2/10/16! Back to the Future of Pain Medicine ! What is Pain?! ! Pain: “An unpleasant sensory and emotional Mark Schumacher Ph.D.,M.D.! experience associated with actual or potential Professor and Chief, Division of Pain Medicine! tissue damage, or described in terms of such Dept. of Anesthesia & Perioperative Care! damage (IASP).”! Medical Director, UCSF Pain Services! University of California, San Francisco! Plant derivatives imitate endogenous Have we made any progress in the analgesic systems pharmacologic treatment of pain?! ! Morphine! " 1805 - Primary therapy for severe pain is:! " Morphine! ! Endorphin! " 2016 - Primary therapy for severe pain is:! " Morphine! •" Sustained Release! Ideal analgesic ?! A revolution is underway in our understanding of the pain pathway! Acts selectively on the “pain-sensing” nerves! Does not depress CNS - respiration! .. and its origin began thousands of Use over time maintains analgesia! years ago with the physicians of ancient times! Easy to administer! Is not addictive! Affordable $$! ! 1! 2/10/16! # Anti-Atlas Mountains-Morocco! Capsaicin vs. Resiniferatoxin (RTX)! ! ! ! ! # Euphorbia Resinifera! Share a Common Modification ! Perception! Peppers Sail the Ocean Blue! Transmission! 2000 BC 63 BC 1428 1492 Euphobia Resinifera Transduction! Descartes 1644 ! Sherrington and the development ! of modern neurobiology - nociceptor! Primary Afferent Nociceptors! Sherrington (1906) ... Proposed: the experience of pain is based on nerves that responded to specific 2000 BC 63 BC 1428 1492 1906 noxious stimuli that can cause tissue damage! Euphobia Resinifera “nociceptor” ! “primary afferent nociceptor”! 2! 2/10/16! The Physiology of Nociceptor Where does “pain” start?# Primary Afferent Nociceptors! Activation / Inactivation! ! -Capsaicin activates / inactivates Small diameter, non / thinly myelinated! ! sensory nerves (Jancso’ 1940’s)! ‘ ’ Subset are activated by the pungent - Nociceptor hypothesis confirmed principle of hot peppers: capsaicin! (Bessou and Perl 1969)! -Activation / desensitization of C- polymodal nociceptors, ‘Capsaicin Distinct properties of activation: Receptor’ (Szolesany 1970’s)! Chemical, Thermal & Mechanical. ! ! Many are polymodal! Cloning of TRPV1: Capsaicin Receptor! TRPV1 Structure & Function! -Prototype of 30+ member H+! superfamily! (o) ! -SubFamlies: TRPC,TRPM, TRPV (1-7), TRPP, TRPML, (i) C 2000 BC 63 BC 1428 1492 1906 1997 TRPA, TRPN! ! A 2+)! Heat! -Cation channel subunit (Ca A ! A N Euphobia Resinifera Forms heteromeric structures Capsaicin! (TRPA1)! Endovanilloids: Zygumunt Nature 1999! ! ! Hwang S PNAS 2002! ! Chu J. Biol. Chem 2003! -Multiple sites of activation - !AA metababolites: Shin PNAS 2002 ! modulation! Pain! Transduction# Specialized Sensory Neurons! Transduction! Descartes 1644 ! ! 3! 2/10/16! Selective Expression of TRPV1 in Why is the application of hot - ‘chili polymodal nociceptors! peppers’ an effective treatment for pain? ! ! ! ! ! ! ! ! !! ! (Caterina, M.J. et al Nature 1997)! Pain Therapies: Capsaicin! TRPV1: Capsaicin! Mechanism?! Mechanisms?! !- Desensitization (Receptor)! -Desensitization (Receptor)! ! ! CAP ++ !- Dysfunction (Nociceptor)! - Dysfunction (Nociceptor)! Ca ! !- Depletion (Neuropeptide)! - Depletion (Neuropeptide) ! ! ++ ! +Ca !- Destruction (Nociceptor)! - Destruction (Nociceptor)! ! ! (Caterina, M.J. et al Nature 1997)! Can peripheral application of potent vanilloid Analgesic Strategies TRPV1 Blockade! agonist produce analgesia?....Limitations?! AMG 517: Double-blind, placebo: " Nolano et al, “Topical capsaicin in humans, controlled, randomized, parallel-group, multi- parallel loss of epidermal nerve fibers”! center study with ibuprofen as the positive control (Gavva, 2008).! " Pain 81; 135-145, 1999! Single doses of 2, 8 or 15ﾊmg of, 400ﾊmg of " Neubert,J. et al, “Peripherally induced ibuprofen, or placebo were administered orally. resiniferatoxin analgesia” ! Has a predicted long half-life in humans that may be amenable to once-a-week dosing…! " Pain 104; 219-228,2003! " DM, Brown S, Tobias J; NGX-4010 HIV Neuropathy Simpson Study Group! " Neurology 2008! Evoked marked hyperthermia in humans! ! 4! 2/10/16! Pain! Analgesic Strategies TRPV1 Blockade! ABT-102 Repeat dosing of ABT-102 enhances TRPV1! mediated analgesia but attenuates hyperthermia (Honore 2009)! AZD-1386: Randomized study in third molar extraction..! Transmission! !discontinued due to elevation of liver enzymes! !!!!!!