW EXCITING DIRECTION WHERE THE -- IT MEETS SENSORY BIOLOGY, I WOULD SAY. LASTLY, ONE OF THE NEWER ONES GOING ON, THERE ARE REPORTS COMING UP IN CERTAIN TYPES OF CANCERS, THE PEOPLE HAVE MORE CHRONIC OPIOIDS -- AGGRESSIVE CANCERS ARE MUCH HIGHER RATE. STUDIES, MANY REPORTS COMING OUT LIKE OPIOIDS, ACTUALLY LIKE MORPHINE, ENHANCE THE TUMOR CELL GROWTH, TUMOR PROLIFERATION, ALL THE HALLMARKS FOR TUMOR GROWTH, BUT AGAIN, THESE ARE STILL CONFERENCES, NOT WELL-SUBSTANTIATED. I THINK THINGS ARE GOING -- THEY ARE MORE AND MORE PROBABLY WILL KNOW MORE THERE. IN TERMS OF CHALLENGES, REALLY UNDERSTANDING CANCER PAIN IS DIFFICULT. THERE ARE NOT MANY GOOD ANIMAL MODELS TO UNDERSTAND ABOUT CANCER PAIN, SO THESE ARE REALLY HOT AREAS OF RESEARCH, BUT VERY CHALLENGING AREAS. AND ALSO LIKE CIP AND CHEMOTHERAPY-INDUCED NEUROPATHY, THERE ARE NO ANIMAL MODELS. FOR EXAMPLE, MOST OF THE WORK HAS BEEN DONE IN -- BUT IN HUMANS, THEY DO NOT HAVE TUMOR, THEY WILL NEVER EXPERIENCE THESE DRUGS. SO THINGS NEED TO IMPROVE AND MORE AND MORE ANIMAL WORK NEEDS TO BE DONE TO UNDERSTAND THOSE MECHANISMS. SO I THINK PAIN IS ONE OF THE BEST EXAMPLES OF INTEGRATIVE MEDICINE, SO -- BECAUSE IF WE LOOK INTO ALL OUR SYSTEMS, ALL OUR PHYSIOLOGICAL SYSTEMS, RECEPTION IS LINKED TO THIS, ALL THESE PROCESSES. -- INDUCES PAIN-LIKE CONDITIONS. ON SO OF THAT, OF COURSE, THE CANCERS AND ALL THE TYPES OF PHYSIOLOGICAL SYSTEM, ALL THE CANCERS LIKE COMMUNICATE WITH THE SENSORY NERVES, SO I THINK THERE IS A VERY CLOSE RELATIONSHIP BETWEEN THESE TWO SYSTEMS, TO BE STUDIED MORE AND MORE. >> SO I WILL STOP HERE. THANK YOU FOR YOUR PATIENT. I'M A LITTLE LATE. SORRY. [APPLAUSE] >> A VERY OBVIOUS QUESTION, I THINK IS WE KNOW AT THE HEART OF THE OPIOID CRISIS IS THE LACK OF OBJECTIVITY IF ASSESSING PAIN, AND WE KNOW THAT'S AN ISSUE, A HUGE ISSUE. AND SO I GUESS ARE THERE ANY -- YOU SHOWED AS PART OF THE HEAL INITIATIVE THAT -- ESTABLISHING BIOMARKERS WAS NOT PLAN, SO HAS ANYTHING -- ANY PROMISING BIOMARKERS OR HAS ANYTHING BEEN LOOKED AT? IS CGRB, HAS THAT BEEN SHOWN, CAN IT BE USED AS A BIOMARKER FOR MIGRAINE? HAVE THESE THINGS BEEN LOOKED AT? ANYBODY? BIOMARKER FOR PAIN, JUST AS A MEASURE OF OBJECTIVITY, NOT LOOKING AT CANCER OR CANCER PAIN. (OFF MIC). HOW ABOUT THE CGRP YOU MENTIONED FOR CHRONIC MIGRAINE? HAS THAT BEEN SHOWN TO CORRELATE THE SERUM LEVELS WITH MIGRAINES, THE -- OKAY, THAT'S A TOUGH ONE. SO THAT'S MORE -- >> (OFF MIC) >> OKAY. THEN ONE MORE QUESTION. I GUESS YOU SHOWED THE NEUROIMAGING HAS SHOWN THE PLEASURE AREAS OF THE BRAIN AND PAIN AREAS ARE MAPPING OUT IN A SIMILAR REGION. SO PERHPS S IS THAT THE REASON WE SEE SOME EFFECTIVENESS OF