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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 $$
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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”
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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
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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
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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
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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
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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)
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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 ~300mg IV/day Unexpected benefits that extend Constipation likely due to increased opioid requirement beyond the initial analgesic plan Ketamine started 3mcg/kg/min Acetaminophen iv started An older agent initially restricted to the ICU at higher dosing, was transformed to fulfill a family Reduced requirement of Hydromorphone use 300mg IV to 20mg IV within 4 days. wish and return pt. comfortably to home Consider Transfer to Hospice ICU > Ward > Hospice > Disneyland > Home
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3. Supraspinal Modulation Non–opioid strategies to Alterations in signal processing above the improve the quality of analgesia spinal cord, especially while reducing opioid changes in plasticity 3 dedicated to requirements descending inhibition of second-order dorsal horn neurons Using established or emerging analgesics (De Felice, 2011) in combinations to achieve improved pain control and mobility, reduce length of stay.
Multimodal Analgesia: Orthopedic Unit: Joint replacement
Advances in Perioperative Analgesia: UCSF Hips and Knees: Outcomes Arthroplasty Leave the Hospital 1 Multimodal Group DAY earlier: ~11 hour earlier Pre-op: discharge in full • Acetaminophen 1000mg po x1 multimodal group • Celecoxib 400mg po x 1 iv PCA opioid use • Gabapentin 600 mg po x 1 Pre = 100% Post less than 5% Post-op: Majority of patient • Acetaminophen 1000mg po every 6 hours mobilized on day • Celecoxib 200 mg po twice daily zero • Gabapentin 600 > 300 mg po every 8 hours IRB 12-12177 (All patients – spinal anesthetic, knees with PNI) Kehlet et al Ray et al. in preparation
What do we do when pain pathway does not return to baseline after Management of Chronic Pain injury. Patient Evaluation
Multimodal or Multidisciplinary Treatment Plan Psychological Treatment Physical or Restorative Therapy Pharmacologic management Interventions: From the nervous system’s point of view, Ablative Techniques ‘routine’ recovery from a thoracotomy, treatment Acupuncture for invasive cancer with chemotherapy & Blocks surgery may represent an “unexpected” Epidural Intrathecal survival…. Neuromodulation Anesthesiology 2010
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The Future of Analgesic Therapy? Acute to Chronic Pain: Modulating Gene Expression Designed to prevent or reverse the deleterious effects of aberrant nociceptive …If transcription factors play a key role plasticity whether arising from peripheral, central sensitization or aberrations in in the ‘design’ of pain transducing descending modulatory pathways. ! sensory neurons…. perhaps they also participate in the transition from Acute to
Require the inclusion of compounds that will Chronic Pain following tissue / nerve selectively block both nociceptive injury. transduction and abnormal gene expression
Transcription based therapeutic targeting-TRPV1 Based on emerging anti-cancer chemotherapeutic development Mithramycin –A: An approach to normalize (Wei 2004, Abdelrahim 2006, Malek 2012) overexpression of nociceptive gene products – TRPV1 Pooled cap responses
Nucleus 4 RNA Pol II
e 3 s n o
TRPV1 Gene p Sp1 s 2 e r
GC box Sp4 p a c 1 Mith-A 0 TRPV1 Promoter DMSO PI3K 50nM MiA Cytoplasm ERK 1,2 Condition
Pooled Percentage cap responses
200 0.8
AAA P cap + e
r cap - ribosome TRPV1 c
150 0.6 e
mRNA n
s percent t
n ( c o r a u X p 100 0.4 e
+ n
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50 0.2 a l TRPV1 ) NGF 0 0.0 DMSO DMSO 50 nM MiA 50 nM MiA Inflammation - CFA Zavala et al Neurosci Letters 2014!
Perception
Transmission
Transduction
Descartes 1644
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