(Quiding 2013)! SB-705498: Antagonist! !Reduced the area of capsaicin-evoked flare! !Heat pain threshold was elevated (Chizh et al 2007, Gunthorpe 2007)! !! !Recent / ongoing human studies (2014):! !!! Migraine, Dental Pain, Rhinitis ! Descartes 1644 ! ! Transmission : Ascending Pain Pathway! Ascending Pathway Mechanisms of Opioid Action " Blockade of transduction or transmission in the afferent (ascending) nociceptive pathways " Three main levels at DRG! which opioids may act " Peripheral (A) " Spinal (B) " Supraspinal (C) Schumacher et al . Chap 31 Katzung 2015! Schumacher et al . Chap 31 Katzung 2015! Mechanisms of Opioid Action Potential Receptor Mechanisms Efferent/Descending " Attenuation of painful " Effect is an stimuli in periphery enhancement of (inflammation) descending inhibition " Pre- and postsynaptic " Controls pain effects in dorsal horn transmission in the " Act to inhibit dorsal horn transmitter release and to stabilize the postsynaptic membrane Schumacher et al . Chap 31 Katzung 2015! Schumacher et al . Chap 31 Katzung 2015! 5! 2/10/16! Pain Perception: Recognition of ! Pain ! Noxious Stimuli & Emotion - Affect! Perception! Descartes 1644 ! Donald D. Price Science 2000;288:1769-1772 ! Perception! What influences the Severity of Pain?! " Psychological! " Helplessness! " Cognitive Distortions! Transmission! " Social! " Social Support! " Partner adjustments! " Biological! " Physical Condition! Transduction! " Disease Process – medications! " Endogenous analgesic systems! 33! Descartes 1644 ! TRPV1 & Peripheral Inflammation! Latin: inflammo, “I ignite, set alight” ! Part of the “revolution” in pain research is … Dolor (pain)! Calor (heat)! the identification of receptor - channels that play key roles in: the development and Rubor (redness)! Tumor (swelling)! persistence (chronification) of inflammatory pain! eicosanoids! cell recruitment! increased blood flow! TRPV1! Thermal Hyperalgesia! Mechanical Allodynia! 6! 2/10/16! TRPV1 is required for Inflammatory Hyperalgesia! Chronic Painful Conditions! •"Caterina et al. Science 288, Inflammatory States! 306-313 (2000! Arthritis! •" Davis et al. Nature 405 183-187 !Bladder Disorders! (2000)! !Bowel Disease! Ischemia! Vascular Disease! !Infection! Nerve Injury! !Diabetes! !HIV Neuropathy! PHN! !Spine! !Traumatic & Post-Operative Pain! ! !! ! 1. Peripheral Sensitization! Is over expression of TRPV1 in response to injury protective or drive painful disorders?! Product Synthesis! CFA Excessive cytokine production, sustained production of lipoxygenase products & NGF SP NGF growth factors.! ++ BK NGF Ca CGRP Blood Vessel 5-HT NGF ++ Histamine TRPV4 Ca TRPV1 Mast Cell TRPA1 Neutrophils NGF Post–translational ++ PLC Lymphocyte Ca PKA BK Primary Afferent Nociceptor modification ! BK B2 NGF Activation of kinases with subsequent Primary Afferent ++ Nociceptor Ca modification and activation of nociceptive NGF + BK PKC BK B2 BK ++ H g B2 BK ion channels.! Ca Nuclear 12-HPETE TRPV1 ++ TRPV1 mRNA 12-HPETE TRPV1 TRPV1 PKC Ca ++ Signaling + + H H PKC Ca TrkA TRPV1 protein + + H H Transcription – Genetics! TrkA Activation or repression of gene Acute NGF NGF (Min - Hours) TrkA promoters within the pain pathway NGF resulting in an over / under-expression of Chronic (Hours - Days) pain transducing channels- receptors.! ++ Ca 2. Central Sensitization! Inflammatory Pain: Central Sensitization! Abnormalities of nociceptive signaling and plasticity in the spinal 1." Central Sensitization – NMDA! cord dorsal horn … ! enhanced facilitation of Abnormalities of nociceptive signaling! nociceptive & plasticity in the spinal cord dorsal horn !! neurotransmission and Enhanced facilitation of nociceptive neurotransmission! !!!!!! (Woolf Pain 2011) ! dependent on NMDA 2! 2. TRPV1 and metabolites of linoleic acid! mediated signaling! !!!!!! (Patwardhan PNAS 2009)! (Woolf 2011) ! ! 3. TRPV1 / TRPA1 12-lipoxygenase – derived HXA3! !!!!!! (Gregus PNAS 2012)! 7! 2/10/16! Inflammatory Hyperalgesia: Central Sensitization! Targets:! NMDA! Case 3 patient M. ! TRPV1! " 22 yo F with h/o recurrent AML s/p bone marrow 9-HODE! transplant, with GvH! Enzymatic pathways! " Intubated / Ventilated! " TRPV1 & TRPA1! Total body pain secondary to 80% skin & oral/GI HXA3! breakdown! TRPV1 Enzymatic pathways! " 2 wks: escalating doses of fentanyl without adequate pain control! TRPA1 •" Fentanyl 7000mcg/hr (3.4L/ day), midazolam 20mg/hr! Schumacher et al . Chap 31 Katzung 2015! (Eilers et al., 2001. Anesth Analgesia)! Outcomes: Low dose Ketamine (3 ug/kg/min )! Case 4 Patient VG! ! ! " 19 yo with h/o desmoplastic small blue round cell tumor dx 7 years ago s/p chemo, surgical resection, autologous transplant, radiation. ! " Admitted in Jan 2013 due to 4 month history of abdominal fullness and abdominal pain. ! " Found to have significant ascites and recurrence of her tumor.! " Pain uncontrolled despite increase in opioids! “Reversal of Fentanyl-Induced Tolerance by administration of Small-Dose Ketamine” ! (Eilers et al., 2001. Anesth Analg 93 (1) p213-214)! Admitted for worsening pain and bowel obstruction ! Lessons Learned! " Increase in hydromorphone requirement