ALTERNATIVE MEASURES OF PAIN TREATMENTS SUCH AS COGNITIVE BEHAVER THERAPY OR MUSIC THERAPY? DO WE SEE SOME BENEFIT AND PERHAPS COULD THAT BE THE REASON? >> (OFF MIC) >> OKAY R THANK YOU. >> WHAT THEY DO IS ACTIVATE THE CIRCUIT, PARTICULARLY THE DESCREENEDDING MODULATION, WHERE THEY ARE RELEASING ENFORENS AND BLOCKING. SO THE BRAIN AREA IS WHERE THE FIBER SIGNAL IS ACTIVATED, THAT IS THE AREA WHICH ALSO IS RESPONSIBLE FOR LIKE SECRETING OR PRODUCING THESE ENDORPHINS. THAT'S HOW IT GOES DOWN. YOU CAN IMAGINE, IN ACUPUNCTURE, COULD BE THE PRINCIPLE BEHIND IT, BUT I AM NOT SURE. WE DON'T REALLY KNOW THAT, BUT HIGH LIKELIHOOD THERE, IN SIMILARITYIES. >> YEAH. SO IN THE SENSORY NERVES, SO WHERE IN SOME CASE, LIKE IN THE SENSORY NERVE TO DETECT THE SCENT OF A SMELL, AND WHEN WE ARE IN A -- LATER, WE DO NOT FEEL IT ANYMORE, BUT IN THE CASE OF PAIN SENSORY NERVE, THEN IT JUST CONTINUOUSLY -- WE FEEL CONTINUOUSLY THE PAIN AND IT NEVER STOP, LIKE IN THE CASE OF SMELL, SENSORY NERVE. THE FIRST QUESTION. AND MY SECOND QUESTION IS THAT IN SOME CASE, AS YOU MENTIONED, LIKE YOU TAKE CHILI, THEN YOU GOT -- WHY YOU DO NOT FEEL ANY REWARD FOR THAT PAIN, FOR SOME OTHER PAIN, YOU DO NOT HAVE THE REWARD. I'M SORRY. >> I CAN ANSWER YOUR SECOND QUESTION FIRST. THAT IS AN INTERESTING ONE, BECAUSE IN THE CANCER PAIN, PARTICULARLY LIKE ONGOING OR THROBBING TYPE OF CANCER PAIN, IT IS MORE OF A MECHANICAL NATURE, SO THAT IS WHY THE NERVE FIBERS WHICH ARE GETTING ACTIVATED AND SENDING SPECIFIC SIGNAL TO THE BRAIN TO CERTAIN AREAS WHERE THE MECHANICAL PAIN IS MORE DETECTED, SO THEY ARE NOT ASSOCIATED WITH REWARD FOR THE SAME STIMULUS. WHEREAS IN TERMS OF CHEMICALLY ACTIVATED NERVE FIBERS, THEY ACTIVATE A DIFFERENT AREA AND THEY ARE INDUCING RELEASE OF DOPAMINE IN THE REWARD CIRCUIT, SO THAT'S WHY YOU FEEL LIKE YES, NEED -- IT FEELS GOOD. YEAH. ON YOUR FIRST QUESTION, SO WHY THE SENSORY NERVES, EVEN WITHOUT HAVING AN INJURY, THEY ARE STILL ALWAYS ACTIVE. SO THERE ARE MULTIPLE REASONS FOR THAT. SOME IS LIKE THERE ARE MORE SPROUTING OF THE NERVE FIBERS. SO IF YOU CAN IMAGINE, YOU HAVE ONLY ONE BRANCH INITIALLY, BUT AFTER INITIAL INJURY, THERE ARE MORE GENE EXPRESSION CHANGES GOING ON AND MORE ANATOMICAL CHANGES, SO LEADS TO SPROUTING OF MORE NERVE FIBERS, SO YOU EVER MORE RECEPTIVE FIELDS, SO KIND OF A SUMMATION OF MULTIPLE SIGNALS INTO THE CENTRAL AXON, SO THAT'S WHY YOU HAVE CONTINUOUS SIGNAL COMING IN AND OUT, SO THAT IS HOW YOU FEEL MORE PAIN THERE, ONGOING CHRONIC SITUATION. DID I ANSWER YOUR QUESTION? >> I HAVE TWO QUICK QUESTION, ONE FOR THE -- YOU SHOWED ONE SLIDE, THE RAT OR MICE, CAN STILL FEEL THE PAIN, BUT YOU SAID THEY WILL BE FINE, WILL NOT BOTHER. HOW THAT HAPPEN, THEN -- IT'S GOOD OR NOT, WHEN YOU HAVE SUCH INJURY, THEN YOU DON'T BOTHER. >> RIGHT. IN THAT CASE, THOSE MICE, IF YOU PRICK THEM, THEY WILL PULL AWAY. SO THEY WILL HAVE A REFLEXIVE MOVEMENT. AND THAT'S THE BEAUT AT THIS TIME OF THAT NUCLEUS, IS THAT IT DOESN'T AFFECT RECEPTION. IT JUST AFFECTS THE NEGATIVE PERCEPTION OF THE PAIN. SO IF YOU HAD THOSE KNOCKED OUT FROM EARLY LIFE, YOU'RE RIGHT, YOU MAY NEVER LEARN TO STAY AWAY FROM PAIN, BUT IN SOMEONE WITH A MATURE NERVOUS SYSTEM, THEY KNOW IF I FEEL HEAT, I PULL AWAY, BUT IF THEY HAVE CHRONIC PAIN, IT WOULDN'T BOTHER THEM, SO IF WE COULD FIND OUT HOW TO DO THAT, THAT WOULD BE HELPFUL. >> OKAY, THANK YOU VERY MUCH. >> KIND OF INTERESTING. RIGHT. >> SO THERE ARE PEOPLE WHO HAVE NO SENSE OF PAIN, PROBABLY SEEN THAT, AND THEY DON'T DO WELL. SO MANY INJURIES. >> YEAH, RIGHT. FOR OLDER PEOPLE, SOMETIMES -- AND ONE MORE LAST QUESTION, SO YOU TALK ABOUT ALL THE RECEPTORS FOR THE PAINS, I KNOW SOME OF THE STUDY -- THE CIRCADIAN, THE TIME OF DAY YOU FEEL MORE PAIN? IS IT NIGHT OR MORNING? MAYBE IT JUST DEPEND ON THE DISEASES TOO. >> OVERALL, MOST OF THE CHRONIC PAIN CONDITIONS INFLUENCE OUR SLEEP. OUR SLEEP IS INFLUENCED OR ALTERED BECAUSE OF, AND THAT IS A RESULT OF CIRCADIAN CHANGES TO -- SOMETIMES, BUT THERE'S SOME EVIDENCE, I THINK IN ALZHEIMER'S PATIENTS WITH PAIN, IF THEY ARE GIVEN MEDICATION IN THE DAYTIME VERSUS NIGHTTIME, SO IT NOT ONLY INFLUENCES THE EFFECTIVENESS OF THE DRUG FOR THE ALZHEIMER'S THERAPY, BUT ALSO SOME LEVEL OF PAIN ASSOCIATED WITH THAT, BUT AGAIN, THAT IS THE ONLY THING I HAVE HEARD SO FAR. I DON'T THINK IT'S SOMETHING WHICH HAS BEEN EXPLORED YET, BUT THESE ARE AREAS NEED TO BE EXPLORED MORE. >> YEAH. I THINK FOR THE PEOPLE HAVE PAIN, FOR THE KINDS OF PAIN, THEY HAVE A HARD TIME TO GO TO THE SLEEP. THEN YOU HAVE THE FEEDBACK -- WORSE, YOU DON'T SLEEP, YOU GET MORE PAIN. >> YEAH. AND LEAP IS ONE OF THE MANGER SOCIATIVE FACTORS FOR PAIN ASSESSMENT. LIKE EVERYBODY PATIENT, CHRONIC PAIN PATIENTS, WHEN THEY GO TO THE PAIN CLINIC, ONE QUESTION IS ALWAYS HOW IS YOUR SLEEP, HOW MUCH IT IS AFFECTED. AND IT IS SEVERELY AFFECTED. >> UH-HUH. >> MENTION THAT I'M AN ONCOLOGIST. I NOTICED MOST OF MY PATIENTS NEUROPATHIC PAIN SEEM TO COMPLAIN OF THAT AT NIGHT, WHEN THEY GO TO BED, SO I DON'T KNOW WHAT -- MAYBE A CIRCADIAN RHYTHM, IF IT HAS ANYTHING TO DO WITH IT, BUT THAT IS SOMETHING I NOTICED, AND THEY FEEL THE BURNING AT NIGHT AND IT WAKES THEM UP FROM SLEEP. SO WHAT THE REASON IS, I DON'T KNOW. OKAY, THAT'S VERY IMPORTANT. >> THANK YOU. >> THANK YOU VERY MUCH. ONE MORE TIME. THANK YOU.